Microbial population (log CFU/g) of fresh-cut paprika and iceberg lettuce washed in different sanitizers for 3 minutes, packaged, and stored for 6 days at 5ºC.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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Fresh-cut products have a limited shelf-life due to rapid deterioration caused by microbial growth as well as physiological disorder. Cutting of fruits and vegetables increases microbial spoilage of fresh-cut produce through transfer of microflora on the outer surface to the interior tissue where microorganisms have access to nutrient-laden juice (Das & Kim, 2010a). Washing with sanitizer is an important step in reducing the microbial population and quality deterioration. The use of chemical compounds to extend postharvest life of fruit and vegetables has become lesser accepted by consumers since these compounds may be contaminant of the environment or harmful to human health. Therefore, the proper application of different sanitizing agents should be highly optimized to guarantee a minimal number of spoilage microorganisms.
\n\t\t\tChlorine has been widely used in produce washes in order to inactivate microorganisms and ensure quality and safety. However, increasing public health concerns about the possible formation of chlorinated organic compounds and the emergence of new more tolerant pathogens, have raised doubts in relation to the use of chlorine by the fresh-cut industry (Kim, 2007). The use of chlorine as a sanitizing agent is prohibited in some countries due to the hazardous byproducts formed by chlorine with process water and other organic matters. Consequently, sanitization of fresh vegetables with chlorine in the industry renders a negative impact to the environment and human health as a whole. Recently, to avoid chlorine the use of non-chemical sanitizers in fresh-cut industries is becoming the more popular trend universally. Therefore, the industry is searching for alternative environment-friendly sanitizing methods to maintain the quality of fresh-cut produce at the best level.
\n\t\t\tOzone is a strong antimicrobial agent with high reactivity, penetrability and spontaneous decomposition to a non-toxic product (Khadre et al., 2001; Kim et al., 2007a). Ozone is found in natural form in the atmosphere or it can be produced by generators. Ozone as an aqueous disinfectant was declared to be generally recognized as safe (GRAS) for food contact applications. Ozone’s primary advantages include fast decomposition in water to oxygen, no residue, and improved microbial reduction efficacy against bacteria and fungal spores than hypochlorite. Ozone forms oxidated radicals in the presence of water that penetrate and act on cell membranes. The use of ozonated water has been applied to fresh-cut vegetables for sanitation purposes reducing microbial populations and extending the shelf-life of some of these products (Beltran et al., 2005; Hassenberg et al., 2007; Kim et al., 2007a). Ozone has been declared in many countries to have potential use for food processing including sanitation of fresh and fresh-cut vegetables. When compared to chlorine, ozone treated with optimum conditions has a greater effect against certain microorganisms and rapidly decomposes to oxygen, leaving no residues (Kim, 2007; Rico et al., 2007). Inactivation of microorganism by ozone is a complex process that attacks various cell membrane and wall constituents (e.g. unsaturated fats) and cell content constituents (e.g. enzymes and nucleic acids). The micro-organism is killed by cell envelope disruption or disintegration leading to leakage of the cell contents. Disruption or lysis is a faster inactivation mechanism than that of other disinfectants which require the disinfectant agent to permeate through the cell membrane in order to be effective (Kim et al., 1999). Bacteria are more sensitive than yeasts and fungi. Gram-positive bacteria are more sensitive to ozone than Gram-negative organisms and spores are more resistant than vegetative cells (Das & Kim, 2010b; Pascual, 2007).
\n\t\t\tElectrolyzed water (EW), the second most popular sanitizer in Korea (Kim, 2008) is considered as an environment-friendly sanitizer compared to chlorine. However, there are different opinions on the effect of EW among industrial users. EW generated by adding NaCl to pure water from non-diaphragm system is one of the major EW systems in Korea. This electrolytic process facilitates the conversion of chlorine oxidants (Cl2, HClO/ OCl-) which are effective for inactivating a variety of microorganisms (Kim, 2007; Yang et al., 2003). The bactericidal effect of EW have been evaluated on several fresh-cut vegetables such as lettuce, carrots, spinach, and cucumber (Izumi, 1999; Nimitkeatkai & Kim, 2009). Acidic EW has a strong bactericidal effect against pathogens and spoilage microorganisms due to its low pH, high oxidation reduction potential (ORP) and the presence of residual chlorine (Kim, 2007). Using acidic EW resulted in moderate control of aerobic bacterial growth during storage of fresh-cut cilantro (Wang et al., 2004). Acidic EW was also tested for its efficacy in inactivating Salmonella on fresh-cut produce. However, the concentration of acid used can influence the organoleptic quality of vegetables, i.e., loss of texture (Kim, 2007; Zhang & Farber, 1996). Electrolyzed water at high pH (pH 6.8, 20 mg/L available chlorine) was tested as a disinfectant and the research found that it did not affect tissue pH, surface color, or general appearance of fresh-cut vegetables (Izumi, 1999).
\n\t\t\tHeat treatments such as hot water and hot air are non-chemical methods that have been used to control microorganism and senescence-related symptoms of fresh produce. Recently, mild heat treatment as physical technology to extend shelf-life of fresh and fresh-cut produce have become of interest. Heat treatment using hot water was used for fungal and insect control, but has been extended to improve the storage quality of fresh-cut produce. Hot water dips to control both decay and quality change of fresh and fresh-cut produce are often applied for 30 seconds to a few minutes at temperatures of 40-60 C (Kim, 2007; Kim et al., 2011). Heat treatments combined with other agents have also been used to prevent the microbial quality, browning, and maintaining texture in various vegetables (Das & Kim, 2010a). A combination of heat treatment followed by calcium dip has also been applied for the primary purpose of controlling postharvest pests and/or diseases and has been found to have very good results in maintaining or improving the texture of various horticultural products. Combined heat treatments with UV-C were applied to fresh-cut processed broccoli (
Acidity is a commonly used factor to control the growth of microorganisms in foods. Organic acids such as citric acid and ascorbic acid have been applied for preserving physicochemical qualities (Rosen & Kader, 1989) and preventing microbial growth at levels that did not adversely affect taste and flavor (Yildiz, 1994). Therefore, organic acids could be a potential sanitizer for fresh-cut vegetables. However, different studies have shown that the inhibitory or bactericidal effect depends on the characteristics of the acid used to adjust the medium pH (Buchanan et al., 1993; Eswaranandam et al., 2004; Parish & Higgins, 1989). Application of organic acids as sanitizers at higher concentration can reduce the overall quality and produce off-flavor in leafy vegetables after few days of storage (Kim 2007; Chandra & Kim, 2011). The acid tolerance of fresh-cut vegetables varies among different microorganisms and products. Organic acid alone treatment is not successful sanitation in controlling pathogens and maintaining food quality during storage. Hurdle technology or combined technology, which involves simultaneous multiple preservation approaches, is generally better to control both microbial safety and food quality of fresh-cut produce.
\n\t\t\tNatural antimicrobial agents derived from fruit, herb, and shell have been investigated as preservatives. The interest in the possible use of natural alternatives to food additives to prevent bacterial and fungal growth has notably increased. Edible coatings containing natural antimicrobial agents are gaining importance as potential treatments to reduce the deleterious effects imposed by fresh-cut processing on fresh-cut fruits. However, application of natural edible coatings for fresh-cut vegetables has not received interest as much as fresh-cut fruits. Essential (volatile) plant oils occur in edible, medicinal and herbal plants which minimizes questions regarding their safe use in food products. Essential oils and their constituents have been widely used as flavouring agents in foods since the earliest recorded history and it is well established that many have wide spectra of antimicrobial action (Holley & Patel, 2005). No fresh-cut company used natural antimicrobial agent to wash or preserve fresh-cut produce in Korea due to less effects than chemical sanitizers and non-economic efficiency. However, these days natural agents are good candidate to replace tap-water washing because these agents have more potency against microorganisms. Natural agents can be used for washing microgreens and organic fresh-cut produce which are sold at a higher price. The growing demand for fresh and fresh-cut produce by consumers had led to the need for natural food preservation methods such as the use of natural antimicrobials and their combination with other hurdles, without adverse effects on the consumer or the food itself (Tiwari et al., 2009).
\n\t\t\tAlthough a wide range of different microbial agents are available for sanitizing fresh-cut produce, their efficacies vary and none are able to ensure elimination of pathogen completely without compromising sensory quality. In addition, recent studies have shown that chlorine lacks efficacy on pathogen reduction; the formation of the chlorine by-products are also deleterious to human health. Thus, there is much interest in developing a safer and more environmental friendly antimicrobial alternative to chlorine. Ozone, electrolyzed water, mild heat treatment, organic acid, and natural antimicrobial agents, or the combination of those sanitizing methods have been applied to various fresh-cut vegetables. It is generally accepted that an ideal sanitizing agent should have two important properties: a sufficient level of antimicrobial activity and a negligible effect on the sensory quality of the product.
\n\t\tOzonated water washing is getting more popular now-a -days due to its high biocidal efficacy, wide antimicrobial spectrum and environment friendly. Research has shown that treatment with ozone appears to have a beneficial effect in extending the storage life of fresh produce such as cucumber, apples, grapes, oranges, pears, raspberries and strawberries by reducing microbial populations and by oxidation of ethylene (Kim, 2007). The effect of ozonated waters with different concentrations and contact times on the quality attributes and microbial population of fresh-cut produce were studied. Two types of ozone generators were used to investigate the efficacy of microbial reduction and quality maintenance of fresh-cut lettuce, cilantro, carrot, broccoli, and paprika. One aqueous ozone solution was prepared by continuously circulating the water through an ozone generator and a stainless steel water tank. The circulating type ozone generator was equipped with a vortexer to facilitate dissolving of gaseous ozone in the water, and a de-gassing system to remove the undissolved ozone. The other ozone solution was prepared by flowing ozonated water into plastic bucket through an ozone generator. The flowing type ozone generator was equipped with a cylinder used as compression tank to facilitate high concentration of ozone. Both circulating type and flowing type ozone solutions were used immediately after the required ozone concentration were reached.
\n\t\t\tOzonated water using circulating type with low ozone concentration (less than 1 ppm) and insufficient contact time was not much effective compared to 100 ppm chlorine in reducing microbial population and maintaining quality of fresh-cut cilantro, iceberg lettuce, romaine lettuce, and baby leaves. Fresh-cut cilantro was washed in tap water, 100 ppm chlorine solution (pH 7), and 0.7 ppm ozonated water for 1 minute separately. The initial total aerobic plate count (APC) on the unwashed cilantro leaves was 6.45 log CFU/g. There was a significant decrease in APC between washed cilantro and unwashed sample after washing. However, no significant difference was found in microbial reduction of fresh-cut cilantro between tap water and ozonated water throughout 6 days storage at 5 C. The chlorine treatment maintained a low level of microbial count compared to other treatments. Fresh-cut romaine lettuce, spinach, microgreens, and baby leaves sanitized with 0.5-0.8 ppm of ozonated water had higher microbial population compared to samples washed in 50-100 ppm of chlorine. Ozonated water sanitation with low ozone concentration (less than 1 ppm) is not inadequate to be used in fresh-cut industry practically because the ozonated water was not effective in microbial decontamination and maintaining storage quality of fresh-cut vegetables (Kim, 2007).
\n\t\t\t\tContinuous flowing type ozonated water containing 1 ppm of ozone concentration was also used to sanitize fresh-cut iceberg lettuce if the sanitation could get much effect in reducing microbial population. The ozonated water was compared with tap water and 100 ppm chlorine solution (pH 6.5). During storage at 5 C, there was a significant increase in APC among all treatments. The highest numbers of APC and coliform plate count (CPC) were observed in tap water washing followed by ozone washing. Chlorine treatment had the most reduction on microbial population on fresh-cut iceberg lettuce throughout storage. In fresh-cut lettuce, cut edge browning commonly occurs during storage making unsuitable for consumers. Discoloration occurred in all fresh-cut iceberg lettuces on day 6. Samples washed in ozonated water had lower degree of cut edge browning index score than samples washed in tap water. However, chlorine solution showed the lowest degree of cut edge browning. Though ozonated water containing 1 ppm of ozone concentration was effective in delaying discoloration and reducing microbial population the effectiveness was lower compared to 100 ppm chlorine solution (Kim, 2007).
\n\t\t\tFlowing ozonated water washing was also used to sanitize ‘Tah Tasai’ Chinese cabbage baby leaves and fresh-cut romaine lettuce. Those fresh-cut products were washed in tap water, 100 ppm chlorine (pH 7.0), and continuous flow of 1.5 ppm ozonated water for 2 minutes separately. Samples treated with the ozonated water had lower APC compared to those washed in tap water. Ozonated water containing 1.5 ppm of ozone concentration reduced APC on fresh-cut baby leaves and romaine lettuce by 0.3 and 0.6 log CFU/g, respectively, on day 0. On the other hand, 100 ppm chlorine solution treatment reduced APC on fresh-cut baby leaves and romaine lettuce by 0.5 and 0.9 log CFU/g on day 0. Fresh-cut produce washed in ozonated water had lower microbial population than samples washed in tap water until middle period of 9 days-storage at 5 C. Ozonated water washing containing 1.5 ppm of ozone concentration and washed for 2 minutes was not sufficient to decontaminate microorganism of fresh-cut romaine lettuce and baby leaves as much as effectiveness of 100 ppm chlorine solution washing. Therefore, it has been required to find optimum ozonated water washing conditions for improving storage quality and microbial food safety of each fresh-cut product to apply to fresh-cut industry as a chlorine alternative.
\n\t\t\t\tHigher ozone concentration with longer contact time has been applied to get much effect in reducing microbial population and maintaining quality of fresh-cut produce. Fresh-cut carrot shreds were washed in tap water for 1 minute, 50 ppm chlorinated water (pH 6.3) once or two times for each 1 minute, or initial 2 ppm ozonated water using circulating type at varying times (1, 5, and 20 minutes). The samples were then centrifuged to remove excess water, packaged in 50 µm PE film bags, and stored at 5 C. Different ozonated water washing time affected microbial growth, off-odor development, color, and overall quality of carrot shreds. A single chlorine wash and 20 minutes ozonated water wash treatments had lower APC and lactic acid bacteria compared to other washing treatments until 2 weeks storage (Fig. 1). The 20 minutes ozone treatment reduced APC on carrot shreds by1.4 and 1.1 log CFU/g on week 1 and week 2, respectively.
\n\t\t\t\t\tOzonated water washing for 20 minutes maintained quality by inhibiting off-odor and high overall quality score due to less whiteness development (Fig. 2). The single chlorine water wash was effective and resulted in better quality compared to two time chlorine water wash. However, samples washed for 20 min in ozonated water had better quality with less off-odor and higher overall visual quality scores than samples washed in chlorine water washed once. The efficacy of optimum ozonated water washing on microbial reduction and quality of those fresh-cut produce was similar to chlorine or better than chlorine. Ozonated water containing initial 2 ppm ozone concentration with sufficient washing time would be effective in reducing microbial population and maintaining quality of fresh-cut carrot and could be an alternative method to maintain quality and shelf-life of fresh-cut carrot shreds (Kim et al., 2007a).
\n\t\t\t\t\tAerobic plate count and lactic acid bacteria of fresh-cut carrot shreds washed in different sanitizers and stored at 5ºC for up to 3 weeks.
Off-odor development and Overall quality of fresh-cut carrot shreds washed in different sanitizers and stored at 5ºC for up to 3 weeks.
Ozonated water washing using flow type with different contact times on storage quality and microbial growth in fresh-cut broccoli was conducted to compare ozone with chlorine. Fresh-cut broccoli samples were washed each for 90 and 180 seconds in normal tap water, 100 ppm chlorinated water (pH 7), and 2 ppm ozonated water separately and respectively. Then, samples were packaged in 30 µm polyethylene bags and stored at 5ºC for 9 days. No significant differences were observed in gas composition and color among different sanitizers with contact times. No off-odor was detected during the 9 days storage. Sanitizers affected microbial population of fresh-cut broccoli. In the color characteristics no difference were marked in L* and a* value and hue angle of the samples among different washing solutions and contact times during the storage period. It was found that electrical conductivity increased with the longer contact time in all washing solutions compared to shorter contact time. Electrolyte leakage is generally considered as an indirect measure of plant cell membrane damage. Ozonated water washing for 180 seconds contact time initially showed highest electrical conductivity probably due to its highly oxidizing nature than chlorine and tap water washing, but at the end of the storage the value is low and nearly equal to the above washings (Fig.3, left). It may be due to quality maintenance without texture damage or decay. Electrical conductivity is relatively high immediately after fresh-cut processing and decrease rapidly, then either decrease gradually or remain relatively stable until the samples have good quality in many fresh-cut produce (Kim et al., 2005a; Kim, 2007). This typical response pattern to processing and storage is similar to the result of fresh-cut broccoli sanitized in ozonated water and stored for 9 days at 5ºC. No color difference was found among the treatments during 9 days storage (Fig. 3, right).
\n\t\t\t\t\tElectrical conductivity and hue angle of fresh-cut broccoli washed in different sanitizers and stored for 9 days at 5ºC. In figure, samples washed for 90 and 180 seconds in tap water (TW), 100 ppm chlorinated water (Cl), and 2 ppm ozonated water (O3).
Among the sanitizers, ozonated water with 180 seconds maintained the lowest numbers of aerobic plate count throughout the storage days in comparison with others (Fig. 4). Ozonated water with 90 seconds was not much effective in reducing microbial population compared to chlorine. However, samples washed with ozonated water for 180 seconds showed the lowest coliform count. Absolutely no coliform were observed in ozonated water with 180 seconds washing treatment on day 0. The result reveals that longer contact time of ozone affects positively whereas other sanitizers don’t affect on the microbial quality and safety aspects of fresh-cut broccoli. The difference of microbial population is may be due to the following causes; the surface wash off might be attached to the samples again during washing time, higher electrical conductivity observed during storage and the reactivity against pathogen may be less effective in comparison with 2 ppm of ozone. Ozone effectiveness against microorganisms depends not only on the amount applied, but also on the effectiveness of ozone delivery method, type of material, the target microorganisms, physiological state of the bacteria cells at the time of treatment (Das & Kim, 2010b).
\n\t\t\t\t\tAerobic plate count and coliform plate count of fresh-cut broccoli washed in different sanitizers and stored for 9 days at 5ºC. In figure, samples washed for 90 and 180 seconds in tap water (TW), 100 ppm chlorinated water (Cl), and 2 ppm ozonated water (O3).
Ozonated water treatment containing 3 ppm of ozone with 3 minutes washing reduced APC and coliform/E. Coli count in both fresh-cut paprika and iceberg lettuce, similar to 100 ppm chlorine at day 0 (Table 1). Treatment with the ozonated water showed the lowest numbers of aerobic plate count and coliform/E. Coli count on day 6 in fresh-cut paprika. There was no difference in quality parameters such as color, off-odor, and visual quality among treatments. The highest numbers of aerobic and coliform/E. Coli were observed in tap water washing. Fresh-cut broccoli washed in 4ppm ozonated water for 5 minutes had lower microbial populations than samples washed in 100 ppm chlorine.
\n\t\t\t\t\tSanitizer | \n\t\t\t\t\t\t\t\tFresh-cut paprika | \n\t\t\t\t\t\t\t\tFresh-cut iceberg lettuce | \n\t\t\t\t\t\t\t||||||
APC | \n\t\t\t\t\t\t\t\tColiform/E. Coli | \n\t\t\t\t\t\t\t\tAPC | \n\t\t\t\t\t\t\t\tColiform/E. Coli | \n\t\t\t\t\t\t\t|||||
Day 0 | \n\t\t\t\t\t\t\t\tDay 6 | \n\t\t\t\t\t\t\t\tDay 0 | \n\t\t\t\t\t\t\t\tDay 6 | \n\t\t\t\t\t\t\t\tDay 0 | \n\t\t\t\t\t\t\t\tDay 6 | \n\t\t\t\t\t\t\t\tDay 0 | \n\t\t\t\t\t\t\t\tDay 6 | \n\t\t\t\t\t\t\t|
Tap water | \n\t\t\t\t\t\t\t\t2.3 | \n\t\t\t\t\t\t\t\t5.3 | \n\t\t\t\t\t\t\t\t1.5 | \n\t\t\t\t\t\t\t\t1.2 | \n\t\t\t\t\t\t\t\t3.6 | \n\t\t\t\t\t\t\t\t5.3 | \n\t\t\t\t\t\t\t\t0.8 | \n\t\t\t\t\t\t\t\t0.9 | \n\t\t\t\t\t\t\t
100ppm Chlorine | \n\t\t\t\t\t\t\t\t2.0 | \n\t\t\t\t\t\t\t\t4.3 | \n\t\t\t\t\t\t\t\t0.5 | \n\t\t\t\t\t\t\t\t1.0 | \n\t\t\t\t\t\t\t\t3.1 | \n\t\t\t\t\t\t\t\t4.7 | \n\t\t\t\t\t\t\t\t0.2 | \n\t\t\t\t\t\t\t\t0.7 | \n\t\t\t\t\t\t\t
3ppm Ozone | \n\t\t\t\t\t\t\t\t2.1 | \n\t\t\t\t\t\t\t\t3.5 | \n\t\t\t\t\t\t\t\t0.7 | \n\t\t\t\t\t\t\t\t0.7 | \n\t\t\t\t\t\t\t\t3.0 | \n\t\t\t\t\t\t\t\t4.7 | \n\t\t\t\t\t\t\t\t0.2 | \n\t\t\t\t\t\t\t\t0.7 | \n\t\t\t\t\t\t\t
Microbial population (log CFU/g) of fresh-cut paprika and iceberg lettuce washed in different sanitizers for 3 minutes, packaged, and stored for 6 days at 5ºC.
No quality deterioration or side effects of higher ozone concentration were found in fresh-cut broccoli. These results showed that ozonated water reduced microbial growth more effectively than 100 ppm chlorine solution. Therefore, ozonated water washing with optimum ozone concentration and sufficient contact time could be a favorite alternative sanitation to chlorine.
\n\t\t\t\tStrong acidic EW (pH2.7) and weak acidic EW (pH 5-6.5), which were generated by electrolysis of NaCl solution and HCl, respectively have been used as disinfectant in fresh-cut industry. Weak alkaline EW (pH 7.5-8) from non-diaphragm EW generator, recently developed is getting popular among three types of EW. In general, strong acidic EW had stronger bactericidal effect compared to alkaline EW which has high pH levels. However, strong acidic EW can cause tissue damage in some fresh-cut produce, especially leafy vegetables during storage or distribution. Little information exists on the efficacy of weak alkaline or weak acidic EW on quality and microbial reduction in fresh-cut produce.
\n\t\t\tThe effect of strong acidic and weak alkaline EW containing 80ppm available chlorine concentration as well as general chlorine solution on storage quality and microbial growth of fresh-cut iceberg lettuce has been studied. The effectiveness of strong acidic EW on microbial reduction was greater than weak alkaline EW at initial storage. However, strong acidic EW affected quality deterioration due to texture damage after 6 days at 10ºC (Table 2). Weak alkaline EW reduced off-odor development and was as effective as chlorine in inhibiting total aerobic bacterial and coliform group on fresh-cut iceberg lettuces (cultivar;
Treatment | \n\t\t\t\t\t\t\tGas composition (%) | \n\t\t\t\t\t\t\tTotal plate count (log CFU/g) | \n\t\t\t\t\t\t\tOff-odorz | \n\t\t\t\t\t\t\tDiscolorationz | \n\t\t\t\t\t\t|
O2 | \n\t\t\t\t\t\t\tCO2 | \n\t\t\t\t\t\t||||
Chlorine | \n\t\t\t\t\t\t\t0 | \n\t\t\t\t\t\t\t25.8 b | \n\t\t\t\t\t\t\t7.0 a | \n\t\t\t\t\t\t\t3.3 b | \n\t\t\t\t\t\t\t0.5 b | \n\t\t\t\t\t\t
Weak alkaline EW | \n\t\t\t\t\t\t\t0 | \n\t\t\t\t\t\t\t31.2 a | \n\t\t\t\t\t\t\t7.3 a | \n\t\t\t\t\t\t\t3.8 a | \n\t\t\t\t\t\t\t1.8 a | \n\t\t\t\t\t\t
Strong acidic EW | \n\t\t\t\t\t\t\t0 | \n\t\t\t\t\t\t\t23.8 b | \n\t\t\t\t\t\t\t7.1 a | \n\t\t\t\t\t\t\t2.7 c | \n\t\t\t\t\t\t\t0.7 b | \n\t\t\t\t\t\t
z 0 = none, 1 = slight, 2 = moderate, 3 = severe, 4 = strong | \n\t\t\t\t\t\t
Gas composition, aerobic plate count, and quality of fresh-cut iceberg lettuce washed in different sanitizers and stored at 10ºC for 6 days
Weak alkaline EW was also used to sanitize fresh-cut broccoli. The fresh-cut samples were washed for 90 seconds in tap water, 80 ppm chlorinated water (pH 7), and EW (pH 7.2) containing 80 ppm free chlorine separately and respectively. Then, samples were packaged in 30 µm polyethylene bags and stored at 5ºC for 9 days. No significant differences were observed in gas composition and color among different sanitizers. No off-odor was detected during the storage. Samples washed with EW showed the lowest total aerobic bacterial population and coliform count. The result reveals that weak alkaline EW affects microbial population of fresh-cut broccoli positively.
\n\t\t\t\t\n\t\t\t\t\t\t\t | Electrical conductivity | \n\t\t\t\t\t\t\tAerobic plate count | \n\t\t\t\t\t\t\tColiform plate count | \n\t\t\t\t\t\t|||
Day 0 | \n\t\t\t\t\t\t\tDay 9 | \n\t\t\t\t\t\t\tDay 0 | \n\t\t\t\t\t\t\tDay 9 | \n\t\t\t\t\t\t\tDay 0 | \n\t\t\t\t\t\t\tDay 9 | \n\t\t\t\t\t\t|
Tap water | \n\t\t\t\t\t\t\t6.1 | \n\t\t\t\t\t\t\t4.2 | \n\t\t\t\t\t\t\t4.28 | \n\t\t\t\t\t\t\t5.52 | \n\t\t\t\t\t\t\t1.39 | \n\t\t\t\t\t\t\t2.20 | \n\t\t\t\t\t\t
Chlorine | \n\t\t\t\t\t\t\t8.9 | \n\t\t\t\t\t\t\t4.5 | \n\t\t\t\t\t\t\t3.62 | \n\t\t\t\t\t\t\t4.61 | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t1.89 | \n\t\t\t\t\t\t
Electrolyzed water | \n\t\t\t\t\t\t\t8.2 | \n\t\t\t\t\t\t\t4.7 | \n\t\t\t\t\t\t\t3.53 | \n\t\t\t\t\t\t\t4.24 | \n\t\t\t\t\t\t\t0.22 | \n\t\t\t\t\t\t\t1.02 | \n\t\t\t\t\t\t
Electrical conductivity and microbial population of fresh-cut broccoli washed in different sanitizers and stored at 5ºC for 9 days.
Study on effect of combined EW washing with modified atmosphere (MA) packaging was carried out to investigate the influence of the combined treatment on quality maintenance and microbial food safety of fresh-cut iceberg lettuce. Fresh-cut iceberg lettuce were washed in alkaline EW (free chlorine 80 ppm), dried, and packaged with 35 μm P-Plus film to compare with conventional technology using combination of chlorine sanitation and vacuum packaging. Samples for control treatment were prepared following industrial practices; 100 ppm chlorine (100ppm, pH 7.5) wash and vacuum packaging with 80㎛ Ny/PE film. Combined EW and MA technology reduced off-odor development of packaged fresh-cut iceberg lettuce during storage (Table 4). The combined technology using EW washing and MA packaging was as effective as control using chlorine in inhibiting total aerobic bacterial counts on fresh-cut iceberg lettuces. The combined EW washing and MA packaging extended two more days of shelf-life of fresh-cut iceberg lettuce compared to control treatment.
\n\t\t\t\tTreatment | \n\t\t\t\t\t\t\tGas composition | \n\t\t\t\t\t\t\tAerobic plate count (log cfu/g) | \n\t\t\t\t\t\t\tOff-odor* | \n\t\t\t\t\t\t\tDis- coloration* | \n\t\t\t\t\t\t|
O2(%) | \n\t\t\t\t\t\t\tCO2(%) | \n\t\t\t\t\t\t||||
Chlorine + Vacuum pack. | \n\t\t\t\t\t\t\t0 | \n\t\t\t\t\t\t\t19.0 | \n\t\t\t\t\t\t\t6.4 | \n\t\t\t\t\t\t\t2.3 | \n\t\t\t\t\t\t\t0.6 | \n\t\t\t\t\t\t
EW + MA packaging | \n\t\t\t\t\t\t\t1.8 | \n\t\t\t\t\t\t\t11.5 | \n\t\t\t\t\t\t\t6.2 | \n\t\t\t\t\t\t\t0.7 | \n\t\t\t\t\t\t\t0.9 | \n\t\t\t\t\t\t
* 0 = none, 1 = slight, 2 = moderate, 3 = severe, 4 = strong | \n\t\t\t\t\t\t
Gas composition, aerobic plate count, and quality of fresh-cut iceberg lettuce treated with hurdle technology and stored at 5ºC for 12 days.
Heat treatments is one of postharvest treatments that has been used to control postharvest decay and; or to improve the storage quality of fresh-cut produce. Heat treatments alone or combined with other agents have also been used to prevent the microbial quality, browning, and maintaining texture in various fresh-cut vegetables.
\n\t\t\tThe effectiveness of heat treatment for fresh-cut winter squash and lotus roots has been applied. Winter squash which had hard rinds can be treated with hot water at 60-65 C for 2-3 minutes to reduce microbial contamination before it is fresh-cut processed (Arvayo-Ortiz et al., 1994; Hawthorne, 1989). However, other vegetables which have soft texture are not recommended to treat at high temperature like winter squash. Winter squash (cultivar;
For peeled potato, the most popular method of retarding surface browning used in the Korean industry is vacuum packaging that induces high CO2 and low O2 levels. However, the presence of high CO2 and low O2 concentrations may cause off-odor development due to anaerobic respiration. Hence, heat treatment methods that reduce browning and off-odor development were investigated. Potatoes (var. \'
Treatment | \n\t\t\t\t\t\t\tGas composition (%) | \n\t\t\t\t\t\t\tColor | \n\t\t\t\t\t\t\tOff-odor z | \n\t\t\t\t\t\t||
O2 | \n\t\t\t\t\t\t\tCO2 | \n\t\t\t\t\t\t\tLightness (L) | \n\t\t\t\t\t\t\tRedness(a) | \n\t\t\t\t\t\t||
Control | \n\t\t\t\t\t\t\t0.67 b | \n\t\t\t\t\t\t\t34.7 a | \n\t\t\t\t\t\t\t69.8 b | \n\t\t\t\t\t\t\t-1.61 a | \n\t\t\t\t\t\t\t3.2 a | \n\t\t\t\t\t\t
Heat treatment at 30ºC for 24 hours | \n\t\t\t\t\t\t\t2.74 a | \n\t\t\t\t\t\t\t16.8 b | \n\t\t\t\t\t\t\t71.2 a | \n\t\t\t\t\t\t\t-2.47 c | \n\t\t\t\t\t\t\t2.5 b | \n\t\t\t\t\t\t
Heat treatment at 45ºC for 3 hours | \n\t\t\t\t\t\t\t0.56 b | \n\t\t\t\t\t\t\t32.4 ab | \n\t\t\t\t\t\t\t70.3 ab | \n\t\t\t\t\t\t\t-2.15 b | \n\t\t\t\t\t\t\t1.7 c | \n\t\t\t\t\t\t
z 0 = none, 1 = slight, 2 = moderate, 3 = severe, 4 = strong | \n\t\t\t\t\t\t
Effect of heat treatment before peeling on gas composition and quality of peeled potato fresh-cut processed and vacuum packaged, and stored at 5ºC for 5 days.
Samples were then vacuum-packaged with 80µm Ny/PE film and stored at 10 C for up to 5 days. Mild heat treatment (30 C) was effective in reducing CO2 concentrations and off-odor development in the package of samples throughout storage. The 30 C mild heat treatment also delayed browning of peeled potatoes and maintained the highest overall quality score. The mild heat treatment at 30ºC before peeling can be a practical method to delay browning and off-odor development of ‘Jopung’ potato (Kim et. al, 2009).
\n\t\t\tThe combined effect of washing solutions and heat treatment were investigated as potential sanitizers for maintaining the quality and microbial safety of fresh-cut paprika. Fresh paprika shreds were washed in tap water and 1% calcium chloride combined with 19ºC (normal tap water) and 50ºC water temperature (heat treatment) for 2 minutes. Then, samples were packaged in 30 µm polypropylene bags and stored at 5ºC for 12 days. No significant differences were observed in color and gas composition of the package among treatments and no off-odor was detected until the end of 12 days storage. However, 50ºC water temperature with calcium chloride had lower microbial numbers upto the storage period in comparison with tap water (Fig. 5). The result reveals that 50 ºC water temperature with calcium chloride can be used as an washing solution to maintain the microbial quality in fresh-cut Paprika (Das & Kim, 2010a).
\n\t\t\t\tAerobic plate count and coliform plate count of fresh-cut paprika during the storage period. In figure, samples washed for 90 seconds in tap water (TW) and calcium chloride solution at 5ºC.
Softening, textural changes are one of the main causes of quality losses in case of fresh-cut products. In general, fresh-cut vegetables that maintain firm and crunchy textures are highly desirable. Though there is no significant difference in gas composition and color among treatments calcium chloride and heat treatment tended to increase firmness of fresh-cut paprika during the beginning of the storage compared to tap water washing treatment. It is well known that calcium plays a major role in maintaining the quality of fruit and vegetables. Increasing the calcium content in the cell wall of fruit tissue can help delay softening of fresh-cut produce. The beneficial effects obtained with heat treatments have generally been explained in terms of pectin esterase activation. Calcium dips have been employed to improve firmness and extend the postharvest shelf-life of a wide range of fruit and vegetables. Similarly, certain commercial additives can maintain the quality of fresh-cut products (Encarna et al., 2008; Luna-Guzman & Barrett, 2000). The changes in electrical conductivity of fresh-cut paprika depend upon the type of washing solution and heat treatment (Fig. 6). Tap water washing treatments (both TW and TW + Heat treatment) showed lower electrolyte leakage compared to calcium chlorine washing during the entire storage period. A combination of heat treatment followed by calcium dip may need more research if it can be applied for the purpose of controlling postharvest pests and/or diseases and have very good results in maintaining or improving the texture of on various fresh-cut produce.
\n\t\t\t\tFirmness and electrical conductivity of fresh-cut paprika heat treated and stored at 5ºC for 12 days. In figure, samples washed for 90 seconds in tap water and calcium chloride solution at 5ºC.
Organic acid and acid compound sanitizers have been used to sanitize fresh and fresh-cut produce. Organic acids are one of the important sanitizers that have been applied largely for preserving physicochemical qualities and for preventing microbial growth in many fresh-cut products. Organic acid with optimum condition did not adversely affect taste and flavor, but leaving no effect on environment. Citric acid can be used to extend the shelf life of fresh-cut produce by reducing the loss of eating quality and disease development. Ibrahim et al. (2009) reported that leaves of some selected vegetables decontaminated with 5% citric acid showed a considerable decrease in microbial count compared to water washing. However, the application of these acids at higher concentration may cause quality deterioration due to off-odor and texture damage in some fresh-cut leafy vegetables. Sequential treatment of citric acid and ethanol on the quality and microbial reduction of organic vegetables has also been examined. Hence, organic acid and the combined technology using have been carried out to find an alternative sanitizer to chlorine.
\n\t\t\tFresh iceberg lettuce leaves were sanitized separately with tap water, 100 µL L-1 chlorine, 0.2% citric acid, 50% ethanol, and the combination of citric acid solution and 50% ethanol spray. Samples were then dried with centrifugal dryer, packaged in 80μm Ny/PE films, and stored for 6 days at 5 C. The 50% ethanol solution dipping was the most effective treatment to reduce microbial population of fresh-cut iceberg lettuce (Fig. 7). However, fresh-cut iceberg lettuce sanitized in ethanol solution had severe injury with lowest visual quality score and highest electrical conductivity among treatments after 6 days storage (Fig. 8). The decline of overall visual quality in ethanol treated sample might be a consequence of tissue damage as reflected from the electrical conductivity data. Citric acid alone was not effective in reducing microbial population, similar to 100ppm chlorine solution treatment (Fig. 7). The combination of citric acid and ethanol spray reduced aerobic microbial population by 1.1 log CFU/g as compared to tap water. The combination with citric acid and ethanol spray also maintained good quality with high overall quality score at the end of 6 days storage (Fig. 8). Therefore, the combination of citric acid and ethanol spray could be an alternative to chlorine as an environment-friendly sanitizer for washing fresh-cut leafy vegetables (Kim et al., 2011).
\n\t\t\t\tAerobic plate count of fresh-cut iceberg lettuce treated with different sanitizers and stored at 5 ºC.
Visual quality and electrical conductivity of fresh-cut iceberg lettuce treated with different sanitizers and stored for 6 days at 5 ºC.
Fresh organic vegetables such as spinach, ‘Tah Tasai’ Chinese cabbage baby leaves, and microgreens were also sanitized separately with tap water, 100 ppm chlorine, 0.2% citric acid (CA), and the sequential treatment of 0.2% CA solution and 50% ethanol spray (CA+Et). In case of spinach, chlorine and CA+Et increased CO2 partial pressures in the headspace of sample packages and generally had higher electrical conductivity compared to tap water. No significant differences were observed in color among different sanitizers during storage at 5 C in fresh-cut spinach samples. The chlorine and CA+Et treatments were effective in reducing microbial population of fresh-cut spinach. However, CA+Et treatment induced off-odor of microgreens resulting more aerobic plate count compared to chlorine treatment. In case of microgreens, samples treated with CA+Et did not have good quality score, worse than score of chlorine at the end of storage probably due to severe texture damage. In ‘Tah Tasai’ Chinese cabbage baby leaves, sanitizer chlorine treatment showed lower number of total aerobic count immediately after washing. However, citric acid in combination with ethanol spray treatment showed the lowest number until day 7. No significant difference was found in microbial number among the treatments at the end of 10 days storage. Wang et al. (2004) also reported that no significant difference in total aerobic plate count at the end of 14 days storage of cilantro leaves. The possible reason might be due to the baby leave samples became softer with the progress in storage which caused damage in texture for all samples. Citric acid and ethanol, on the other hand, both are used as anti-microbial agents leaving no effect to the environment. Their combined use was almost similarly effective as of chlorine possibly due to the dual sanitization effects on the sample used.
\n\t\t\tAcid compound sanitizers such as acidified sodium chlorite (ASC) and peroxyacetic acid-based sanitizer (PA) have been used for food safety of fresh and fresh-cut produce. Peroxyacetic acid is a strong oxidizing agent that has been used extensively to disinfect food processing equipment and has been approved by the U.S. Food and Drug Administration (FDA) as a disinfectant for fruits and vegetables (Gonzalez et al., 2004). Recent studies undertaken to determine the suitability of PA (Tsunami, Ecolab, USA) for washing fresh-cut vegetables showed it to be effective against
Fresh-cut shredded carrots were washed in tap water, 100 ppm chlorinated water, 30 ppm ASC, or 30 ppm PA. Samples were then packaged in 35
Aerobic plate count and coliform plate count of fresh-cut carrot shreds. In figure, samples washed for 2 minutes in tap water, chlorinated water, peroxyacetic acid-based sanitizer (PA), and acidified sodium chlorite (ASC).
Peroxyacetic acid-based sanitizer also maintained initial color values, inhibited off-odor development and skin whitening of samples, and achieved the highest overall quality score among those sanitizer treatments. Off-odor was detected in all samples on day 8 and day 11 (Fig. 10, left). Off-odor was lower in samples treated with PA than in any other treated samples. Fresh-cut produce is known to develop undesirable off-odors under low O2 and elevated CO2 atmospheres (Kim et al., 2005a). Carrot shreds treated with water, chlorine, or ASC reached score 2.0 (the limit of marketability) at the end of storage, whereas samples PA-treated had score 1.9 after 11 days of storage. In fresh-cut produce, patterns of off-odor development correlate with ethanol and acetaldehyde and there is also a strong relationship between package atmospheric conditions and off-odor development (Kim et al., 2005b). The degree of off-odor of fresh-cut carrot shreds may be influenced by fermentation due to anaerobic microorganism. Surface whitening which is one of major postharvest quality problems in carrot was significantly retarded by applying sanitizer PA. Samples treated with PA maintained inherent color and exhibited the lowest rate of increase in whitening scores (Fig. 10, right). Surface discoloration during storage is most detrimental to the quality of shredded carrots. The possible reasons for whiteness development on carrot surface are dehydration and lignification (Kim et al., 2006). Visual observation of carrot shreds treated with PA showed a moister surface compared to other sanitizer treatments. The PA-treated samples had the highest overall quality score, with relatively low levels of whitening. Therefore, sanitizer PA treatment significantly affected quality and shelf-life of fresh-cut shredded carrots. At present, chlorine is the most practical, efficient, and low cost disinfectant available. Due to concerns about the formation of by-products, however, a safer alternative is needed. Peroxyacetic acid-based sanitizer treatment resulted in comparable antimicrobial effectiveness and sensory quality of carrot shreds throughout storage.
\n\t\t\t\t\tOff-odor development and surface whitening of fresh-cut carrot shreds after storage at 5ºC for 8 and 11 days. In figure, samples washed for 2 minutes in tap water, chlorinated water, peroxyacetic acid-based sanitizer (PA), and acidified sodium chlorite (ASC).
Natural compounds can serve as carriers for a wide range of food additives, including anti-browning agents, colorants, and antimicrobials that can extend product shelf-life and reduce the risk of pathogen growth on fresh-cut produce surface. In recent years there has been a considerable pressure by consumers to reduce or eliminate chemically synthesized additives in foods. Plants and plant products can represent a source of natural alternatives to improve the shelf-life and the safety of food. In fact, they are characterised by a wide range of volatile compounds, some of which are important flavour quality factors (Patrignani et al., 2008; Utama et al., 2002). A key role in the defence systems of fresh produce against decay microorganisms has been attributed to the presence of some of these volatile compounds (Patrignani et al., 2008). However, no plant volatiles have been used as natural antimicrobial agent for fresh-cut produce practically. Recently developed natural antimicrobial agents from marine resource product have been applied to fresh-cut vegetables.
\n\t\t\tThe heated scallop shell powder; calcinated calcium (CC) was investigated as potential sanitizers for maintaining storage quality and microbial safety of fresh-cut iceberg lettuce. Samples were washed in normal tap water, 50 ppm chlorinated water (pH 6.5), 1.5 g L-1 CC for 2 minutes separately. Samples were then packaged in 80 μm nylon/polyethylene bags and stored at 5ºC. The initial aerobic plate count of unwashed iceberg lettuce was 6.5 log CFU g-1. The aerobic plate count on fresh-cut lettuce increased with storing time, reaching 6.05 to 7.05 log CFU g-1 on 12 days-storage. Washing in CC was effective in reducing aerobic plate count of fresh-cut lettuce samples by 0.4 to 1.0 log CFU g-1 as well as chlorine treatment throughout storage as compared to tap water (Fig. 11, left). Electrical conductivity of all samples decreased during the initial period of storage, remained stable thereafter or increased slightly at the end of storage (Fig. 11, right). Electrical conductivity of fresh-cut lettuces increased after 8 days. Electrical conductivity is generally considered as an indirect measure of plant cell membrane damage and deterioration of fresh-cut vegetables (Jiang et al., 2001; Kim et al., 2005b). Increased electrical conductivity after fresh-cut processing is a common phenomenon due to the leakage from cut ends of the samples or otherwise wounded tissues.
\n\t\t\t\tAerobic plate count and electrical conductivity of fresh-cut iceberg lettuce sanitized with different washing solutions (tap water, chlorinated water, and calcinated calcium) and stored at 5ºC for 12days.
Samples treated with CC had good quality with low off-odor at the end of storage. Visual quality score of all fresh-cut iceberg lettuce samples was lower than score 3, which was considered the limit of marketability at the end of 12 days-storage (Fig. 12, left). The visual quality related to browning was probably induced by relatively high O2 and low CO2 concentration in sample packages. Off-odor was first detected in fresh-cut lettuce samples treated with TW after 6 days and increased relatively until the end of storage. Off-odor of fresh-cut lettuce samples washed in chlorine and CC was lower than tap water (Fig. 12, right). Samples sanitized with chlorine or CC reached score 1.3 which was lower score than the limit of marketability on the 12 days-storage. Fresh-cut produce is known to develop undesirable off-odors under low O2 and elevated CO2 atmospheres (Kim, 2007). In fresh-cut lettuce, patterns of off-odor development correlated with ethanol and acetaldehyde and there was also a strong relationship between package atmospheric conditions and off-odor development (Kim et al., 2005a; Kim et al 2005b). The degree of off-odor in the packaged fresh-cut lettuce was influenced by subsequently fermentation due to anaerobic microorganism.
\n\t\t\t\tOverall visual quality and off-odor development of fresh-cut iceberg lettuce sanitized with different washing solutions (tap water, chlorinated water, and calcinated calcium) after 12 days storage at 5ºC.
Natural materials, calcinated calcium and fruit extract compound from Japanese apricot were used as sanitizer to maintain quality and reduce microbial population of bok choi with different maturities. Microgreen, baby leaf, and mature bok choies were washed in tap water, 50 ppm chlorine, and 500 fruit extract compound, for 2 min separately. Those samples were then packaged in 50 μm PE film and stored at 5 C for 6 days. One of natural compounds, the fruit extract compound was not effective significantly in reducing microbial population and quality such as off-odor. However, samples treated with CC had better quality with less off-odor until 4 to 6 days-storage in baby leaf and mature Bok choi. Calcinated calcium affected in reducing microbial population of microgreen, baby leaf, and mature Bok choi for 2, 4, and 6 days, respectively (Fig. 13). Bok choi micrggreens had highest microbial population, followed baby leaves, and mature samples in terms with maturity. Therefore, mature and baby leaf Bok choi samples can have 6 and 4 days of shelf-life with CC sanitation, respectively. Fresh-cut broccoli was also washed in CC at normal tap water temperature. Broccoli samples sanitized in CC solution had good quality with lower off-odor and microbial count at the end of 9 days-storage (Kim et al., 2010). To avoid chlorine which may lead to the formation of carcinogenic compounds, CC can be used as environmental friendly sanitizer and an alternative to chlorine washing for fresh-cut broccoli without affecting microbial and sensorial quality.
\n\t\t\t\tAerobic plate count of mature, baby leaf, and microgreen fresh-cut bok choi samples sanitized with different washing solutions (tap water, chlorine, fruit extract compound, and calcinated calcium).
Use of chlorine to reduce microbial populations of fresh-cut vegetables has faced with challenges to find alternatives which are more environmental friendly and not harmful to human health. Wide ranges of different agents are available for sanitizing fresh-cut produce, their efficacies vary and none are able to ensure elimination of pathogen completely without compromising sensory quality. Therefore, application of different environment-friendly sanitizing agents has been conducted to investigate highly optimized condition to guarantee a minimal number of spoilage microorganisms in many fresh-cut vegetables. As alternatives to chlorine, ozone, electrolyzed water, mild heat treatment, organic acid with ethanol, and natural antimicrobial agents, or the combination of those sanitizing methods can be used for fresh-cut vegetables. But, selection of washing solution and use of optimum condition to meet each fresh-cut vegetable should be performed to get similar or better efficacy to chlorine. Ideal sanitizing agent should have effectiveness in two important properties: antimicrobial activity and sensory quality of the fresh-cut product.
\n\t\t\tFor organic fresh-cut leafy vegetables which are facing challenges to find the means to extend shelf-life and to enhance microbial food safety, combined citric acid with ethanol spray or calcinated calcium alone solution can be used in fresh-cut industry. Those environment friendly agents are good candidate to replace tap water washing or organic acid solution because these agents have more potency against microorganisms. Heat treatment without chemical use can be used for washing of fresh-cut produce which have firm texture such as winter squash, potato, lotus roots, and paprika. To get much effectiveness in reducing microbial population of fresh-cut vegetables constant 1~4 ppm of ozonated water and week alkaline or weak acidic electrolyzed water can be used practically. However, the concentration of ozone and contact time is very important for microbial safety of fresh-cut vegetables such as broccoli, iceberg lettuce, carrot, etc. Calcinated calcium, a natural and an environment-friendly sanitizer can be an alternative to mild heat treatment for washing of fresh-cut vegetables without affecting sensorial quality.
\n\t\tGamma-aminobutyric acid (GABA), an amino acid, is the primary inhibitory neurotransmitter in the vertebrate central nervous system (CNS). Although it was first identified in plants in the late nineteenth century, only in 1950 was it first identified in fresh extracts of animal brain including reptiles, avian, mammals and man [1]. It is now accepted that GABA is present almost exclusively within the brain and retina of vertebrates and only in extremely limited amounts in the peripheral nervous system and other organs of the body. It has been estimated that within the CNS, GABA is the neurotransmitter for as many as one-third of the neurons with the majority of these cells as interneurons that modulate the activity of neural networks. GABA neurons are widely expressed throughout the CNS including the cerebral cortex, hippocampus, striatum, substantia nigra, globus pallidus, cerebellum and olfactory bulbs. Within the structures, GABA receptors are found not only on the cell membranes of neurons but on supporting glial tissue and astrocytes [2].
As an amino acid, GABA serves other biological roles in addition to that of a neurotransmitter. It also functions as a precursor for the assembly of proteins and as metabolic intermediary. Despite these multiple functions, GABA is also responsible for regulation of neuronal excitability and is the primary inhibitory messenger in the CNS. GABA is highly concentrated in the CNS and present in millimoles per gram in the brain compared to nanomoles per gram of the more more commonly recognized neurotransmitters including dopamine, 5-hydroxytryptamine (serotonin) and norepinephrine [3].
GABA is known to have affinity for two distinct families of receptors similar to the excitatory amino acid Glutamate. The first and most prevalent of the two in the brain is the ionotropic GABAA receptor, a large glycoprotein of ~275 kDa and consists of a pentameric transmembrane receptor typically including two α subunits, two β subunits and one γ. Variations frequently occur and may even include δ subunit substituted for γ that encircle a central, chloride-permeable pore. The GABAA is found on both presynaptic and postsynaptic neuronal cell membranes. Upon the binding of two GABA molecules to the extracellular site, the pore opens and allows the flow of chloride ions into the cell with hyperpolarization of the cell membrane and inhibition of action potentials [4].
The GABAA receptor was cloned in 1987 and multiple subunits have subsequently been identified and grouped within seven functionally unique families. These multiple isoforms result in a highly complex system of receptors with functions dependent upon the expression of subunits.
Two binding sites for GABA sit on the GABAA receptor along with other sites that include a benzodiazepine receptor, a barbiturate receptor, and alcohol. In every instance, these binding sites function independently of each other. As a result, each receptor does not compete with activation of other receptors and the overall effect is synergestic rather than competitive [5].
The GABAB receptor is a second type of receptor and is a metabotropic site that belongs to the G-Protein Coupled Receptor (GPCR) superfamily. Pretreatment of isolated tissue from rodent atria and vas deferens with the GABAA antagonist bicucullin in 1979 first eslablished that two populations of receptors existed when the expected response to GABA was not found [6]. Twenty years passed before the GABAB receptor was finally cloned. As a GPCR, this receptor is broadly distributed throughout the CNS and mediates slow and prolonged inhibitory messaging through Gai/o-type proteins. As a GPCR, GABAB contains seven transmembrane domains with an extracellular N-terminus tail and acts through a second messenger system by inhibition of adenylate cyclase and cAMP formation inactivating voltage-gated Ca2+ channels and K+ channels [5].
Three receptor subunits are associated with GABAB site. A long, extracellular N-terminal called the Venus fly-trap (VFT) domain includes an orthosteric binding site, a seven transmembrane domain and the C-terminus tail within the cell comprise the GABAB receptor. Ligands to the GABAB receptor have been identified and include the selective GABAB agonist Baclofen, various investigational antagonists that poorly penetrate the blood- brain barrier (BB) and several allosteric modulators under study [7].
Because of the ubiquity of GABA in the CNS It is not surprising that disordered GABA signaling has been implicated in several human neurological and psychiatric diseases. Anxiety, sleep, seizure, Alzheimer’s, Parkinson’s and substance abuse are some of several disorders suspected to be linked to the GABA system. Already several medication classes that have affinity for the GABA receptor, including benzodiazepines, muscle relaxants, sedative-hypnotics and anticonvulsants, are now routinely used in clinical medicine.
The production, release and degradation of GABA is mediated through multiple processes. The main precursor of GABA is glutamic acid, an excitatory neurotransmitter itself. GABA is synthesized by the irreversible single-step α-decarboxylation of glutamic acid by the enzyme glutamic acid decarboxylase (GAD), found initially in bacteria and plants and then later in the mammalian CNS and retina. There are two isoforms of the decarboxylase GAD (GAD65 and GAD67) that are involved in the synthesis of GABA with GAD65 closely associated with the presynaptic vesicles. This relationship strongly suggests that a coupled process is involved in the the conversion of cytosol glutamate to storage of intravesicular GABA. There are also vesicular transports systems termed VGAT for the sequestration of the neurotransmitter into the vesicle. VGAT is also the same vesicular transport for another inhibitory amino acid transmitter glycine in the spinal cord [8].
Similar to most decarboxylases, pyridoxine is required as a co-factor [1]. The localization of GAD in the brain generally correlates closely with the distribution of GABA. After synthesis, GABA is stored in vesicles in the presynaptic terminals in cells classified as “GABAergic” cells. When GABAergic cells receive a depolarizing stimulus, vesicular fusion and exocytosis occurs and GABA is released into the synaptic cleft. GABA signaling is primarily terminated by its reuptake into both neuronal and glial cells through membrane transporter systems. Through this uptake system the presynaptic cytosol and vesicles can reuse GABA. Astrocytes also express membrane transporters systems for GABA and play a significant role in GABA metabolism. When reuptake occurs in these non-neuronal cells or non-GABAergic cells, the availability of GABA as a neurotransmitter is reduced [8].
In addition to uptake through membrane transporters, GABA may also be broken down by the enzyme GABA Transaminase (GABA-T). GABA-T is, unlike GAD, widely expressed in both central and peripheral systems and possibly helps limit exogenous GABA from influencing CNS activities. In the CNS, this primary enzyzme is associated with GABA breakdown and is found both in GABA-ergic neurons and astrocytes. One product of GABA-T is glutamate which may be involved in the recycling of glutamate to form new GABA. GABA is also metabolized extracellularly by GABA-transaminase (GABA-T) into succinate semialdehyde, which then enters the krebs cycle for further metabolism [9].
The identification of Δ9-tetrahydrocannabinol (THC) as the psychoactive constituent of cannabis opened a door to unexpected discoveries in neuroscience. Cannabis is the generic name for
It was initially believed that these plant-based cannabinoids like THC, now referred to as phytocannabinoids, probably influenced animal physiology through a nonspecific mechanism to alter cellular membranes. Soon after establishing the laboratory synthesis of THC, modifications of the structure were created and tested in the laboratory. The availability of these synthetic analogs of THC led to the unexpected finding that the psychoactive effect of THC was stereospecific and occurred through binding to an unknown endogenous receptor [10, 11]. Evidence of an endogenous receptor was discovered in 1988 that revealed affinity for the THC molecule in rodent brain [12]. This previously unknown receptor was named CB1 and found to be a G-Protein Coupled Receptor (GPCR) with seven transmembrane helices. Within a few years, a second peripheral receptor was cloned and named CB2. Both receptors in humans were found to have 44% of the amino acid residues identical and in the transmembrane crossings 68% were the same. Although CB1 was the first receptor identified in the brain and was considered a central receptor, it is now known that it is widely distributed outside the CNS but at lower expression, including the respiratory, cardiovascular, skin, ophthalmic systems, and the adrenal glands. CB2, originally discovered in the spleen and thought to be a peripheral receptor, was later found to be present in limited amounts within the CNS and widely available in immune tissue and skin [13].
Although only recently discovered in the late 20th century, it is now recognized that the CB1 and CB2 receptors are the most plentiful G-protein coupled receptors (GPCR) in the body. CB1 is especially abundant in the brain and is more plentiful than all other receptors including GABA.
The presence of these two endogenous cannabinoid receptors led to the expectation that endogenous ligands must lay ahead. Several years earlier the opiate receptors had been discovered in the brain that had affinity for compounds obtained from the opium plant. This led to the isolation of a class of endogenous ligands termed the enkephalins that were bioactive neuropeptides.
Soon after the identification of the cannabinoid receptors, the endogenous ligand arachidonylethanolamine was isolated in 1993 and found to have agonist properties for CB1. This ligand was found in rodent brain and was composed of elements from arachidonic acid and ethanolamine. This unexpected ligand was soon christened Anandamide (AEA), a Sanskrit word for ‘bliss’ [14].
Arachidonic acid is a polyunsaturated fatty acid found in membrane phospholipids in several body organs including the brain [15, 16, 17]. In addition to being a precursor for AEA, arachidonic acid is also an important precursor for eicosanoids including prostaglandins. Shortly after the discovery of AEA, a second bioactive lipid that also included arachidonic acid, 2-arachidonylglycerol (2-AG), was found with binding affinity for both cannabinoid receptors. Unlike AEA, 2-AG had been known for over fifty years as an intermediary in metabolic pathways of triglycerides and other glyceride molecules and is far more available than AEA. 2-AG was found to be a full agonist of CB1 and CB2 and abundantly available throughout the body [18, 19]. In contrast, anandamide is a partial agonist of CB1 and CB2 and belongs to the family of N-acylethanolamines (NAE). NAEs consist of saturated and monounsaturated fatty acids that include palmitic and oleic acids and these other NAEs are more abundant than AEA but do not bind to cannabinoid receptors [20]. Although only recently discovered in the late 20th century, it is now established that the CB1 and CB2 receptors are the most plentiful G-protein coupled receptors (GPCR) in the body. CB1 is especially abundant in the brain and is more plentiful than all other receptors including GABA. The observation that the ECS is so highly expressed within the brain and the finding that the system is highly conserved in the evolution of animals illustrate the importance of the system in the healthy function of man.
Together AEA and 2-AG are referred to as endocannabinoids. These two endogenous ligands are produced in multiple body systems and activate cannabinoid receptors. These endocannabinoid chemical structures are long-chain, polyunsaturated fatty acid chains and differ significantly from the ring structured phytocannabinoids present in cannabis, with different binding affinities to the cannabinoid receptors. The endogenous 2-AG, for example, is a full agonist to the CB1 and CB2 receptors while the plant-derived THC is only a partial agonist. In addition, another important phytocannabinoid, CBD, has even less affinity with only very limited binding to cannabinoid receptors. As endogenous lipids, although both bind to the cannabinoid receptors, the NAE molecule AEA and the monoacylglycerol (MAG 2-AG as) belong to two distinct families with different synthetic and degradative pathways. Both AEA and 2-AG appear unique among their separate families as they are the only molecules that bind to the cannabinoid receptors CB1 and CB2.although they share affinities with the several similar lipids for non-cannabinoid receptors. In addition, both endocannabinoids and other bioactive lipids have redundant pathways in the synthesis and breakdown of the lipid molecules. This diversity in metabolism and binding to multiple receptor families by the NAEs and MAG lead to a highly complex system that regulates many important functions [21].
Collectively, the cannabinoid receptors CB1 and CB2, the two endocannabinoid messengers AEA and 2-AG, and the associated and separate enzymatic systems are called the endocannabinoid system (ECS). The ECS is a major system in human and the CB1 and CB2 receptors are expressed within the CNS and several peripheral organs including heart, liver, fat, skin, eye and the intestines [22].
As details about the ECS emerged during the 1990s and into this century, it has become apparent that endocannabinoids interact with several neurotransmitter systems and play an important role in regulating physiological functions. Autoradiographic localization of cannabinoid receptors in the rat established the rich co-localization of cannabinoid receptors with GABA-containing neurons [23, 24]. It has been reported that GABA is produced and released by inhibitory interneurons comprising between 20–60% of neurons in some areas of the brain [25]. The CB1 and CB2 receptors have been found to be highly expressed in areas rich with GABA neurons including the cortex, basal ganglia, substantia nigra and cerebellum. Compared to classic neurotransmitters including GABA and Glutamate [24, 26], the ECS is far more abundant and widely distributed compared to these systems. Thus, activation of the CB1 receptor (the most abundant GPCR in the CNS) interacts with adjacent neurons including GABA and regulates neurotransmitter function to express their central effects.
The ECS is also one of the most pleiotropic systems in mammals and differs from other neurotransmitter systems in several ways. Importantly, most intercellular transmission proceeds anterograde with the release of neurotransmitters from presynaptic neurons that bind to receptors on the postsynaptic membranes. Neurotransmitters, stored in vesicles within the presynaptic cytosol, are released as chemical messengers upon activation of the presynaptic neuron. After release into the synapse, the chemical messengers are subsequently broken down in the synaptic cleft or taken up by transport systems into the neuron or adjacent supporting cells [27].
Endocannabinoids act in the opposite direction from a postsynaptic neuron to presynaptic neuron. This retrograde direction allows the ECS to neuromodulate the forward direction of chemical communication. Because of their highly lipophilic properties, endocannabinoids are not stored in vesicles but are synthesized from membrane lipids only when required. Once released, the endocannabinoid diffuses to its’ receptor target on the presynaptic neuron and helps regulate overall neurotransmission. In the brain, the presynaptic receptor is predominantly CB1 with limited CB2 found in microglia and other tissue. Eventually the endocannabinoid is released by the receptor and taken up by either the pre- or postsynaptic neuron for final degradation [17].
The endocannabinoids are synthesized in the post-synaptic membrane only after the cell is activated and then rapidly degraded after binding to the presynaptic cannabinoid receptor, the effect of stimulation is localized and limited in duration similar to GABA and other neurotransmitters. In addition, although these actions occur binding of AEA and 2-AG primarily to the CB1 receptor in the brain, other non-cannabinoid receptors have also been identified that directly bind and are activated by endocannabinoids [28].
Anandamide (AEA) was isolated from pig brain in 1992 and found to be a derivative of the fatty acid arachidonic acid. As the first endocannabinoid to be discovered, the molecule was named anandamide after the Sanskrit word Ananda that means bliss [29]. As a member of the N-acylethanolamines, it was established that AEA shared multiple synthetic pathways with other glycophospholipids [17].
Typical of other neurotransmitters, AEA functions as a chemical messenger between neurons. However, there are significant differences between endocannabinoids and neurotransmitters including GABA. Soon after its discovery, the uniqueness of AEA was established with the observation that the messenger was synthesized only on demand and diffuse across the synaptic cleft in a retrograde direction to the presynaptic neuron [17].
Following the inflow of calcium2+ into the postsynaptic cell, AEA is synthesized from the precursor membrane lipid N-arachidonyl-phosphatidylethanolamine (NAPE). NAPE is present in brain only in small amounts and cannot sustain prolonged synthesis of AEA. As with 2-AG, AEA contains arachidonic acid and combines this membrane constituent with phosphatidylethanolamine (PE), utilizing a calcium2+ dependent enzyme N-acyltransferase (NAT). The primary pathway for synthesis of anandamide is conversion of NAPE to anandamide through the action of a NAPE-specific phospholipase D (PLD), although several other pathways are known to exist. Similar to other synthesis in the NAE family, the NAPE pathway is not exclusive for AEA. Although the importance of other pathways have yet to be established, it is known that in genetically modified mice without NAPE-PLD, no reduction of the production of AEA is found [30].
Since multiple pathways may be associated with the synthesis of AEA, the abundance of choices has been suggested to enhance the number of stimuli that may initiate the production of AEA. Lipopolysaccharide (LPS), for example, is an endotoxin in the outer membrane of gram-negative bacteria that plays a critical role in the protection of the microbe. Exposure to macrophages activates LPS to defend the bacteria and numerous lipid mediators including AEA are released. The synthesis and release of AEA and the other bioactive lipids is not believed to occur through the intermediate NAPE but rather through the secondary pathways that lead to AEA [20].
The breakdown of AEA results in the release of arachidonic acid and ethanolamine. Within the post-synaptic cell, an intracellular serine amidase named fatty acid amide hydrolase (FAAH) cleaves the long-chain fatty acid of AEA although other available hydrolytic enzyme systems in the cytosol appear to have little effect on AEA. Numerous studies have used disruption of this serine hydrolase through genetic or pharmacological manipulation to increase AEA activity. Manipulation of the FAAH system has already become the target of new drug development in an attempt to increase AEA in the treatment of human pathology [31, 32].
Other non-hydrolytic enzymes also break down AEA including lipoxygenases and cyclooxygenases. These non-FAAH systems are very active at non-cannabinoid receptors although their importance in deactivation of AEA at cannabinoid receptors has yet to be determined [20].
AEA is not the only ethanolamide that can bind to cannabinoid receptors. Other bioactive lipids in this class include numerous compounds including palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) bind to the CB1 receptor. Each of these ligands has distinctive physiological effects associated with them. PEA is associated with several indications including use as an anti-inflammatory or analgesic, while OEA appears useful as an appetite suppressant to reduce body weight [33, 34].
Both PEA and OEA are polyunsaturated fatty acids with multiple double bonds within the long chain. Other polyunsaturated fatty acids have also been reported to have agonist activity for the cannabinoid receptors. Only AEA, among the saturated and monounsaturated fatty acids, has been found to have affinity for the cannabinoid receptors.
2-arachidonylglycerol (2-AG) is a monoacylglycerol that incorporates arachidonic acid at the 2 position of the glycerol backbone. This molecule serves the dual function of a lipid intermediary while also functioning as a chemical messenger within the ECS. Although this endocannabinoid was discovered later than AEA, 2-AG is several hundred fold more common in the CNS compared to AEA and is a full agonist to both the CB1 and CB2 receptors.
There are two major pathways for the synthesis of 2-AG. Similar to AEA, initiation of the process to manufacture 2-AG requires an inflow of calcium2+ into the neuron. The primary pathway for synthesis involves a precursor, phosphatidylinositol, converted by phospholipaseβ or phospholipaseγ, to the intermediary lipid 1,2-diacylglycerol (1,2-DAG). The 1,2-DAG is then hydrolyzed by a DAG lipase to form the endocannabinoid 2-AG.
There is a secondary pathway also available that involves the production of the intermediary 2-arachidonyl lysophospholipid. Once 2-arachidonyl lysophospholipid is available, this lysophospholipid in the presence of the enzyme lysophosphotase-C (LYSOPLC) is rapidly converted to 2-AG.
The breakdown of 2-AG also occurs through a primary pathway but several minor alternatives are also present. Hydrolysis of 2-AG by monoacylglycerol lipase (MAGL) is the most common pathway and involves the cleavage of the ester bond within the 2-AG structure to form arachidonic acid and glycerol. There are at least two forms of MAGL that have been found in rodent and rabbit models. In comparison to the small amounts of AEA and its associated degradative enzymes, 2-AG is widely distributed throughout the CNS along with its synthetic and degradative enzymes. Perhaps because of the breadth of distribution of 2-AG in the CNS, some overlap with AEA occurs. However, a more important distinction is that MAGL is found only in the presynaptic neuron and degradation of 2-AG occurs after release from the presynaptic cannabinoid receptor. AEA, in comparison, after its release from the presynaptic cannabinoid receptor must traverse the synaptic cleft and enter the postsynaptic neuron where it is broken down by the NAE degrading enzyme FAAH [17, 35, 36].
The development of genetically modified mice deficient in MAGL along with the synthesis of MAGL inhibitors have provided useful tools to study the properties of 2-AG. Use of these ligands that block the synthesis of MAGL have revealed elevations of this endocannabinoid, especially in the brain and to a lesser extent multiple organs in the body including the heart, liver, kidney, and brown adipose tissue. Although 2-AG is the major endocannabinoid that binds to the cannabinoid receptors in brain, it clearly also serves an important role in the the regulation of chemical signaling in other organ systems. When the breakdown of 2-AG appears is impaired due to these receptor anatagonists or genetic manipulations, arachidonic acid is significantly reduced in the brain. This suggests that the production of 2-AG serves an important role not just in the formation of an endocannabinoid but also in the in the production of proinflammatory molecules [37].
Other alternative routes for 2-AG degradation are also available. Cycloxygenase-2 (COX-2) and lipoxygenases are secondary enzyme systems that also reduce 2-AG. COX-2 serves an important role in the inflammatory process and converts arachidonic acid to prostaglandins. Lipoxygenases oxidizes polyunsaturated fatty acids and these are non-heme, iron-containing enzymes that are found in a broad range of eukaryotes. They are known to be involved in the metabolism of the eicosanoids including the prostaglandins [37].
In the 1990s, the phenomenon of “depolarization-induced suppression of inhibition” (DSI) was first reported in the purkinje cells of the cerebellum [38] and later in hippocampal pyramidal cells [39]. DSI occurs through the activation of the CB1 receptor and is considered the classic example how endocannabinoids regulate neuronal behavior through retrograde signaling and suppression of GABA release. The CB1 receptor is densely expressed on the GABA presynaptic neurons that are abundantly found in the cerebral cortex, hippocampus and amygdala and are essential for higher cortical functions including learning and memory. Small interneurons release GABA and communicate with the larger purkinje cells and pyramidal neurons. This interaction moderated by the release of GABA results in hyperpolarization of the larger post-synaptic cell and subsequent inactivation. Activation of the CB1 receptor located on the presynaptic interneuron inhibits the release of GABA and thus suppresses the inhibition of the larger cells. It is now well established that this inhibition of GABA release from the interneuron is the result of retrograde communication from the activated postsynaptic cell to the presynaptic GABA-containing interneurons through the release of endocannabinoids that facilitate an increase of intracellular calcium2+ and the initiation of the DSI. Other cannabinoid agonists in addition to endocannabinoids are also known to block interneuron release of GABA through depolarization-induced suppression of inhibition. Presynaptic CB1 antagonists, such as rimonabant, have also been reported to block the effect of CB1 receptor activation further establishing the critical role of retrograde modulation of chemical signaling through the ECS [22]. Thus, inhibition of GABA release is governed through depolarization of the presynaptic neuron by endocannabinoid binding to the presynaptic CB1 receptor [40, 41].
A few years after the discovery of DSI, presynaptic stimulation of CB1 through retrograde transmission of endocannabinoids was found to also occur with excitatory neurons and the phenomenon was termed “depolarization induced suppression of excitation”(DSE). Unlike DSI and the inhibition of GABA release, DSE inhibits the release of excitatory neurotransmitters including glutamate through a similar retrograde release of endocannabinoids. Although initially discovered the inactivation of Purkinje cells, DSE has also been observed in other regions of the brain although the role of endocannabinoids in these areas is less well established [42].
Dependent upon the presynaptic neurotransmitter, stimulation of presynaptic CB1 receptor through retrograde release of endocannabinoids moderates the communication between cells. This changing effect of the endocannabinoids on GABA and glutamate release and the shaping of synapses occrs through a process called synaptic plasticity. Activation of a single synapse is usually insufficient to activate the post-synaptic cell and multiple synapses must fire simultaneously. The coordination and magnitude of the synaptic communication determines the change of voltage in the post-synaptic cell and the strength of the signal. Reductions in the number of presynaptic cells or incoordination of firing results in weakening of the signal.
The strengthening of synapses over time is termed long term potentiation and requires coordination of firing of the pre and post synaptic cells within a window of 20 msec. Cellular firing outside the temporal window weakens the synapse and reduces the voltage difference over time and is referred to as long term depression.
There is a balance in the regulation of excitation and inhibition that allows the brain to physically adapt for learning and memory [43]. Generally these changes are incremental and occur continuously at the synaptic level through a process termed synaptic plasticity [44].
Although glutamate has received a great deal of attention in the process of neuroplasticity, GABA also plays an important, or perhaps equal, role in the adaptation of the nervous system. Changes in neuronal activity and excitation by glutamate release may initiate off-setting activation of inhibitory inputs through GABA interneurons. In both activation and inhibition of the synaptic signal, retrograde release of endocannabinoids through DSI and DSE likely mediates synaptic depression [43].
The endocannabinoid system maintains homeostatsis in the CNS primarily through activation of the CB1 receptor. This receptor is also responsible for the well-known behavioral and physiological effects of the phytocannabinoids. The mechanism of how this modulation of the CNS occurs is by retrograde signaling through activation of the CB1 receptor. As noted earlier, the ECS and GABA neurons are collocated in many areas of the brain and this close proximity may explain how CB1 binding influences the GABA system. The cortex, hippocampus, hypothalamus and cerebellum are areas in the brain where this overlap of the ECS and GABA is especially prominent.
There are several preclinical studies that have examined the inhibition of GABA release in the presence of cannabinoid agonists. One early
Acute administration of the phytocannabinoid THC has also been studied. In an
Two other studies also evaluated the effect of THC on GABA release in rodent models. One evaluated THC alone and reported a dose-dependent reduction in GABA uptake in the rat globus pallidus [47, 48].
The abundance of CB1 receptors on presynaptic neurons and their relationship to the strength of inhibition was assessed in a study of cholecystokinin (CCK) expressing GABA interneurons in the hippocampus. Earlier studies had demonstrated that the number of ion-channel-forming AMPA receptors could predict the magnitude of the postsynaptic response [49, 50] and that more GABA receptors were associated with greater inhibition. However, CB1 receptors are GPCR and operate through different mechanisms including modulation of voltage-gated Ca2+ and K+ channels and second messenger systems. Using the CB1 receptor antagonist AM251, the effect of activation was measured in basket cells and dendritic-layer innervating (DLI) cells. Basket cells have a significant higher expression of CB1 receptors and DLI have significantly less receptor density. The CB1 receptor antagonist AM251 increased the action-potential inflow of Ca2 by 54% in basket cells but not in DLI. However, this increase was significantly reduced from the expected effect of the large number of receptors. A CB1 agonist decreased Ca2+ independent from the CB1 receptor expression. Collectively this suggests that only a subpopulation of CB1 receptors in close proximity to the Ca2+ channel participate in the endocannabinoid modulation of GABA release [51].
Another study evaluated the effect of exposure to cannabinoids in adolescent rats. Using electrophysiological and immunohistochemical techniques, early-, mid- and late adolescent rats were treated with a CB1 agonist (WIN). Early and middle adolescent rats were found to exhibit significant disinhibition of prefrontal cortex (PFC) behaviors at the later adult stage. This result was reversed when the adolescent rat was infused with the positive allosteric modulator GABAA agonist Indiplon. This response suggests that at certain stages of development exposure to cannabinoid agonists may be critical in the downregulation of GABA in the PFC and expressed in the adult stage of maturation [52].
A recent review summarized the literature on the interaction of endocannabinoids and neurotransmitters [22] although only a few have been reported for GABA. Administration orally or intravenously of the endogenous cannabinoid agonists including the endocannabinoids is technically difficult and their interpretation limited. On the other hand, phytocannabinoids can be smoked, ingested or applied as a topical with significant absorption and physiological effects mediated through cannabinoid receptors. In one report of adolescents, thirteen habitual users of cannabis were compared to sixteen non-canabis normal controls in a study using standard 1H MRS techniques performed on a MAGNETOM trio whole body MRI/MRS system to determine GABA metabolism in the anterior cingulate cortex (ACC) [53]. reported reduced levels of GABA in the anterior cingulate cortex (ACC) of adolescents that were habitual users of marijuana when compared to match controls. The ACC surrounds the anterior area of the corpus callosum and communicates with the prefrontal cortex and parietal lobe in addition to deeper limbic structures including the amygdala, nucleus accumbens and hippocampus. It is well established that GABA plays an important role in the maturation of these area in the adolescent brain and disruption of this process may result in neuropsychiatric and substance abuse issues later in life.
Results of the MRS scans revealed significantly lower levels of ACC GABA activity in adolescents that habitually used cannabis. Reduced ACC glutamate levels in adolescents that habitually used cannabis had been reported in an earlier study [54] with MRS imaging and in this follow-up report these findings paralleled the reduction in glutamate with a similar reduction of GABA.
Enhancement of GABA activity has been proposed as a therapeutic approach to the treatment of cannabis use. In one randomized clinical trial (RCT) fifty patients with cannabis dependency were treated with Gabapentin 1200 mg/day or placebo for twelve weeks. Compared to placebo, the study reported significant reduced use of cannabis measured by several assessments including urine drug screens. Gabapentin is a structural analog of GABA and was initially thought to act on the GABA system. Later studies demonstrated that Gabapentin does not alter GABA activity or receptors although it may increase GABA synthesis and non-synaptic GABA release [55].
In the first of two studies, the GABA reuptake inhibitor Tiagabine (Gabitril), was assessed in eight cannabis users and compared when combined with oral THC. THC was dosed at 30 mg p.o. and tiagabine at 6 and 12 mg p.o. Subjects were trained to use established drug-discriminationprocedures to identify placebo and drug conditions, blinded to the study condition and were informed they would receive placebo, THC and tiagabine, alone or in combination during the study. Tiagabine was found to enhance the discriminative-stimulus, self-report and performance results when given with THC and to produce similar outcomes when administered alone [56].
In a subsequent study the investigators replaced tiagabine with baclofen and repeated the trial. In contrast to tiagabine, baclofen is a selective GABAB agonist but has not effect on the GABAA. Results of both studies were similar suggesting that GABAB receptors are involved at least in part with the effect of elevated GABA on cannabinoid-related behaviors [57].
The authors commented that although GABAB enhanced the effects of THC, they could not rule out that accentuation of GABA at GABAA receptors could also contribute to the outcome.
In addition to evaluation of the ECS and GABA through pharmacological enhancement of GABA, an interesting clinical study reporting that pharmacological-induced deficiency of GABA increased the effects of THC in several psychiatric assessments. Using normal subjects, this double-blind, placebo-controlled study evaluated flumazenil, an antagonist and partial inverse agonist of the GABAa receptor, against intravenous THC or placebo. Blocking the GABAa receptor with flumazenil accentuated the psychological effects of THC including psychoses and anxiety and a decrease in the THC-induced P300 amplitude [58].
Through imaging studies of the ECS, manipulation of the synthesis and degradation of endocannabinoids, and pharmacological interventions much has been learned about the cannabinoids since the initial discovery of of the first cannabinoid receptor CB1 in 1988 [59]. The ECS plays a major role in the maturation and homeostatsis of the CNS and activation of the CB1 receptor is the primary initiating event. Modulation of other neurotransmitter systems including GABA can then occur through retrograde transmission [60].
Ligands other than the endocannabinoids also bind to CB1 and CB2 receptors and much can be learned through observation of the effects of these non-endocannabinoids. Although phytocannabinoids, evolved through time in the plant kingdom and differ significantly from endocannabinoids, the overlap in affinity for cannabinoid receptors offer additional means to study the modulation by the ECS and neurotransmitter systems.
Phytocannabinoids are produced in the plant
There are several large epidemiological studies of phytocannabinoid effects on the ECS. Although banned in many areas, Cannabis is the most used illicit drug globally with an estimated 3.8% (182.5 million) of the global population exposed to cannabis [62, 63]. Within the United States, the estimated exposure is even higher with 8.4% (22.2 million) of the population reported to have used cannabis in one year. With relaxation of laws and greater duration of use combined with the change in composition and potency of cannabis, real world studies can provide us important information in understanding the function of the ECS system and the effects of disruption of normal processes.
Among the most important epidemiological studies are reports of exposure to cannabis of pregnant women and the effects on their offspring. In a recent study it was estimated that 5.2% (115,000) of pregnant women are exposed during their preganancy. Some of these women likely use cannabis unaware of their pregnancy and inadvertently expose the first trimester fetus to THC when the nervous system is first initiated. Others may choose to use THC later in pregnancy believing it is a safe remedy for pregnancy-associated nausea and vomiting while neurotransmitter systems are evolving. Others may just believe that cannabis use is safe and be unaware of the potential hazard to the unborn [64].
As with many drugs, however, cannabinoids carry significant safety concerns for pregnant women and as a lipophilic molecule easily traverse the placenta into the fetal bloodstream. Animal studies have shown a clear association between cannabinoids and lower birth weight. In humans, several large, well-conducted studies have explored the short- and long-term effects on fetal, child and adolescents and possible teratogenicity of prenatal cannabis exposure on fetal development (Hurd et al. 2005).
The Ottawa Prenatal Prospective Study (OPPS) was a large, epidemiological study of 291 expectant, middle class Canadian women. Within this group of expectant mothers, 20% used cannabis sometime during their pregnancy. All subjects were evaluated during their pregnancy and for the first six years using standardiazed neuropsychological tools.
At birth, there were observations made of increased startle reflex in children exposed in utero to cannabis, but no significant change in weight or increased presence of congenital malformations. By age four, however, behavioral changes including decreased visual performance, attention, and memory were apparent. In older children, impaired executive function was reported [65, 66].
In 1991 a second longitudinal study named the Maternal Health Practices and Child Development Study (MHPCD) was reported on 519 expectant mothers and live born infants. Unlike the earlier study in Ottawa, expectant mothers were largely lower class economically with poorer prenatal care. Expectant mothers were evaluated at 4 and 7-month gestation offspring evaluated until young adulthood. Growth parameters including birth weight, head or chest circumference, and gestational age were analyzed at birth with no statistical differences noted between newborns with non-exposure in utero and in newborns with maternal use of cannabis. There was a small effect on decreased birth length in exposure the first two months and a positive effect on body weight with usage in the third trimester [67]. In a follow-up of the offspring in this study up to two decades later, prenatal maternal exposure to cannabis was found to result in a greater risk of cannabis use in their children at adolescence (38% before age 15). By age 22 in-utero cannabis-exposed children were more apt to not complete high school (54.4% vs. 37.2% in controls), be unemployed (67.6% vs. 52.1%) and more likely to have been arrested (56% vs. 27.3%) [68].
The Dunedin study was a third, and more controversial, project conducted in New Zealand on 1037 individuals followed from birth to 38 years. One measurement obtained over the course of the study was the evaluation of the association between cannabis use and neuropsychological outcomes. Neuropsychological assessments were obtained before the age when cannabis use occurred and changes studied. Cannabis use was obtained at age 13 and then at age 38 after a pattern of consistent use. It was found that there was an associated decline in IQ related to the frequency and length of exposure to cannabis. The greatest vulnerability appeared to occur with adolescent exposure. The authors found that persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, most significantly in the domains of executive functioning and processing speed. Study participants with more persistent cannabis dependence also showed greater IQ decline over the years, along with greater overall cognitive decline. Greater cognitive impairment was observed in those who began cannabis use in adolescence. The investigators also pointed out that cessation of cannabis use did not fully restore neuropsychological functioning in these adolescence-onset users [69, 70].
Another recent large, retrospective, cohort study of 661,617 pregnant women study conducted over six years in Ontario, Canada examined the association between self-reported cannabis use in pregnancy and any adverse maternal or perinatal outcomes. The investigators accounted for known confounding factors, such as tobacco use, in one of two cohorts by the use of a matched design analysis. The results showed that preterm birth rate, at less than 37 weeks’ gestation, for both the matched and unmatched cohorts were significantly higher in the women who reported cannabis use. The rate of preterm birth rate in the unmatched cohort was 12.0% in cannabis users, compared to 6.1% in nonusers. In the matched cohort, the rate of preterm birth was 10.2% in cannabis users versus 7.2% in nonusers. A continuous increase in relative risk of preterm birth from cannabis exposure was observed between 34 to 36 6/7 weeks’ and 28 to 31 6/7 weeks’ gestation, respectively. Because this type of increase was not observed for very preterm birth at less than 28 weeks’ gestation, it was conjectured that cannabis exposure may be more strongly associated with early and moderate preterm births versus very preterm births. Cannabis use in the subjects was also significantly associated with the following secondary outcomes: small for gestational age, placental abruption, transfer to neonatal intensive care, and 5-minute Apgar score of less than 4 [71].
Both the OPPS and MHPCD studies were consistent in demonstrating behavioral and cognitive impairment years after exposure to cannabis in-utero. The Dunedin study also reported decline in IQ related to cannabis exposure beginning in adolescence. Collectively, all three studies report important deficits that emerge over time in child and adolescent maturation. A limitation of these studies, however, is the continuing social acceptance of cannabis use and increasing potency of THC.
To provide more current information, an NIH-initiative, the Adolescent Brain Cognitive Development (ABCD) Study is ongoing. This is a national, multisite, longitudinal cohort study that is prospectively following subjects from childhood through adolescence to explore the effects of substance use such as cannabinoids, among other experiences, on neurocognitive development. There are, of course, many challenges associated with long epidemiologic studies. Aside from participant loss and difficulty maintaining controls, the constant flux in the content of cannabinoid products over the years, namely the significant increases in the ratio of THC to CBD, presents significant inconsistency in comparing these long studies or predicting current risk.
GABA is an amino acid concentrated within the CNS and is recognized as the major inhibitory neurotransmitter in the brain [1]. With the exception of a second, excitatory amino acid neurotransmitter glutamate, GABA is present in millimoles/gm in brain tissue compared to nanomolar/gm concentrations of the other classic neurotransmitters [72].
The physiological effects of GABA do not occur in isolation. The functional relationship beween the two systems begins after the release of GABA from an activated presynaptic neuron and stimulation of the postsynaptic cell. Endocannabinoids are then manufactured on-demand and released to bind to cannabinoid receptors on the presynaptic membrane terminating the release of GABA.
The CB1 receptor is highly expressed in several regions of the brain including the forebrain, amygdala, hippocampus, substantia nigra and cerebellum. This receptor is frequently in GABA containing neurons and this overlap allows for close coordination and interaction between the two systems. As a result, the ECS provides an important feedback to the GABA system and participates in the maturation of the CNS and the function of the adult brain [72, 73].
The GABA system and the ECS, similar to all neurotransmitters, are limited to brief synaptic activity at discrete locations and are quickly terminated through either enzymatic breakdown or reuptake mechanisms. GABA is stored in presynaptic vesicles and released after excitation by an action potential into the synapse to stimulate the postsynaptic cell. The endocannabinoids, in contrast, are synthesized in the postsynaptic membrane on demand only after the cell is stimulated. Upon release, the endocannabinoid moves in a retrograde direction across the synapse and binds to the CB1 receptor on the presynaptic neuron. Once the endocannabinoid is bound to the CB1 receptor, the release of neurotransmitters from the presynaptic neuron is terminated.
How endocannabinoids work in moderating GABA is introduced in the discussion of depolarization induced suppression of inhibition (DSI). This is a critical concept on how the chemical signal with GABA release is moderated by the activation of the CB1 receptor. Although less established, activation of this cannabinoid receptor may also activate another amino acid transmitter glutamate through a similar mechanism termed depolarization induced suppression of excitation (DSE).
Several preclinical studies of ECS and GABA in this chapter followed the initial papers on DSI and DSE and the concept of CB1 receptor activation influencing the release of GABA (and potentially glutamate). Although for technical reasons it has not been possible to study the effect of AEA and 2-AG directly, these studies chose to utilize several laboratory-created CB1 agonists under investigation or the phytocannabinoid THC. No matter the source of the agonist, the findings consistently found that stimulation of the CB1 receptor reduced the release of GABA.
From these studies it is apparent that activation of the CB1 receptor is not exclusive to endocannabinoids. As discussed earlier, the plant
Earlier in this chapter several large epidemiological studies were reviewed reporting the effects of cannabis on the development of the nervous system in utero to maturity. These studies are informative because they describe the effects of cannabinoids on the developing nervous system and adult where GABA plays an important role. From these reports it is likely that early maternal exposure to phytocannabinoids results in impairment in the offspring through disruption of the development of the nervous system with behavioral abnormalities appearing later in life [65, 68, 75, 76].
There are obvious limitations in large scale studies since In normal circumstances ECS and GABA collaborate in limited and localized coordination in development. Phytocannabinoids act systemically throughout the body and are not limited to discrete synapses. In addition, since phytocannabinoids are lipid soluble, sequestered in fat tissue, and broken down by hepatic enzymes, the location and duration of exposure to phytocannabinoids differs from the brief, focused synaptic interaction between GABA and the endocannabinoids. Nevertheless, these large studies of cannabis use provide important information on how phytocannabinoids may disrupt GABA function that may be reflected in the abnormalities reported in these larg scale studies. Cannabis is regarded by many as relatively ‘safe’ and is becoming ‘legal’ in many areas. However, other ‘safe’ and ‘legal’ drugs including nicotine and alcohol are associated with serious public health concerns. These studies give us insight into the possible risks associated with using phytocannabinoids and influencing the communication between GABA and the endocannabinoids.
The interaction of GABA and the ECS is important for normal physiological function. As our knowledge of this modulation of the CNS advances, additional knowledge and treatments will likely emerge that will provide unexpected benefits to patients. However, epidemiological studies of exposure to cannabis also provide important information they reveal the disadvantages and risks of disruption of the GABA-ECS systems. As increased access and duration of usage evolve, we will learn more of the benefits, and risks, of cannabiods.
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Heat stress decreases the secretion of luteinizing hormone and estradiol resulting in reduced length and intensity of estrus expression, increased incidence of anoestrus and silent heat in farm animals. Oocytes exposed to thermal stress lose its competence for fertilization and development into the blastocyst stage, which results in decreased fertility because of the production of poor quality oocytes and embryos. Furthermore, low progesterone secretion limits the endometrial functions, and subsequently embryo development. In addition, the increased secretion of endometrial prostaglandin F2 alpha during heat stress threatens the maintenance of pregnancy. In general, the percentage of conception rate was found to be reduced by 4.6% for each unit increase in temperature humidity index (THI) above 70, and heat stress during pregnancy further slows down the growth of the foetus and results in lower birth weight. In tropical and subtropical regions, during hot days, the testicular temperature may increase and impair both the spermatogenic cycle and semen quality, which culminates in decreased bull fertility. The effects of heat stress on livestock can be minimized via adapting suitable scientific strategies comprising physical modifications of the environment, nutritional management and genetic development of breeds that are less sensitive to heat stress. In addition, the summer infertility may be countered through advanced reproductive technologies involving hormonal treatments, timed artificial insemination and embryo transfer, which may enhance the chances for establishing pregnancy in farm animals.",book:{id:"5861",slug:"theriogenology",title:"Theriogenology",fullTitle:"Theriogenology"},signatures:"Govindan Krishnan, Madiajagan Bagath, Prathap Pragna,\nMallenahally Kusha Vidya, Joy Aleena, Payyanakkal Ravindranathan\nArchana, Veerasamy Sejian and Raghavendra Bhatta",authors:[{id:"89780",title:"Dr.",name:"Veerasamy",middleName:null,surname:"Sejian",slug:"veerasamy-sejian",fullName:"Veerasamy Sejian"},{id:"177210",title:"Dr.",name:"Raghavendra",middleName:null,surname:"Bhatta",slug:"raghavendra-bhatta",fullName:"Raghavendra Bhatta"},{id:"177220",title:"Dr.",name:"M",middleName:null,surname:"Bagath",slug:"m-bagath",fullName:"M Bagath"},{id:"201967",title:"Dr.",name:"Govindan",middleName:null,surname:"Krishnan",slug:"govindan-krishnan",fullName:"Govindan Krishnan"},{id:"201968",title:"Ms.",name:"Archana",middleName:null,surname:"Pr",slug:"archana-pr",fullName:"Archana Pr"},{id:"201969",title:"Ms.",name:"Pragna",middleName:null,surname:"Prathap",slug:"pragna-prathap",fullName:"Pragna Prathap"},{id:"201970",title:"Ms.",name:"Aleena",middleName:null,surname:"Joy",slug:"aleena-joy",fullName:"Aleena Joy"},{id:"201971",title:"Dr.",name:"Vidya",middleName:null,surname:"Mk",slug:"vidya-mk",fullName:"Vidya Mk"}]},{id:"55006",doi:"10.5772/intechopen.68650",title:"Immunocastration as Alternative to Surgical Castration in Pigs",slug:"immunocastration-as-alternative-to-surgical-castration-in-pigs",totalDownloads:1931,totalCrossrefCites:11,totalDimensionsCites:22,abstract:"Surgical castration of piglets is a routine practice in pig production used to prevent the incidence of boar taint of pig meat, which may develop in entire male pigs as they reach puberty. This practice is being presently questioned in the European Union, and there is a strong initiative to end it. The initiative is presently voluntary; however, key stakeholders of European pig production sector have signed a declaration, and the actions undertaken by them already affect the business. Before such new concepts in pig production can be implemented, alternative solutions are needed, one of them being immunocastration. The present chapter will thus focus on the presentation of immunocastration as one of the promising alternatives to surgical castration. Theoretical and practical aspects of immunocastration in pig production will be described, and the advantages and disadvantages of this alternative will be summarised. Physiological principles of immunocastration and impacts on metabolism, growth performance, body composition and meat quality will be described and aspects of public acceptability reviewed.",book:{id:"5861",slug:"theriogenology",title:"Theriogenology",fullTitle:"Theriogenology"},signatures:"Marjeta Čandek-Potokar, Martin Škrlep and Galia Zamaratskaia",authors:[{id:"23161",title:"Dr.",name:"Marjeta",middleName:null,surname:"Čandek-Potokar",slug:"marjeta-candek-potokar",fullName:"Marjeta Čandek-Potokar"},{id:"198220",title:"Dr.",name:"Martin",middleName:null,surname:"Škrlep",slug:"martin-skrlep",fullName:"Martin Škrlep"},{id:"198221",title:"Prof.",name:"Galia",middleName:null,surname:"Zamaratskaia",slug:"galia-zamaratskaia",fullName:"Galia Zamaratskaia"}]},{id:"55696",doi:"10.5772/intechopen.69444",title:"Estrus Cycle Monitoring in Wild Mammals: Challenges and Perspectives",slug:"estrus-cycle-monitoring-in-wild-mammals-challenges-and-perspectives",totalDownloads:1888,totalCrossrefCites:0,totalDimensionsCites:6,abstract:"The knowledge of reproductive physiology is of paramount importance to guide reproductive management and to make possible future application of assisted reproduction techniques (ARTs) aiming ex situ conservation of wild mammals. Nevertheless, information on the basic reproductive aspects of wild mammals remain scarce, and appropriate management practices have not yet been developed for all the species. This chapter discusses the methods most currently used for reproductive monitoring in wild females. Additionally, the difficulties regarding their use in different species and the possibilities of these procedures in captivity or in free-living mammals are addressed.",book:{id:"5861",slug:"theriogenology",title:"Theriogenology",fullTitle:"Theriogenology"},signatures:"Alexandre R. Silva, Nei Moreira, Alexsandra F. Pereira, Gislayne C.X.\nPeixoto, Keilla M. Maia, Lívia B. Campos and Alana A. Borges",authors:[{id:"90066",title:"Dr.",name:"Alexandre",middleName:"Rodrigues",surname:"Silva",slug:"alexandre-silva",fullName:"Alexandre Silva"},{id:"177090",title:"Dr.",name:"Alexsandra Fernandes",middleName:null,surname:"Pereira",slug:"alexsandra-fernandes-pereira",fullName:"Alexsandra Fernandes Pereira"},{id:"177093",title:"MSc.",name:"Gislayne Christianne Xavier",middleName:null,surname:"Peixoto",slug:"gislayne-christianne-xavier-peixoto",fullName:"Gislayne Christianne Xavier Peixoto"},{id:"198314",title:"Prof.",name:"Nei",middleName:null,surname:"Moreira",slug:"nei-moreira",fullName:"Nei Moreira"},{id:"198315",title:"MSc.",name:"Keilla Moreira",middleName:null,surname:"Maia",slug:"keilla-moreira-maia",fullName:"Keilla Moreira Maia"},{id:"198316",title:"MSc.",name:"Lívia Batista",middleName:null,surname:"Campos",slug:"livia-batista-campos",fullName:"Lívia Batista Campos"},{id:"198317",title:"MSc.",name:"Alana Azevedo",middleName:null,surname:"Borges",slug:"alana-azevedo-borges",fullName:"Alana Azevedo Borges"}]},{id:"56522",doi:"10.5772/intechopen.69549",title:"Role of Melatonin in Reproductive Seasonality in Buffaloes",slug:"role-of-melatonin-in-reproductive-seasonality-in-buffaloes",totalDownloads:1772,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Buffaloes are characterized by seasonal reproductive activity. Anestrus buffalo heifers and lactating buffaloes were used to study the effect of melatonin treatment on the resumption of ovarian activity during out-of-breeding season. Buffaloes of treated group were injected or implanted with melatonin (18 mg melatonin/50 kg body weight). Using CIDR-eCG protocol preceded with melatonin successfully achieved estrus behavior and induced conception rate during out-of-breeding season. Furthermore, the reproductive performance of buffaloes during out-of-breeding season was clearly improved by melatonin implantation in conjunction with CIDR-eCG protocol due to the luteotrophic effect of melatonin expressed as increasing diameter of CL (corpus luteum) and progesterone concentration. This improvement resulted in greater values of conception rate, in melatonin implanted compared to not implanted buffaloes. Melatonin implantation in anestrus buffalo heifers increased the diameter of largest follicles and melatonin concentration but progesterone and luteinizing hormone (LH) concentrations were decreased. In addition, melatonin implantation in anestrus lactating buffaloes increased the SOD (superoxide dismutase) enzyme activity. Sustained release of exogenous melatonin significantly protects against oxidative stress while increasing beneficial total antioxidant capacity (TAC) concentration in summer-stressed anestrus buffaloes. Melatonin implantation in conjunction with CIDR-eCG protocol successfully improved some blood metabolites, in anestrus buffalo heifers during out-of-breeding season under tropical conditions.",book:{id:"5861",slug:"theriogenology",title:"Theriogenology",fullTitle:"Theriogenology"},signatures:"Tamer Awad Ramadan",authors:[{id:"197651",title:"Dr.",name:"Tamer",middleName:"Awad",surname:"Ramadan",slug:"tamer-ramadan",fullName:"Tamer Ramadan"}]},{id:"54974",doi:"10.5772/intechopen.68651",title:"Markers for Sperm Freezability and Relevance of Transcriptome Studies in Semen Cryopreservation: A Review",slug:"markers-for-sperm-freezability-and-relevance-of-transcriptome-studies-in-semen-cryopreservation-a-re",totalDownloads:1618,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"Advances in sperm assessment techniques have offered new perspectives to improve the technology of semen cryopreservation. This review addresses some recent achievements in the proteomics of seminal plasma and spermatozoa and exemplifies its importance as markers for sperm fertility following cryopreservation. Recent advances in transcriptome studies on sperm RNA-Seq data have generated new information aimed to unravel the physiological roles of RNAs in the sperm-egg fertilization processes and their associations with male fertility. The relevance of the sperm freezability markers and the potential associations of RNA-profiling sequences with the sperm biological functions have been discussed.",book:{id:"5861",slug:"theriogenology",title:"Theriogenology",fullTitle:"Theriogenology"},signatures:"Leyland Fraser",authors:[{id:"199650",title:"Dr.",name:"Leyland",middleName:null,surname:"Fraser",slug:"leyland-fraser",fullName:"Leyland Fraser"}]}],mostDownloadedChaptersLast30Days:[{id:"79344",title:"Epidemiology of Bovine Mastitis and Its Diagnosis, Prevention, and Control",slug:"epidemiology-of-bovine-mastitis-and-its-diagnosis-prevention-and-control",totalDownloads:312,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Mastitis is an inflammation of mammary glands that is prevalent in dairy bovines. It causes a significant proportion of economic losses to the dairy farmers in India. Cattle and buffalo farming contribute significantly to the economy of the state. Various infectious agents such as bacteria, fungi, and algae may cause mastitis. Hence, it is essential to understand the etiological agents and predisposing factors that lead to mastitis in susceptible bovine populations in Madhya Pradesh state so that appropriate prevention and control strategies can be implemented. In this chapter, epidemiology, diagnosis, prevention, and control measures of mastitis in general and in India, the state of Madhya Pradesh, in particular, will be presented.",book:{id:"10589",slug:"mastitis-in-dairy-cattle-sheep-and-goats",title:"Mastitis in Dairy Cattle, Sheep and Goats",fullTitle:"Mastitis in Dairy Cattle, Sheep and Goats"},signatures:"S.D. Audarya, D. Chhabra, R. Sharda, R. Gangil, R. Sikrodia, J. Jogi and N. Shrivastava",authors:[{id:"291434",title:"Dr.",name:"N.",middleName:null,surname:"Shrivastav",slug:"n.-shrivastav",fullName:"N. Shrivastav"},{id:"317236",title:"Dr.",name:"S.D.",middleName:null,surname:"Audarya",slug:"s.d.-audarya",fullName:"S.D. Audarya"},{id:"344698",title:"Dr.",name:"D.",middleName:null,surname:"Chhabra",slug:"d.-chhabra",fullName:"D. Chhabra"},{id:"344699",title:"Dr.",name:"R.",middleName:null,surname:"Sharda",slug:"r.-sharda",fullName:"R. Sharda"},{id:"344700",title:"Dr.",name:"R.",middleName:null,surname:"Gangil",slug:"r.-gangil",fullName:"R. Gangil"},{id:"344702",title:"Dr.",name:"R.",middleName:null,surname:"Sikrodia",slug:"r.-sikrodia",fullName:"R. Sikrodia"},{id:"344703",title:"Dr.",name:"J.",middleName:null,surname:"Jogi",slug:"j.-jogi",fullName:"J. Jogi"}]},{id:"55696",title:"Estrus Cycle Monitoring in Wild Mammals: Challenges and Perspectives",slug:"estrus-cycle-monitoring-in-wild-mammals-challenges-and-perspectives",totalDownloads:1886,totalCrossrefCites:0,totalDimensionsCites:6,abstract:"The knowledge of reproductive physiology is of paramount importance to guide reproductive management and to make possible future application of assisted reproduction techniques (ARTs) aiming ex situ conservation of wild mammals. Nevertheless, information on the basic reproductive aspects of wild mammals remain scarce, and appropriate management practices have not yet been developed for all the species. This chapter discusses the methods most currently used for reproductive monitoring in wild females. Additionally, the difficulties regarding their use in different species and the possibilities of these procedures in captivity or in free-living mammals are addressed.",book:{id:"5861",slug:"theriogenology",title:"Theriogenology",fullTitle:"Theriogenology"},signatures:"Alexandre R. Silva, Nei Moreira, Alexsandra F. Pereira, Gislayne C.X.\nPeixoto, Keilla M. Maia, Lívia B. Campos and Alana A. Borges",authors:[{id:"90066",title:"Dr.",name:"Alexandre",middleName:"Rodrigues",surname:"Silva",slug:"alexandre-silva",fullName:"Alexandre Silva"},{id:"177090",title:"Dr.",name:"Alexsandra Fernandes",middleName:null,surname:"Pereira",slug:"alexsandra-fernandes-pereira",fullName:"Alexsandra Fernandes Pereira"},{id:"177093",title:"MSc.",name:"Gislayne Christianne Xavier",middleName:null,surname:"Peixoto",slug:"gislayne-christianne-xavier-peixoto",fullName:"Gislayne Christianne Xavier Peixoto"},{id:"198314",title:"Prof.",name:"Nei",middleName:null,surname:"Moreira",slug:"nei-moreira",fullName:"Nei Moreira"},{id:"198315",title:"MSc.",name:"Keilla Moreira",middleName:null,surname:"Maia",slug:"keilla-moreira-maia",fullName:"Keilla Moreira Maia"},{id:"198316",title:"MSc.",name:"Lívia Batista",middleName:null,surname:"Campos",slug:"livia-batista-campos",fullName:"Lívia Batista Campos"},{id:"198317",title:"MSc.",name:"Alana Azevedo",middleName:null,surname:"Borges",slug:"alana-azevedo-borges",fullName:"Alana Azevedo Borges"}]},{id:"76529",title:"Mastitis in Small Ruminants",slug:"mastitis-in-small-ruminants",totalDownloads:226,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Bacterial mastitis in small ruminants is a complex disease, with massive economic loss in dairy sheep/goat industry due to poor productivity. The current mastitis prevention strategy relies on culling of infected ewes or does and or the use of antimicrobial agents to eliminate the bacterial infection. This has a potential risk for developing antibiotic resistant bacteria, posing human health risk from consumption of raw sheep or goat dairy products. Existing experimental and licensed vaccines on the market are ineffective against reducing the risk of mastitis in herds or flocks. Raising the needs for development of improved vaccines against mastitis for use in sheep and goats. This review examines, current understanding of the pathological processes and immunological responses against bacterial mastitis, using S. aureus as an example. By highlighting the protective defense mechanism induced in the udder against S. aureus mastitis. Based on evidence from published studies on pathological process and protective immune response mechanism, the need for improved vaccines for prevention of mastitis in small ruminant is highlighted and the development of a vaccine capable of enhancing immune response mechanism, that reduce the establishment of intramammary infection through induction of local IgA, IgG2 and Th17 immune responses is proposed.",book:{id:"10589",slug:"mastitis-in-dairy-cattle-sheep-and-goats",title:"Mastitis in Dairy Cattle, Sheep and Goats",fullTitle:"Mastitis in Dairy Cattle, Sheep and Goats"},signatures:"Christine T. Mwenge Kahinda",authors:[{id:"335924",title:"Dr.",name:"Christine T.",middleName:"Christine",surname:"Mwenge Kahinda",slug:"christine-t.-mwenge-kahinda",fullName:"Christine T. Mwenge Kahinda"}]},{id:"55491",title:"Mitigation of the Heat Stress Impact in Livestock Reproduction",slug:"mitigation-of-the-heat-stress-impact-in-livestock-reproduction",totalDownloads:4337,totalCrossrefCites:10,totalDimensionsCites:24,abstract:"Heat stress affects the fertility and reproductive livestock performance by compromising the physiology reproductive tract, through hormonal imbalance, decreased oocyte quality and poor semen quality, and decreased embryo development and survival. Heat stress decreases the secretion of luteinizing hormone and estradiol resulting in reduced length and intensity of estrus expression, increased incidence of anoestrus and silent heat in farm animals. Oocytes exposed to thermal stress lose its competence for fertilization and development into the blastocyst stage, which results in decreased fertility because of the production of poor quality oocytes and embryos. Furthermore, low progesterone secretion limits the endometrial functions, and subsequently embryo development. In addition, the increased secretion of endometrial prostaglandin F2 alpha during heat stress threatens the maintenance of pregnancy. In general, the percentage of conception rate was found to be reduced by 4.6% for each unit increase in temperature humidity index (THI) above 70, and heat stress during pregnancy further slows down the growth of the foetus and results in lower birth weight. In tropical and subtropical regions, during hot days, the testicular temperature may increase and impair both the spermatogenic cycle and semen quality, which culminates in decreased bull fertility. The effects of heat stress on livestock can be minimized via adapting suitable scientific strategies comprising physical modifications of the environment, nutritional management and genetic development of breeds that are less sensitive to heat stress. In addition, the summer infertility may be countered through advanced reproductive technologies involving hormonal treatments, timed artificial insemination and embryo transfer, which may enhance the chances for establishing pregnancy in farm animals.",book:{id:"5861",slug:"theriogenology",title:"Theriogenology",fullTitle:"Theriogenology"},signatures:"Govindan Krishnan, Madiajagan Bagath, Prathap Pragna,\nMallenahally Kusha Vidya, Joy Aleena, Payyanakkal Ravindranathan\nArchana, Veerasamy Sejian and Raghavendra Bhatta",authors:[{id:"89780",title:"Dr.",name:"Veerasamy",middleName:null,surname:"Sejian",slug:"veerasamy-sejian",fullName:"Veerasamy Sejian"},{id:"177210",title:"Dr.",name:"Raghavendra",middleName:null,surname:"Bhatta",slug:"raghavendra-bhatta",fullName:"Raghavendra Bhatta"},{id:"177220",title:"Dr.",name:"M",middleName:null,surname:"Bagath",slug:"m-bagath",fullName:"M Bagath"},{id:"201967",title:"Dr.",name:"Govindan",middleName:null,surname:"Krishnan",slug:"govindan-krishnan",fullName:"Govindan Krishnan"},{id:"201968",title:"Ms.",name:"Archana",middleName:null,surname:"Pr",slug:"archana-pr",fullName:"Archana Pr"},{id:"201969",title:"Ms.",name:"Pragna",middleName:null,surname:"Prathap",slug:"pragna-prathap",fullName:"Pragna Prathap"},{id:"201970",title:"Ms.",name:"Aleena",middleName:null,surname:"Joy",slug:"aleena-joy",fullName:"Aleena Joy"},{id:"201971",title:"Dr.",name:"Vidya",middleName:null,surname:"Mk",slug:"vidya-mk",fullName:"Vidya Mk"}]},{id:"79839",title:"Antimicrobial Usage for the Management of Mastitis in the USA: Impacts on Antimicrobial Resistance and Potential Alternative Approaches",slug:"antimicrobial-usage-for-the-management-of-mastitis-in-the-usa-impacts-on-antimicrobial-resistance-an",totalDownloads:176,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Mastitis is the most frequently diagnosed disease of dairy cattle responsible for the reduction in milk quantity and quality and major economic losses. Dairy farmers use antibiotics for the prevention and treatment of mastitis. Frequent antimicrobial usage (AMU) undeniably increased antimicrobial resistance (AMR) in bacteria from dairy farms. Antimicrobial-resistant bacteria (ARB) from dairy farms can spread to humans directly through contact with carrier animals or indirectly through the consumption of raw milk or undercooked meat from culled dairy cows. Indirect spread from dairy farms to humans can also be through dairy manure fertilized vegetables or run-off waters from dairy farms to the environment. The most frequently used antibiotics in dairy farms are medically important and high-priority classes of antibiotics. As a result, dairy farms are considered one of the potential reservoirs of ARB and antimicrobial resistance genes (ARGs). To mitigate the rise of ARB in dairy farms, reducing AMU by adopting one or more of alternative disease control methods such as good herd health management, selective dry-cow therapy, probiotics, and others is critically important. This chapter is a concise review of the effects of antimicrobials usage to control mastitis in dairy cattle farms and its potential impact on human health.",book:{id:"10589",slug:"mastitis-in-dairy-cattle-sheep-and-goats",title:"Mastitis in Dairy Cattle, Sheep and Goats",fullTitle:"Mastitis in Dairy Cattle, Sheep and Goats"},signatures:"Benti D. Gelalcha, Getahun E. Agga and Oudessa Kerro Dego",authors:[{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego"},{id:"332974",title:"Ph.D. Student",name:"Benti D.",middleName:"Deresa",surname:"Gelalcha",slug:"benti-d.-gelalcha",fullName:"Benti D. 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",coverUrl:"https://cdn.intechopen.com/series/covers/23.jpg",latestPublicationDate:"August 17th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"280770",title:"Dr.",name:"Katherine K.M.",middleName:null,surname:"Stavropoulos",slug:"katherine-k.m.-stavropoulos",fullName:"Katherine K.M. Stavropoulos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRdFuQAK/Profile_Picture_2022-05-24T09:03:48.jpg",biography:"Katherine Stavropoulos received her BA in Psychology from Trinity College, in Connecticut, USA and her Ph.D. in Experimental Psychology from the University of California, San Diego. She completed her postdoctoral work at the Yale Child Study Center with Dr. James McPartland. Dr. Stavropoulos’ doctoral dissertation explored neural correlates of reward anticipation to social versus nonsocial stimuli in children with and without autism spectrum disorders (ASD). She has been a faculty member at the University of California, Riverside in the School of Education since 2016. Her research focuses on translational studies to explore the reward system in ASD, as well as how anxiety contributes to social challenges in ASD. She also investigates how behavioral interventions affect neural activity, behavior, and school performance in children with ASD. She is also involved in the diagnosis of children with ASD and is a licensed clinical psychologist in California. 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He graduated from the Physics Department of the University of Crete and continued his post-graduate studies at the University Paris 7-Denis Diderot (D.E.A. in Didactic of Physics), University Paris 5-René Descartes-Sorbonne (D.E.A. in Science Education) and received his Ph.D. degree at the University Paris 5-René Descartes-Sorbonne (PhD in Science Education). His research interests include science education in early childhood, science teaching and learning, e-learning, the use of ICT in science education, games simulations, and mobile learning. He has published over 120 articles in international conferences and journals and has served on the program committees of numerous international conferences.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorTwo:{id:"422488",title:"Dr.",name:"Maria",middleName:null,surname:"Ampartzaki",slug:"maria-ampartzaki",fullName:"Maria Ampartzaki",profilePictureURL:"https://mts.intechopen.com/storage/users/422488/images/system/422488.jpg",biography:"Dr Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education. She also has the experience of participating in five Erasmus+ projects.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorThree:null},{id:"90",title:"Human Development",coverUrl:"https://cdn.intechopen.com/series_topics/covers/90.jpg",isOpenForSubmission:!0,editor:{id:"191040",title:"Dr.",name:"Tal",middleName:null,surname:"Dotan Ben-Soussan",slug:"tal-dotan-ben-soussan",fullName:"Tal Dotan Ben-Soussan",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBf1QAG/Profile_Picture_2022-03-18T07:56:11.jpg",biography:"Tal Dotan Ben-Soussan, Ph.D., is the director of the Research Institute for Neuroscience, Education and Didactics (RINED) – Paoletti Foundation. Ben-Soussan leads international studies on training and neuroplasticity from neurophysiological and psychobiological perspectives. As a neuroscientist and bio-psychologist, she has published numerous articles on neuroplasticity, movement and meditation. She acts as an editor and reviewer in several renowned journals and coordinates international conferences integrating theoretical, methodological and practical approaches on various topics, such as silence, logics and neuro-education. 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He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. 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Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a scientist and Principal Investigator at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering the lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via artificial intelligence-based analyses of exosomal Raman signatures. Dr. Paul also works on spatial multiplex immunofluorescence-based tissue mapping to understand the immune repertoire in lung cancer. Dr. Paul has published in more than sixty-five peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award and the 2022 AAISCR-R Vijayalaxmi Award for Innovative Cancer Research. He is a senior member of the Institute of Electrical and Electronics Engineers (IEEE) and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"9",type:"subseries",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. 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