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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!
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"10151",leadTitle:null,fullTitle:"Technology, Science and Culture - A Global Vision, Volume II",title:"Technology, Science and Culture",subtitle:"A Global Vision, Volume II",reviewType:"peer-reviewed",abstract:"From the success of the first volume of this series, we are enthusiastic to continue our discussions on research topics related to the fields of Food Science, Intelligent Systems, Molecular Biomedicine, Water Science, and Creation and Theories of Culture. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"58321",title:"Urinary Tract Infections in Renal Transplant Recipients",doi:"10.5772/intechopen.72430",slug:"urinary-tract-infections-in-renal-transplant-recipients",body:'\n
Kidney transplantation is the renal replacement therapy of choice for the constantly increasing number of patients with end-stage renal disease (ESRD). The huge headway in immunosuppressive treatment has resulted in improved renal graft survival rates, at the same time making infectious complications an even more common problem in the renal transplant (RTx) population, with the urinary tract being the most prevalent infection site. Apart from immunodeficiency resulting from the use of immunosuppressive drugs, RTx patients often suffer from numerous urological malformations, vesicoureteral reflux (VUR) that is a permanent symptom after RTx, and are exposed to invasive diagnostic and therapeutic procedures involving the urinary tract. That is why urinary tract infections (UTIs) are the most common infectious complication among RTx recipients with up to 60% prevalence during the first year post-transplant [1, 2]. UTIs are important not only because of the scale of the problem but due to their potential negative influence on graft and RTx recipients’ outcomes.
\nUrinary tract infections (UTIs) are major causes of morbidity and hospitalization in renal transplant recipients. Infections, with the urinary tract as a major site, are the most common cause of acute kidney allograft injury, and prevalence of UTI-associated acute kidney injury far outnumbers episodes of acute rejection and calcineurin inhibitor toxicity [3].
\nThere is a wide variation in the reported incidence of UTIs, most likely associated with differences in the definition of UTI, length of follow-up and variation in the use of post-transplant antibiotic prophylaxis. In a recently published meta-analysis on the prevalence and predictive factors of UTI in patients undergoing renal transplantation that included 13 studies with a total of 3364 patients evaluated, 1033 (30.71%) had UTIs [4]. The included studies provided different estimates of prevalence, which ranged from 16.0 to 75.0%, and the pooled prevalence of UTIs was 38% (95% CI, 29–47%; p < 0.01). Of note, RTx recipients followed for 1–2 years had significantly higher prevalence than those followed for 2–5 years (34 vs. 43%).
\nAll UTIs can be classified into one of the four following categories:
Asymptomatic bacteriuria (AB), defined as isolation of bacterial strain in quantitative counts ≥105 CFU in a clean-catch voided urine specimen in the absence of any symptoms of lower or upper UTI or <105 CFU in patients treated with antibiotics or ≥103 CFU in a single catheterized urine specimen, irrespective of the presence of leukocyturia.
Lower UTI, which is the presence of bacteriuria and clinical manifestations of dysuria, frequency or urinary urgency and fever <38°C in the absence of acute graft pyelonephritis (AGPN) criteria.
Upper UTI (AGPN), defined by the presence of significant bacteriuria, fever >38°C and/or graft pain and/or acute graft function impairment.
Urosepsis—life-threatening organ dysfunction caused by a dysregulated host response to the upper UTI.
Recurrent infections are defined as 3 or more episodes of symptomatic UTIs over a 12-month period or 2 episodes in the previous 6 months and can be divided into:
Relapses: defined as the isolation of the same microorganism that caused the preceding infection in a urine culture obtained ≥2 weeks after finishing the previous treatment. The isolation of the same microorganism that caused the preceding infection in a urine culture obtained <2 weeks after finishing the previous treatment should be considered a treatment failure.
Reinfections: defined by a new episode of UTI with the isolation of an agent other than the one that caused the previous infection.
Definitions of multidrug-resistant (MDR) bacterial infections:
Criteria for multidrug-resistant (MDR) bacteria: non-susceptible to ≥1 agent in ≥3 antimicrobial categories or methicillin resistance in the case of
Criteria for extensively drug-resistant (XDR) bacteria: non-susceptible to ≥1 agent in all but ≤2 categories (i.e. bacterial isolates remain susceptible to only one or two categories).
Criteria for pan drug-resistant (PDR) bacteria: non-susceptible to all the antimicrobials.
Heteroresistance is defined as the presence of mixed populations of drug-resistant and drug-sensitive cells in a single clinical specimen.
Many factors are believed to contribute to the high incidence of UTI in RTx recipients. Some exist prior to transplant, including female gender, diabetes mellitus and underlying urinary tract abnormalities. Peri-transplant factors are often related to instrumentation of the urinary tract, including ureteral stenting and prolonged urinary catheterization. Additional risk factors contributing to UTI post-transplant include immunosuppression and graft dysfunction or rejection. It is noteworthy that so far no direct association has been found between the risk of UTI and dose or type of maintenance immunosuppression. It is the net state of immunosuppression that impairs host defense capability against infections in general. Various authors have suggested different potential UTI risk factors, and their findings are not always consistent. The potential pre-, peri- and post-transplant risk factors for UTI in RTx recipients are shown in Table 1.
\nPre-transplant | \nPeri-transplant | \nPost-transplant | \n
---|---|---|
Urine flow impairmentFemale genderDiabetesUrinary tract anomaliesGlomerulonephritis | \nUreteral stentsBladder instrumentationDeceased-donor graftsDouble kidney transplants | \nUrine flow impairment
| \n
Risk factors for UTI in renal transplant recipients.
Of note, significant urine flow impairment, both existing pre-transplant or appearing post-transplant, seems to be of major importance. The bladder outlet obstruction, particularly in males, may not be appreciated until after the transplant, leading to prolonged instrumentation and an increased risk of UTI. The likelihood of AGPN development is 20-fold higher in patients with vesicoureteral reflux (VUR) or strictures at the uretero-vesical junction or benign prostate hyperplasia (BPH). Active reflux has long been reported as being significantly associated with poor graft outcome [5]. In a study by Dupont et al., VUR was found in almost half of RTx patients with recurrent UTIs, and patients with VUR were more prone to develop renal scarring than those without VUR [6]. On the other hand, in a recent study by Margreiter et al., 40% of 646 consecutive RTx recipients were diagnosed with VUR by voiding cystourethrography, and VUR did not affect the occurrence of UTIs. Simple UTI was diagnosed in 24.7% of patients with VUR and 27.2% of patients without VUR (p = 0.78). Recurrent UTIs were noted in 4.2% (with VUR) versus 3.9% (without VUR) of the enrolled patients (p = 0.67). However, the authors did not analyze the incidence of UTI according to VUR grade [7]. In a retrospective cohort of 23,622 adult male primary RTx recipients, also benign prostate hyperplasia was independently associated with recurrent UTI [8]. Considering the significant influence of urinary flow abnormalities on the likelihood of AGPN development, we would strongly recommend examination for VUR or urine flow obstruction even at the first AGPN episode.
\nThe reports on the influence of UTIs on long-term kidney allograft function are inconsistent. The true impact of the whole spectrum of clinical manifestations of UTIs, on patient and graft outcome, so far has not been established. The general assumption is that asymptomatic bacteriuria (AB) is benign, as opposed to acute graft pyelonephritis or urosepsis. Still, the paucity of symptoms might be attributable to immunosuppression with actual ongoing inflammation of unrecognized significance. In one small study, kidney transplant patients with asymptomatic bacteriuria had elevated urine IL-8 level; and the authors hypothesized that this phenomenon may reflect an impaired immune response to bacterial infection and occult inflammatory process in the urinary tract [9]. Pellé et al. showed that acute graft pyelonephritis (AGPN) was an independent risk factor for the decline in renal function in a group of 172 RTx recipients [10]. Also a more recent study analyzing the effects of recurrent UTIs on graft and patient outcomes, in a population of 2469 RTx recipients, showed both poorer graft and patient survival in patients with a history of ≥3 UTIs in any 12-month period or ≥2 UTIs in any 6-month period, irrespective of the causative organism [11]. However other reports did not confirm this relationship. Not only asymptomatic bacteriuria but also AGPN did not affect long-term renal graft function prognosis [12, 13, 14, 15]. However, even if UTIs do not influence graft survival directly, they can pose a significant risk indirectly by leading to bacteraemia, acute rejection or cytomegalovirus (CMV) infection.
\nUTI after kidney transplantation is most often caused by Gram-negative organisms (around 50–90%), with
Beginning from the second month,
Proportion of different causative agents according to the type of UTI (a) during the first month post-transplant and (b) during 2–12 months post-transplant [
With the widespread use of antibiotics, including the routine use of antimicrobial prophylaxis in RTx recipients, the prevalence of multidrug resistance (MDR) among uropathogenic bacteria is increasing, irrespectively of region and country. The most widely accepted definition of MDR includes lack of susceptibility to one or more agents in three or more antimicrobial categories active against the isolated bacteria. Of note, also extensively drug-resistant (XDR) and pan drug-resistant (PDR) strains have been identified.
\nIn patients receiving trimethoprim-sulfamethoxazole prophylaxis, over 60% of UTIs have been reported as caused by trimethoprim-sulfamethoxazole-resistant organisms [19]. The treatment of AB has also been associated with antimicrobial resistance. In a study of patients with asymptomatic
It seems that immunosuppression may influence the resistance of enterococcal spp. to 𝛽-lactam-based antibiotics by affecting the expression of the penicillin-binding proteins (PBPs). In enterococcal strains isolated from RTx patients, the expression of the PBP5 gene was higher than in commensal strains. As cyclosporine seemed to promote higher expression of PBP5 than tacrolimus, 𝛽-lactam antibiotics may be more effective when tacrolimus-based immunosuppression protocols are implemented [22].
\nIn a recently published study analyzing recurrent UTIs in a cohort of 2469 RTx recipients, the authors found pronounced differences in antimicrobial resistance patterns between nonrecurrent and recurrent UTIs [11]. Isolates from the cases of recurrent UTIs were more likely to be resistant to first- and third-generation cephalosporins, trimethoprim-sulfamethoxazole, nitrofurantoin and fluoroquinolones, to extended-spectrum b-lactams and aminoglycosides.
\nIn a retrospective case series by Winters et al., 85% of solid-organ transplant recipients diagnosed with infection due to ESBL-producing bacteria received inadequate empiric therapy [23]. This means that all RTx recipients with a history of UTI due to ESBL-producing Gram-negative pathogens, presenting with symptoms of a new UTI, should receive an empiric therapy with a carbapenem until a urine culture result with susceptibility profile is available.
\nUTIs in RTx recipients may either be asymptomatic or have an atypical clinical presentation. Therefore the diagnosis based solely on clinical grounds may be of questionable accuracy. What is more, every symptomatic, either lower or upper UTI in any transplant recipient, is considered complicated: as it is associated with structural and functional abnormalities of the genitourinary tract and immunocompromised status that increases the risk for acquiring an infection or of failing therapy. For this reason urine cultures should be obtained in every single case, in order to base therapy upon susceptibility pattern determinations.
\nAsymptomatic bacteriuria is a frequent finding in kidney allograft recipients, with almost 40% incidence [16]. So far there are no evidence-based recommendations for screening and treatment of AB in renal transplant recipients, because sufficient data is lacking [24]. The American Society of Transplantation Infectious Diseases Guidelines recommend limiting screening to the first post-transplant month, but these recommendations are mostly expert opinion [25]. Fiorante et al. showed that the incidence of AGPN was significantly higher in patients with a history of multiple episodes of AB than in patients without, despite or due to the provided antibiotic treatment [26].
\nPatients with no episodes of AB seem to develop significantly fewer symptomatic infections than patients with a history of recurrent AB. As reinfections seem to outnumber relapses and only a very few episodes of symptomatic UTIs are preceded by AB with the same causative agent in patients with a history of recurrent AB, it seems that AB is more of a marker of increased susceptibility to infections, not a direct risk factor [16]. This is in agreement with the findings from a non-transplant population of young women, where the treatment of AB in patients affected by recurrent UTI was associated with a higher rate of symptomatic UTI [27]. The authors hypothesized that this phenomenon resulted from ecological effects of antibacterial agents on the human microflora. However, Rice et al. found an association between AB progression to systemic infection with acute kidney allograft injury and a unique pattern of adherence factors that is P fimbriae but not Dr. fimbriae expression [28]. So, AB might be an actual risk factor for symptomatic UTIs depending on the virulence of uropathogens.
\nA number of studies attempted to elucidate if the treatment of AB in RTx patients is in fact helpful or harmful in preventing symptomatic infections [19, 20]. One retrospective observational study included a total of 112 patients with AB. The decision as to whether, or not, to treat AB was made by the attending physician. The primary outcome, defined as hospitalization for symptomatic UTI or a 25% decline in the eGFR, occurred more frequently among patients treated with antibiotics. However, the authors called attention to the fact that those treated patients may have initially been at higher risk for adverse outcomes, thus masking the benefit of the treatment [19]. Another retrospective study included 77 RTx recipients who developed 334 AB episodes later than 1-month post transplantation. AB episodes were classified into four groups depending on the presence of pyuria and grade of bacteriuria. Spontaneous bacterial clearance occurred in 59% of untreated episodes. The resolution of bacteriuria was not more frequent in treated, as compared to untreated, episodes. However, antibiotic treatment in patients with high-grade bacteriuria and concurrent pyuria resulted more frequently in negative control cultures than untreated episodes. The authors concluded that a watch-and-wait strategy for bacteriuria in the absence of pyuria might be safe in the RTx population [20]. In 2016, the results of a randomized controlled study were published. Systematic screening and treatment of AB beyond the second month after transplantation provided no apparent benefit among KT recipients when the occurrence of acute pyelonephritis at 24-month follow-up was considered. The treatment also did not affect the secondary outcomes, which included lower UTI, acute rejection,
Selection of initial empiric treatment should be based on local epidemiological data and the patient’s history of resistant organisms. Once susceptibility data are available, the initial therapy should be deescalated, so that the most narrow-spectrum antibiotic is used to complete the course of therapy. Care should be taken to avoid treating asymptomatic patients, in order to reduce the possibility of infection with MDR pathogens.
\nLower UTIs require minimum 7-day therapy with an effective agent while upper UTIs at least 2–3 weeks. The resolution of infection should be demonstrated before the cessation of treatment. Stents or catheters may be covered with bacterial biofilm, so their removal is generally required for resolution of UTI. For empirical treatment of suspected bacterial infections in RTx patients, the selection of antimicrobial agents should be based on local epidemiological data and on the patient’s history of colonization or infection with antibiotic-resistant organisms.
\nThere is no evidence to support the use of combination antibiotic therapy for the treatment of ESBL, but in haemodynamically unstable or critically ill patients, adding an aminoglycoside to carbapenem seems a reasonable strategy. Amoxicillin-clavulanate and fosfomycin showed a clinical efficacy of 84 and 93%, respectively, in the treatment of cystitis caused by ESBL-producing
The combination antibiotic therapy is a standard of care in carbapenemase-producing
In the case of severe infection with sepsis, the option of reduction/discontinuation of immunosuppression together with surgical/urological intervention should also be considered.
\nIn severe upper UTIs and/or recurrent infections, imaging should always be obtained to rule out structural causes or persistent foci of infection. Ultrasound may confirm the presence of hydronephrosis. When there are no visible structural abnormalities on ultrasound, it may be necessary to perform fluoroscopic voiding cystourethrogram to diagnose severe vesicoureteral reflux (VUR), computed tomography urography to visualize the cause of urine flow obstruction or uroflowmetry to recognize the problem with delayed bladder emptying. In elderly RTx recipients, the aforementioned functional abnormalities may be secondary to benign prostate hyperplasia (BPH). Since most patients undergoing dialysis are oliguric or anuric, urinary obstruction due to BPH and related lower urinary tract symptoms become evident after RTx and restoration of diuresis. As opposed to native kidneys, the transplanted kidney’s ureter is shorter, and there is no valve at the vesicoureteral junction preventing backflow, so low-grade BPH may cause symptoms that would not be present in a non-RTx patient. Medical therapy of BPH, both pharmacologic and surgical, such as transurethral resection of the prostate is safe and improves urinary flow and bladder emptying, to allow a significant and durable improvement of the kidney allograft function.
\nAppropriate attention should be given to the prevention of UTI with correction of structural abnormalities of the urinary tract in the potential RTx recipients prior to transplantation. Any type of voiding dysfunction should be considered and addressed.
\nIn the immediate post-transplant period, vigilance for donor-transmitted infection is important, together with routine perioperative antibiotic prophylaxis recommended by the hospital’s epidemiologist, taking into account current antibiotic resistance of Gram-negative strains. In the case of a positive donor’s or organ preservation fluid cultures, the antibiotic should be chosen according to susceptibility profiles. The use of indwelling urethral catheters and ureteral stents should be minimized.
\nPatients should be instructed to drink a lot of fluids and urinate frequently, without waiting for the urge to urinate.
\nThere is no consensus regarding the optimal strategy and duration of recurrent UTI prophylaxis, so the decision to give it, or not, depends on the experience of the treating physician. Traditionally trimethoprim/sulfamethoxazole prophylaxis has been used as the prevention of both asymptomatic bacteriuria/UTI and Pneumocystis pneumonia after RTx. However, over the past few years, it has become less effective as uropathogens have become more resistant to this regimen. Of note, ESBL-producing
Several possibilities exist in an attempt to mitigate the damage caused by resistant pathogens. In the general population, there are ongoing attempts to use nonantibiotic strategies, such as cranberry products, D-mannose, probiotics, immunoactive prophylaxis with several types of vaccines, intravesical glycosaminoglycan replenishment therapy with the use of chondroitin sulfate and low molecular weight hyaluronic acid in the treatment and/or prevention of recurrent UTIs [35]. So far the use of all these products has not been extensively studied in RTx population, except for single-case reports on the use of cranberry products. Little information is also available about the usefulness of intestinal decolonization in RTx patients.
\nSeveral problems might arise when producing secondary metabolites using both spontaneous and cultivated plants or parts of plants. If the material for extraction is collected by spontaneous plants, the major risk is related to the impoverishment of resources and biodiversity, consequently. Although natural ecosystems are usually rich in officinal plants that can be used by humans, an excessive collection of spontaneous flora can act as a direct cause of biodiversity loss [1, 2]. Currently, it is estimated that at least 50,000 plant species are used, which in the majority of cases grow spontaneously, however, sometimes products come from specific cultivation. Based on what was reported by the 2020 edition of the State of the World’s Plants and Fungi [3], climate change is threatening two-fifths of the plants currently known; this value is doubled compared to what observed in 2016 and, among these, species are included many medicinal plants used both as a natural remedy and for drug production. According to such data collection that involved 210 scientists and 42 countries, over 140,000 plants should be classified as under extinction threat, including 730 medicinal plants. Among known species, 5500 medicinal plants can be found and approximately 13% of these are under extinction threat [4]. Concerning the most vulnerable plants, we can mention
A large number of species belonging to the plant kingdom have always coexisted on Earth, over the years they have created a great heritage of biodiversity. Plants have always been a primary source of sustenance for herbivorous and omnivorous animals including the human species, the latter, however, over time, has realized the possibility of using plant biomass to also obtain substances to be utilized in various effective ways, for example as medication or food supplements.
Western medical culture can be traced back to the Sumerian Nippur tablets of 3000 BC on which the names of medicinal herbs are reported. The first known writing on the subject is a papyrus (1552 BC), dating back to an Egyptian dynasty. It features numerous herbal formulas and, between magic and medicine, even invocations to ward off disease and a catalog of plants, minerals, magical amulets, and useful spells. It is based on more than 500 plants, nearly a third of which are still found in today’s Western pharmacopoeias.
The most famous Egyptian physician was Imhotep (Memphis around 2500 BC) whose “materia medica” included practices to reduce head and thoracic trauma, wound care, prevention, treatment of infections, and principles of hygiene.
The first Chinese manual of materia medica, Shennong Ben Cao Jing (Emperor Shennong’s classic Materia medica), written in the first century, describes 365 medicines, 252 derived from herbs.
Ancient literature also provided the manuscript “Recipes for fifty-two foods,” the longest medical text found in the Chinese tomb of Mawangdui, (168 BC), the Wushi’er Bingfang (9950 characters). It along with others shows the early development of Chinese medicine while subsequent generations have developed Yaoxing Lun, a “Treatise on the Nature of Medicinal Herbs.”
Ayurveda is the traditional medicine in India that emphasizes plant-based treatments, hygiene, and the balance of the state of the body. The Indian Materia Medica included knowledge of plants, the place of its growth, the methods of conservation, and the duration of the collected materials; includes also directions for extracting juices, powders, cold infusions, and extracts.
Later in Greece, it was Hippocrates, a philosopher known as the father of medicine, who in 460 BC founded a school focused on the necessity to discover the causes of disease to combat them. His treatises, aphorisms, and prognostics, in addition to describing 265 drugs, supported the importance of diet for the treatment of diseases.
Theophrastus (390–280 BC), a disciple of Aristotle’s, historically known as the “father of botany,” wrote the treatise Historia Plantarium, the first attempt to classify plants and botanical morphology in Greece with details of medicinal herbs and concoctions based on them.
Later Galen, philosopher, physician, pharmacist, and prolific writer of medical matters, collected the medical knowledge of his time in an extensive report and wrote on the structure of organs, the impulse and its association with respiration, arteries, and blood circulation, and the uses of the “Theriac” “In treatises such as on Theriac to Piso, on Theriac to Pamphilius, and on Antidotes, Galen identified in the Teriaca a compound of 64 ingredients, which can be defined as a polypharmaceutical, suitable for treating every known disease.” His work rediscovered in the fifteenth century became the authority on medicine and healing for the next two centuries.
The Greek physician Dioscorides treated medical questions in five volumes, entitled Περὶ ὕλης ἰατρικῆς in Greek and De Materia Medica in Latin; they include about 500 plants and direct observations of the plants and the effects that the various drugs have had on patients. De Materia Medica was the first extensive drug system comprising a 1000 natural drugs (products for most basic plants). The classification used by Dioscorides is of an elementary type even if he uses a botanical taxonomy. The books written by Dioscorides on medicinal herbs of history are considered the precursors of the modern pharmacopeia remaining in use until the 1600s.
Active principles synthesized through secondary metabolites act as a defense strategy, playing an active role in plant ecophysiology against herbivores, attacks by pathogens but also as a response to abiotic stress, and competition with other plants; at the same time, they play a crucial role in attracting beneficial organisms, such as symbionts and pollinators. Recently, several studies on “secondary metabolism” highlighted additional features related to these molecules, which make them essential for the organism that produces them as they provide useful information on quality and on specific features of a range of raw materials, both of animal and vegetal origin as well as on food produced with them [6, 7]. As a matter of fact, the secondary metabolites pool is often influenced by specific environmental conditions, for instance, in the case of essential oil profile; for this reason, secondary metabolite products in essential oils may provide important support in acquiring valuable information on their origin.
Unlike primary metabolites that are stable in concentration and chemical structure, ensuring cell structural and functional integrity, secondary metabolites show a “high degree of freedom” as far as these aspects are concerned [8, 9].
Due to an enormous diversity in structure and intraspecific variability, biosynthesis in secondary metabolites is limited to definite groups of plants and thus they are not ubiquitous. Synthesis in secondary metabolites was selected when during evolution such compounds managed to respond to specific needs by vegetal organisms [10]. This is the case, for instance, of the variation of scents and colors in flowers to attract pollinators and promote and increase efficiency in pollination [11].
Secondary metabolism-derived molecules are released in the environment through different mechanisms, among others we can mention volatilization that leads to a dispersion of substances such as ethylene and sesquiterpenes that can be absorbed by surrounding plants directly through the soil or atmosphere; lisciviation, instead, promotes the release of substances, such as sugar, amino acids, alkaloids, fatty acids, terpenoids, and phenolic acids, from the aerial part of the plant through hydrosolubility caused by rain or fog. Other mechanisms promoting dispersion are 40 exudation and decomposition.
The activity of substances released also depends on the physiological and nutritional status of plants and environmental abiotic factors, such as light, rain, and temperature [12].
During the nineteenth century, chemists showed interest in the study of secondary metabolism and metabolites, concerning especially drugs, poison, aromatizers, and industrial products, all representing as a whole the final products of metabolic pathways or networks of these; actually, more than 200,000 are known to date.
Recently, potential roles of secondary products at the cell level that have been identified are—plant growth regulation, gene expression modulation, and compounds involved in signal transduction [13, 14]. Hence, while for centuries secondary metabolites have been used in traditional medicine, nowadays, they act as valuable pharmaceutical, cosmetic, chemical compounds, and nutraceuticals in the recent past [15].
Active principles can be divided into three big molecule families based on the biosynthesis pathways from which they are originated—terpenoids and steroids, alkaloids and phenolics [15].
These are the most recurrent compounds; lipid molecules synthesized starting from acetyl CoA or from glycolysis intermediates reaching a total of 35,000, abundant in essential oils, resins, rubber, volatile molecules, scented, colorless, soluble in oil or highly lipophilic solutions, and inflammable. They function as protectors for wood tissues, exert antibacterial effects, are responsible for insect attraction and repulsion, as well as represent the base material for vegetal hormones or pigments (chlorophyll and carotenoids) synthesis; they also take part in the mitochondrial electron transport and plastoquinone.
These molecules, which accumulate nitrogen becoming an important source of it, are produced by approximately 20% of plants; more than 20,000 different alkaloids are known and are synthesized principally from amino acids.
They play an important role as an advanced chemical defense system of plants under predators’ pressure (larvae, insects, herbivores, mammals). They work as antibiotics and pesticides with a deterrent action to prevent plants from being ingested.
Alkaloids used as drugs, poison, with stimulating and narcotizing effects were used even by Greek and Romans, such as atropine (
Secondary plant metabolites belonging to the big family of polyphenols [16], having mostly hydrosoluble characteristics. They represent one of the main classes of secondary metabolites that includes a wide range of highly heterogeneous substances having all in common an aromatic ring. They are formed through the biosynthesis pathway of shikimic or mevalonic acids; a total of 15,000 are known and represent a group of substances easily occurring in superior plants; the most common cinnamic acid derivatives are caffeic, p-Coumaric, ferulic, gallic, and synaptic acids.
Compounds of different colors accumulate especially in aerial plant organs (stems, leaves, flowers, and fruits) rather than in roots; such a preferred location is related to a light-induced effect on phenolic metabolism; besides, phenolic compounds play a protective role against UV that are successfully absorbed and accumulated into leaves epidermis to avoid damage caused to cell DNA [16]. They influence the color, generally yellow, of flowers and fruits where they can be found as glycosides diluted in cell juice except for anthocyanidines and their glucosides (anthocyanins) that are red, purple, or blue depending on the pH of cell juice [17]. The flavonoids content in plants depends not only on the genotype but is also closely related to environmental conditions especially by light radiation such as UV; the latter, in fact, induces a significant increase of flavonoids in leaves [18, 19].
Flavonoids and phenolic acids are the most important antioxidants in the diet and can be found also in tea, wine, and beer [8].
They are considered pharmacologically active compounds having anti-inflammatory activity, active against liver injury due to hepatotoxicity, and acting as antitumoral, antimicrobials, antivirals, enzyme inhibitors, antioxidants, protect against capillary fragility, as well as playing a role as insect repellents and signaling in plant-organism interactions.
In the recent past, the most common use involving the antioxidant properties has been represented by the “scavenger” activity exerted by a series of enzymes, such as dismutase, superoxide, catalase, glutathione peroxidase; they play a role in halting the radical reaction cascade causing acceleration of cell senescence processes.
Among multiple biological activities exerted by these secondary metabolism molecules, we highlight the role of antioxidants against aging, such as in the case of cocoa (
The high variety of phenolic structures shows the same amount of function diversification—they can play a role as low molecular weight flower pigments, antibiotics, and anti-UV screens.
Likewise, elicitation on a secondary metabolic pathway by a pathogen can lead to
Antioxidants can be defined as any substance that is able to delay or significantly inhibit oxidation in a specific substrate even if it shows a really low concentration compared to the oxidable substrate [20]. Nutrition plays a crucial role in ensuring the efficacy of antioxidant enzyme defenses—many essential oligoelements, such as selenium, copper, manganese, and zinc, are involved in the molecular structure or in the catalytic activity of these enzymes. The main antioxidant compounds in food are—ascorbic acid (vitamin C), tocopherols (vitamin E), carotenoids, flavonoids.
Over the years, pharmaceutical companies have been focusing on antioxidant compounds from food to promote healthy properties of food as available data show that an increase in oxidant intake from natural sources, specifically from fruit and vegetables, may have a beneficial effect on disease prevention. Their production can be effectively achieved through
Secondary metabolites can be produced
Cultures of vegetal tissues (Figure 1) or isolated cells (Figure 2) are inoculated in sterile conditions starting from explants, such as leaves, stems, meristems, roots, buds, callus (Figure 3) both for multiplication and secondary metabolite production. Production can take place in more than one tissue.
Culture of shoots on liquid substrate.
Cell suspension culture.
Isolated callus on solidified medium.
Depending on the species, biomass production can be initiated from an undifferentiated callus or cell suspension. In other cases, sprouts, roots, and somatic embryos can be cultured. Using differentiated tissues or organs is crucial when the requested metabolite is produced in specific plant tissue or organ or also in specialized glands such as in the case of essential oils [24, 25]. Although different studies showed efficacy in secondary metabolite production through cultures of differentiated tissues and callus, the technique mostly used is cell suspension [22, 23, 26, 27]. The latter is a culture of cells isolated in a liquid medium that exploits cell totipotency for large-scale production. Each cell, in fact, keeps the biosynthesis ability of the plant and under the right conditions can produce metabolites identical to the ones produced by the mother plant. Furthermore, it can be noticed that cell cultures have greater and faster potential application to the market compared to other production methods [25, 28]. This technique ensures the continuous production of metabolites of interest while offering an elevated quality standard and product uniformity. In addition, it is possible through biotechnology applications to produce new metabolites not synthesized by the mother plant [29, 30]. Currently, different metabolites with an interesting market value are produced using cell suspension culture, such as taxol [31, 32], resveratrol [33], artemisinin [34], ginsenosides [35], raubasine [36].
Among differentiated tissues, hairy roots should be highlighted as they enable the production of secondary metabolites from a considerable number of plants.
Hairy roots are formed in nature on plants following an infection caused by
Agrobacterium can transfer genetic information to plants inducing transformations. Once the infection takes place, a plasmid fragment called T-DNA can be integrated into the plant nuclear DNA where genes are integrated. The composition and organization of T-DNA sequences vary considerably. As some cT-DNA genes show strong growth effects when expressed in other species, they can also influence the growth of natural transformants. However, there is still a need to fully identify the mechanisms through which these genes alter growth models and their regulation by promoters and plant transcription factors [38]. Among the advantages of such a technique, we can mention the high level of cell differentiation, rapid growth, relatively easy production, genetic, and biochemical stability. It should also be taken into consideration the potential accumulation of secondary metabolites in the aerial part of the plant. However, technical problems might arise in cultivation systems for the market [37].
The process can involve both cells and elicitors. They are bound inside a matrix through trapping, absorption, or covalent bonding. The system must be integrated with an adequate substrate as in the case of cultures of suspended cells, as well as regulating chemical and physical parameters, such as pH and temperature.
In a system of this kind, secondary metabolites must be released by cells in the culture media naturally or through induced secretion. One of the advantages of this methodology is the potential stabilization of a continuous production process through the adoption of a specific system of bioreactors.
Generally, the substrate contains mineral elements formed by macro and microelements and an organic component formed by vitamins, amino acids, and other nitrogen components as well as carbohydrates. There are different substrates that can play a specific role in achieving different objectives, as a consequence of the concentration of specific substances contained in them, such as those indicated, for example, in Table 1.
Macro and microelements | MS (mg/L) | WPM (mg/L) | B5 (mg/L) | NN (mg/L) |
---|---|---|---|---|
Ammonium nitrate | 1650.000 | 400.000 | 720.000 | |
Boric acid | 6.200 | 6.200 | 3.000 | 10.000 |
Anhydrous calcium chloride | 332.200 | 72.500 | 113.24 | |
Cobalt chloride hexahydrate 6H2O | 0.025 | 0.025 | ||
Tripotassium phosphate | 170.000 | 170.000 | 130.500 | 68.000 |
Potassium iodide | 0.830 | 0.750 | ||
Sodium molybdate 2H2O | 0.250 | 0.250 | 0.250 | 0.250 |
Calcium nitrate | 386.000 | |||
Potassium nitrate | 1900.000 | 2500.000 | 950.000 | |
Ammonium sulfate | 134.000 | |||
Iron sulfate·7H2O | 27.800 | 27.800 | 27.850 | 27.850 |
Anhydrous magnesium sulfate | 180.700 | 180.700 | 122.09 | 90.340 |
Manganese sulfate·H2O | 16.900 | 22.300 | 10.000 | 18.940 |
Potassium sulfate | 990.000 | |||
Copper sulfate 5H2O | 0.025 | 0.250 | 0.025 | 0.025 |
Zinc sulfate 7H2O | 8.600 | 8.600 | 2.000 | 10.000 |
VITAMINS | ||||
Folate | 0.500 | |||
Nicotinic acid | 0.500 | 0.500 | 1.000 | 5.000 |
Biotin | 0.050 | |||
Myo-inositol | 100.000 | 100.000 | 100.000 | 100.000 |
Pyridoxine·HCl | 0.500 | 0.500 | 1.000 | 0.500 |
Thiamine·HCl | 0.100 | 1.00 | 10.000 | 0.500 |
OTHER ADDITIVES | ||||
Disodium EDTA (·2H2O) | 37.260 | 37.300 | 37.250 | 37.250 |
Glycine | 2.000 | 2.000 | 2.000 |
The choice of an appropriate substrate should be based on the following [43]:
the type of ions contained
macroelements balance
total ionic concentration of medium
Microelements are used in small quantities; lack of such elements causes specific symptoms as they intervene in plant metabolism; they are integrated into enzymes. Some microelements can influence the production of secondary metabolites, acting as elicitors [44].
Hormones carry out an essential role as growth regulators in plants [45, 46]. The need to add growth regulators to substrates is based on the fact that normal tissues or small organs placed
Among known hormones mostly utilized we can find:
Auxin: Natural auxin is Indole-3-acetic acid (IAA, 3-IAA); in substrates for
IBA (Indole-3-butyric acid), the most commonly used;
NAA (1-Naphthaleneacetic acid);
2,4 D (2,4-Dichlorophenoxyacetic acid).
Natural auxins are added in variable quantities (0.01–10 mg/l) and the synthetic ones are added in quantities between 0.001 and 10 mg/l, determining—elongation and tissue distension, cell division, adventitious roots formation [47, 48].
Cytokines: Natural cytokinins are as follows:
Kinetin (N6-Furfuryladenine, 6-Furfurylaminopurine)
Zeatin [6-(4-Hydroxy-3-methylbut-2-enylamino)purine]
2Ip [N6-(2-Isopentenyl)adenine]
Cytokines are used in concentrations between 1 and 10 mg/l to stimulate cell division, stimulate adventitious buds production from tissues or from callus, and growth of somatic embryos, to induce the development of axillary buds. In addition, cytokines inhibit root development [49].
Gibberellins: Among gibberellins, the most used is GA3 (gibberellic acid) which promotes internode elongation, meristem, and bud development while inhibiting the formation of roots; thus, it is employed in subsequent phases after planting [50, 51].
pH: Another factor essential for a cultural substrate is pH as its value influences—salt solubility, elements absorption, and substrate solidification; for these reasons, the pH range is quite limited ranging from 5.2 to 5.8. As far as secondary metabolites are concerned, optimal ranges are established both for pH and temperature according to the cultured species.
To achieve secondary metabolite production, elicitation is one of the most important strategies and is used to increase productivity; it takes place through the addition of compounds called elicitors—they can be defined as stress-inducing compounds that induce or improve biosynthesis of specific compounds when a specific amount is applied to a living system [52, 53].
Elicitors can be biotic, such as jasmonic acid, hydrolyzed casein, cellulase, macerozyme, yeast extract, fungal extract, chitin; in addition, chemical compounds usually synthesized from pathogens; abiotic elicitors that include nonorganic substances and can be divided into physical, chemical, and hormonal factors (Figure 4) [53, 54].
Classification of elicitor based on different features.
In cell suspension, depending on environmental parameters and on bioreactor features, the development of cells cultured on the liquid substrate is based on specific phases illustrated in Figure 5. The graph shows time (horizontal axis) and cell number (vertical axis). At the beginning a slow-growth phase is shown, known as lag phase followed by a phase in which cell concentration grows based on a logarithmic scale, log phase; then a second slow-growth phase occurs followed by a phase in which the culture is numerically constant indicated as a plateau or steady state.
Growth curve of a cell suspension culture.
During the latency phase, reduced growth and an accumulation of substances useful for cell development occur, while during the exponential growth phase a considerable biomass increase can be observed. In a discontinue culture, in the case that cells accumulate metabolites in vacuoles, the biomass is removed at the end of the exponential phase; during the stationary phase a balance occurs between new cells and dead cells, then secondary metabolites are excreted in culture media. In this case, the collection is carried out by replacing from time to time or continuously the culture media.
In the production of high-value secondary metabolites, a good strategy is offered by the use of technologies that ensure elevated yield and stable over time. It should be underlined that the production of secondary metabolites from plants is genotype-dependent and this fact influences both metabolite type and quantity. Mother plants can be selected to a first selection to identify plants that ensure also
The output can also be increased through conventional systems or metabolic engineering methodologies [22, 96].
By using metabolic engineering, the biosynthesis pathways can be studied more efficiently [97, 98] through studying gene overexpression that alterates pathways. The study design includes analysis of enzyme reactions and biosynthesis processes at genetic, transcriptomic, and proteomic levels; in addition, it is also studied the manipulation of genes that encode critical enzymes and those that regulate the speed in the biosynthesis pathways [99, 100]. However, to date this system is limited to experimental settings and no method has been identified yet for industrial transfer of such methodology. Currently, the study of the biosynthesis pathway in phenylpropanol seems to be one of the most promising given that this substance is involved in the biosynthesis of different secondary metabolites in plants [101, 102].
Culture parameters are among the factors that mostly influence secondary metabolite production—substrate composition both in terms of mineral and organic compounds; pH; characteristics of cell inoculation; physical parameters, such as temperature, light intensity, duration, shaking, and aeration [22, 23, 27]. The substrate should be selected based on the requirements of plant species. Each substrate parameter can be modified to better adjust to the species and to metabolites to be obtained by it—salt type and concentration, carbon source, growth regulators. In nature, secondary metabolites production is in response to environmental stimuli, or for defensive purposes. This mechanism can be simulated in the laboratory through the modification of the culture parameters, for example, light, temperature, or through the use of substances called elicitors. To elicitors belong both organic and inorganic molecules, such as methyl jasmonate, salicylic acid, microbial cell wall extracts (e.g., yeast extract, chitosan), inorganic salts, heavy metals, physical agents (e.g., UV radiation) among others (Tables 2 and 3).
Elicitor | Plant species | Culture | Compound | References |
---|---|---|---|---|
Ozone (O3) | Shoot | Rosmarinic acid | [55] | |
Cell suspension | Hypericin | [56] | ||
Cell suspension | Puerarin | [57] | ||
pH | Shoot | Bacoside A | [58, 59] | |
Hairy root | Withanolide A | [60] | ||
Cell suspension | Withanolide A | [61] | ||
Sucrose | Seedling | Hypericin and pseudohypericin | [62] | |
Cell suspension | Paclitaxel | [63] | ||
Shoot | Bacoside A | [58, 59] | ||
Cell suspension | Withanolide A | [61] | ||
Ultraviolet C | Cell suspension | Stilbene | [64] | |
Proline | Callus and suspension | Steviol glycoside | [65] | |
Polyethylene glycol | Callus and suspension | Steviol glycoside | [65] | |
Seedling | Hypericin and pseudohypericin | [62] | ||
Jasmonic acid | Shoot | Bacoside A | [66] | |
Hairy root | Plumbagin | [67] | ||
Cell suspension | Plumbagin | [68] | ||
Methyl jasmonate | Hairy root | Tanshinone | [69] | |
Adventitious roots | Cryptotanshinone and tanshinone IIA | [70] | ||
Cell suspension | Stilbene | [64] | ||
Shoot | Bacoside | [66] | ||
Shoot | Diterpenoid | [71] | ||
Cell suspension | Silymarin | [72] | ||
Hairy root | Tanshinone | [73] | ||
Cell suspension | Gymnemic acid | [74] | ||
Hairy roots | Withanolide A, withanone, and withaferin A | [75] | ||
Cell suspension | Andrographolide | [76] | ||
Cell suspension | trans-Resveratrol | [77] | ||
Root | Glycyrrhizic acid | [78] | ||
Gibberellic acid | Hairy root | Tanshinones | [79] | |
Hairy root | Caffeic acid derivatives | [80] | ||
Salicylic acid | Hairy root | Tanshinone | [69] | |
Cell suspension | Stilbene | [64] | ||
Shoot | Digitoxin | [81] | ||
Shoot | Hypericin and pseudohypericin | [82] | ||
Cell suspension | Gymnemic acid | [74] | ||
Hairy root | Withanolide A, withanone, and withaferin A | [75] | ||
Root | Hyoscyamine and scopolamine | [83] | ||
Adventitious root | Glycyrrhizic acid | [84] | ||
Sodium salicylate | Shoot | Carnosol | [85] | |
Sodium chloride | Embryogenic tissues | Vinblastine and vincristine | [86] | |
Sorbitol | Adventitious roots | Cryptotanshinone and tanshinone IIA | [70] | |
Silver (Ag) | Adventitious roots | Cryptotanshinone and tanshinone IIA | [70] | |
Cell suspension | Resveratrol | [87] | ||
Hairy root | Tanshinone | [73] | ||
Hairy root | Atropine | [88] | ||
Cadmium (Cd) | Cell suspension | Resveratrol | [87] | |
Root | Sesquiterpenoid | [89] | ||
Cobalt (Co) | Cell suspension | Resveratrol | [87] | |
Copper (Cu) | Shoot | Xanthotoxin | [90] | |
Shoot | Bacoside | [66] | ||
Root | Sesquiterpenoid | [89] |
Abiotic elicitors.
Elicitor | Plant species | Culture | Compounds | References |
---|---|---|---|---|
Chitin | Shoot | Hypericin and pseudohypericin | [91] | |
Cell suspension | Phenylpropanoid and naphtodianthrone | [92] | ||
Cell suspension | trans-Resveratrol and viniferins | [76] | ||
Pectin | Shoot | Hypericin and pseudohypericin | [91] | |
Dextran | Shoot | Hypericin and pseudohypericin | [91] | |
Yeast extract | Adventitious roots | Cryptotanshinone and tanshinone IIA | [70] | |
Cell suspension | Plumbagin | [68] | ||
Cell suspension | Silymarin | [72] | ||
Hairy root | Tanshinone | [93] | ||
Hairy root | Thiarubrine A | [94] | ||
Hairy root | Azadirachtin | [95] | ||
Root | Glycyrrhizic acid | [78] | ||
Cell suspension | Phenylpropanoid and naphtodianthrone | [92] | ||
Cell suspension | Phenylpropanoid and naphtodianthrone | [92] | ||
Cell suspension | Phenylpropanoid and naphtodianthrone | [92] | ||
Cell suspension | Gymnemic acid | [96] | ||
Cell suspension | Gymnemic acid | [96] | ||
Cell suspension | Gymnemic acid | [96] | ||
Cell suspension | Gymnemic acid | [96] | ||
Cell suspension | Gymnemic acid | [96] | ||
Hairy root | Atropine | [88] | ||
Hairy root | Atropine | [88] | ||
Hairy root | Atropine | [88] | ||
Root | Gymnemic acid | [78] |
Biotic elicitors.
Aid to the production of new secondary metabolites, or increased production of those already known and used, can come from new technologies, such as transgenic cultures. Several works have demonstrated the safety of these technologies, and their effectiveness, at low cost, for the production of secondary metabolites for medicine and industry [103].
Focusing on biodiversity can be useful to strengthen food security and human nutrition aiming at promoting general sustainable development. Traditional crops represent an important biodiversity source and carry out a key role in preserving the identity of specific production areas as well the consumer behavior and transfer of cultural heritage to next generations. However, these cultures and foods require to be preserved from genetic erosion that can determine tragic effects on biodiversity, environmental sustainability, and rural economies.
As a matter of fact, this methodology based exclusively on a phenotypic evaluation does not allow to easily distinguish between genotype and effects on the environment. Recent methodologies based on gene markers enable us to identify species, cultivars, and autochthone varieties easily and rapidly.
Elevated costs and technical problems that might arise when the relationship between phenotype features and gene expression is studied, make the application of these methodologies often difficult. Recently, secondary metabolite analysis has been proposed as a crucial tool to identify a specific species; the metabolic profile, in fact, can lead to the identification of a huge quantity of local autochthone varieties, acting against globalization of agriculture production and being at the same time a tool to identify metabolites useful in traditional project characterization.
The parts of plants to be used for therapy, nutrition, and other activities can be obtained from spontaneous or cultivated plants; the choice of production method is mostly determined by economic factors is affordable to collect spontaneous plants when abundant and costs are relatively low, however, in case of high collection costs and lack of spontaneous plants, cultivation can be less expensive [17]. Furthermore, a lot of spontaneous plants are collected without any control and are currently under extinction threat; just a small percentage is cultivated [104]—all these factors are of concern due to the decrease and loss of gene diversity and environmental degradation. Advantages of open field cultivations are related not only to the fact that they give a solution to a lack of vegetal material available in nature, but also to the fact that the wild plant often offers a highly heterogeneous which might be at the same time inadequate in terms of continuous supply and quality standards. Production of secondary metabolites from cell cultures is a valuable option for molecules that have elevated extraction costs and low output from plant material coming from cultivation [105, 106].
For these reasons and due to the current increased demand for natural food products and drugs of natural origin, the employment of biotechnological artificial culture systems might be a good alternative to conventional cultivations for
On one hand,
Plant tissue culture is based on the principle that the same substances found in nature inside an organ, a fruit, or other plant tissues can be induced to accumulate in undifferentiated cells while keeping gene information and the ability to produce that range of active principles detected in the mother plant [108].
Multiple factors influencing
Plant cell cultures are defined also as “chemical factories for secondary metabolites” [25] and represent to date a viable alternative to the cultivation of pharmaceutical plants both from
The most important reason for pharmaceutical companies to obtain valuable secondary metabolites in this way is due to the fact that conventional cultivations in fields of pharmaceutical plants of some species are time-consuming, expensive, and generate a reduced output.
Some large-scale protocols of productions for the market have been set up for extractions of berberine, shikonin, and
Further research was performed on other secondary metabolites such as flavoring agents (i.e., vanillin produced in bioreactors from calluses explanted from
Although for the production of food from plants there is an increasing tendency toward natural agriculture, in the production of substances intended for industry, in particular the medicinal industry, a cultivated or spontaneous plant cannot always guarantee a constant and high-quality product. Pollution problems, climate change, and the political unsafe of some harvesting and cultivation areas also make production uncertain. In this situation, the production of secondary metabolites
New technologies, always evolving, can give an even greater push toward
The present work is co-financed by the RAS (Autonomous Region of Sardinia), under the Advanced Technologies for LANds management and Tools for Innovative Development of an EcoSustainable agriculture.
The authors declare no conflict of interest.
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by",editors:[{id:"196461",title:"Prof.",name:"Hideki",middleName:null,surname:"Nakano",slug:"hideki-nakano",fullName:"Hideki Nakano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10475",title:"Smart Biofeedback",subtitle:"Perspectives and Applications",isOpenForSubmission:!1,hash:"8d2bd9997707c905959eaa41e55ba8f1",slug:"smart-biofeedback-perspectives-and-applications",bookSignature:"Edward Da-Yin Liao",coverURL:"https://cdn.intechopen.com/books/images_new/10475.jpg",editedByType:"Edited by",editors:[{id:"3875",title:"Dr.",name:"Edward Da-Yin",middleName:null,surname:"Liao",slug:"edward-da-yin-liao",fullName:"Edward Da-Yin Liao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8059",title:"Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice",subtitle:null,isOpenForSubmission:!1,hash:"8cc2c649900edf37ff3374fdc96a1586",slug:"neurostimulation-and-neuromodulation-in-contemporary-therapeutic-practice",bookSignature:"Denis Larrivee and Seyed Mansoor Rayegani",coverURL:"https://cdn.intechopen.com/books/images_new/8059.jpg",editedByType:"Edited by",editors:[{id:"206412",title:"Prof.",name:"Denis",middleName:null,surname:"Larrivee",slug:"denis-larrivee",fullName:"Denis Larrivee"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8851",title:"Advances in Neural Signal Processing",subtitle:null,isOpenForSubmission:!1,hash:"a44ac118b233b29a3d5b57d61680ec38",slug:"advances-in-neural-signal-processing",bookSignature:"Ramana Vinjamuri",coverURL:"https://cdn.intechopen.com/books/images_new/8851.jpg",editedByType:"Edited by",editors:[{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",slug:"ramana-vinjamuri",fullName:"Ramana Vinjamuri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8751",title:"Somatosensory and Motor Research",subtitle:null,isOpenForSubmission:!1,hash:"86191c18f06e524e0f97a5534fdb2b4c",slug:"somatosensory-and-motor-research",bookSignature:"Toshiaki Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/8751.jpg",editedByType:"Edited by",editors:[{id:"70872",title:"Prof.",name:"Toshiaki",middleName:null,surname:"Suzuki",slug:"toshiaki-suzuki",fullName:"Toshiaki Suzuki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9347",title:"Neuroimaging",subtitle:"Neurobiology, Multimodal and Network Applications",isOpenForSubmission:!1,hash:"a3479e76c6ac538aac76409c9efb7e41",slug:"neuroimaging-neurobiology-multimodal-and-network-applications",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/9347.jpg",editedByType:"Edited by",editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8938",title:"Inhibitory Control Training",subtitle:"A Multidisciplinary Approach",isOpenForSubmission:!1,hash:"bd82354f3bba4af5421337cd42052f86",slug:"inhibitory-control-training-a-multidisciplinary-approach",bookSignature:"Sara Palermo and Massimo Bartoli",coverURL:"https://cdn.intechopen.com/books/images_new/8938.jpg",editedByType:"Edited by",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6998",title:"Synucleins",subtitle:"Biochemistry and Role in Diseases",isOpenForSubmission:!1,hash:"2b4b802fec508928ce8ab9deebd1375f",slug:"synucleins-biochemistry-and-role-in-diseases",bookSignature:"Andrei Surguchov",coverURL:"https://cdn.intechopen.com/books/images_new/6998.jpg",editedByType:"Edited by",editors:[{id:"266540",title:"Dr.",name:"Andrei",middleName:null,surname:"Surguchov",slug:"andrei-surguchov",fullName:"Andrei Surguchov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:65,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"46296",doi:"10.5772/57398",title:"Physiological Role of Amyloid Beta in Neural Cells: The Cellular Trophic Activity",slug:"physiological-role-of-amyloid-beta-in-neural-cells-the-cellular-trophic-activity",totalDownloads:5886,totalCrossrefCites:18,totalDimensionsCites:31,abstract:null,book:{id:"3846",slug:"neurochemistry",title:"Neurochemistry",fullTitle:"Neurochemistry"},signatures:"M. del C. Cárdenas-Aguayo, M. del C. Silva-Lucero, M. Cortes-Ortiz,\nB. Jiménez-Ramos, L. Gómez-Virgilio, G. Ramírez-Rodríguez, E. Vera-\nArroyo, R. Fiorentino-Pérez, U. García, J. Luna-Muñoz and M.A.\nMeraz-Ríos",authors:[{id:"42225",title:"Dr.",name:"Jose",middleName:null,surname:"Luna-Muñoz",slug:"jose-luna-munoz",fullName:"Jose Luna-Muñoz"},{id:"114746",title:"Dr.",name:"Marco",middleName:null,surname:"Meraz-Ríos",slug:"marco-meraz-rios",fullName:"Marco Meraz-Ríos"},{id:"169616",title:"Dr.",name:"Maria del Carmen",middleName:null,surname:"Cardenas-Aguayo",slug:"maria-del-carmen-cardenas-aguayo",fullName:"Maria del Carmen Cardenas-Aguayo"},{id:"169857",title:"Dr.",name:"Maria del Carmen",middleName:null,surname:"Silva-Lucero",slug:"maria-del-carmen-silva-lucero",fullName:"Maria del Carmen Silva-Lucero"},{id:"169858",title:"Dr.",name:"Maribel",middleName:null,surname:"Cortes-Ortiz",slug:"maribel-cortes-ortiz",fullName:"Maribel Cortes-Ortiz"},{id:"169859",title:"Dr.",name:"Berenice",middleName:null,surname:"Jimenez-Ramos",slug:"berenice-jimenez-ramos",fullName:"Berenice Jimenez-Ramos"},{id:"169860",title:"Dr.",name:"Laura",middleName:null,surname:"Gomez-Virgilio",slug:"laura-gomez-virgilio",fullName:"Laura Gomez-Virgilio"},{id:"169861",title:"Dr.",name:"Gerardo",middleName:null,surname:"Ramirez-Rodriguez",slug:"gerardo-ramirez-rodriguez",fullName:"Gerardo Ramirez-Rodriguez"},{id:"169862",title:"Dr.",name:"Eduardo",middleName:null,surname:"Vera-Arroyo",slug:"eduardo-vera-arroyo",fullName:"Eduardo Vera-Arroyo"},{id:"169863",title:"Dr.",name:"Rosana Sofia",middleName:null,surname:"Fiorentino-Perez",slug:"rosana-sofia-fiorentino-perez",fullName:"Rosana Sofia Fiorentino-Perez"},{id:"169864",title:"Dr.",name:"Ubaldo",middleName:null,surname:"Garcia",slug:"ubaldo-garcia",fullName:"Ubaldo Garcia"}]},{id:"58070",doi:"10.5772/intechopen.72427",title:"MRI Medical Image Denoising by Fundamental Filters",slug:"mri-medical-image-denoising-by-fundamental-filters",totalDownloads:2564,totalCrossrefCites:17,totalDimensionsCites:30,abstract:"Nowadays Medical imaging technique Magnetic Resonance Imaging (MRI) plays an important role in medical setting to form high standard images contained in the human brain. MRI is commonly used once treating brain, prostate cancers, ankle and foot. The Magnetic Resonance Imaging (MRI) images are usually liable to suffer from noises such as Gaussian noise, salt and pepper noise and speckle noise. So getting of brain image with accuracy is very extremely task. An accurate brain image is very necessary for further diagnosis process. During this chapter, a median filter algorithm will be modified. Gaussian noise and Salt and pepper noise will be added to MRI image. A proposed Median filter (MF), Adaptive Median filter (AMF) and Adaptive Wiener filter (AWF) will be implemented. The filters will be used to remove the additive noises present in the MRI images. The noise density will be added gradually to MRI image to compare performance of the filters evaluation. The performance of these filters will be compared exploitation the applied mathematics parameter Peak Signal-to-Noise Ratio (PSNR).",book:{id:"6144",slug:"high-resolution-neuroimaging-basic-physical-principles-and-clinical-applications",title:"High-Resolution Neuroimaging",fullTitle:"High-Resolution Neuroimaging - Basic Physical Principles and Clinical Applications"},signatures:"Hanafy M. Ali",authors:[{id:"213318",title:"Dr.",name:"Hanafy",middleName:"M.",surname:"Ali",slug:"hanafy-ali",fullName:"Hanafy Ali"}]},{id:"41589",doi:"10.5772/50323",title:"The Role of the Amygdala in Anxiety Disorders",slug:"the-role-of-the-amygdala-in-anxiety-disorders",totalDownloads:9671,totalCrossrefCites:4,totalDimensionsCites:28,abstract:null,book:{id:"2599",slug:"the-amygdala-a-discrete-multitasking-manager",title:"The Amygdala",fullTitle:"The Amygdala - A Discrete Multitasking Manager"},signatures:"Gina L. Forster, Andrew M. Novick, Jamie L. Scholl and Michael J. Watt",authors:[{id:"145620",title:"Dr.",name:"Gina",middleName:null,surname:"Forster",slug:"gina-forster",fullName:"Gina Forster"},{id:"146553",title:"BSc.",name:"Andrew",middleName:null,surname:"Novick",slug:"andrew-novick",fullName:"Andrew Novick"},{id:"146554",title:"MSc.",name:"Jamie",middleName:null,surname:"Scholl",slug:"jamie-scholl",fullName:"Jamie Scholl"},{id:"146555",title:"Dr.",name:"Michael",middleName:null,surname:"Watt",slug:"michael-watt",fullName:"Michael Watt"}]},{id:"26258",doi:"10.5772/28300",title:"Excitotoxicity and Oxidative Stress in Acute Ischemic Stroke",slug:"excitotoxicity-and-oxidative-stress-in-acute-ischemic-stroke",totalDownloads:7157,totalCrossrefCites:6,totalDimensionsCites:25,abstract:null,book:{id:"931",slug:"acute-ischemic-stroke",title:"Acute Ischemic Stroke",fullTitle:"Acute Ischemic Stroke"},signatures:"Ramón Rama Bretón and Julio César García Rodríguez",authors:[{id:"73430",title:"Prof.",name:"Ramon",middleName:null,surname:"Rama",slug:"ramon-rama",fullName:"Ramon Rama"},{id:"124643",title:"Prof.",name:"Julio Cesar",middleName:null,surname:"García",slug:"julio-cesar-garcia",fullName:"Julio Cesar García"}]},{id:"62072",doi:"10.5772/intechopen.78695",title:"Brain-Computer Interface and Motor Imagery Training: The Role of Visual Feedback and Embodiment",slug:"brain-computer-interface-and-motor-imagery-training-the-role-of-visual-feedback-and-embodiment",totalDownloads:1439,totalCrossrefCites:13,totalDimensionsCites:23,abstract:"Controlling a brain-computer interface (BCI) is a difficult task that requires extensive training. Particularly in the case of motor imagery BCIs, users may need several training sessions before they learn how to generate desired brain activity and reach an acceptable performance. A typical training protocol for such BCIs includes execution of a motor imagery task by the user, followed by presentation of an extending bar or a moving object on a computer screen. In this chapter, we discuss the importance of a visual feedback that resembles human actions, the effect of human factors such as confidence and motivation, and the role of embodiment in the learning process of a motor imagery task. Our results from a series of experiments in which users BCI-operated a humanlike android robot confirm that realistic visual feedback can induce a sense of embodiment, which promotes a significant learning of the motor imagery task in a short amount of time. We review the impact of humanlike visual feedback in optimized modulation of brain activity by the BCI users.",book:{id:"6610",slug:"evolving-bci-therapy-engaging-brain-state-dynamics",title:"Evolving BCI Therapy",fullTitle:"Evolving BCI Therapy - Engaging Brain State Dynamics"},signatures:"Maryam Alimardani, Shuichi Nishio and Hiroshi Ishiguro",authors:[{id:"11981",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Ishiguro",slug:"hiroshi-ishiguro",fullName:"Hiroshi Ishiguro"},{id:"231131",title:"Dr.",name:"Maryam",middleName:null,surname:"Alimardani",slug:"maryam-alimardani",fullName:"Maryam Alimardani"},{id:"231134",title:"Dr.",name:"Shuichi",middleName:null,surname:"Nishio",slug:"shuichi-nishio",fullName:"Shuichi Nishio"}]}],mostDownloadedChaptersLast30Days:[{id:"29764",title:"Underlying Causes of Paresthesia",slug:"underlying-causes-of-paresthesia",totalDownloads:192666,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"1069",slug:"paresthesia",title:"Paresthesia",fullTitle:"Paresthesia"},signatures:"Mahdi Sharif-Alhoseini, Vafa Rahimi-Movaghar and Alexander R. Vaccaro",authors:[{id:"91165",title:"Prof.",name:"Vafa",middleName:null,surname:"Rahimi-Movaghar",slug:"vafa-rahimi-movaghar",fullName:"Vafa Rahimi-Movaghar"}]},{id:"63258",title:"Anatomy and Function of the Hypothalamus",slug:"anatomy-and-function-of-the-hypothalamus",totalDownloads:4558,totalCrossrefCites:6,totalDimensionsCites:12,abstract:"The hypothalamus is a small but important area of the brain formed by various nucleus and nervous fibers. Through its neuronal connections, it is involved in many complex functions of the organism such as vegetative system control, homeostasis of the organism, thermoregulation, and also in adjusting the emotional behavior. The hypothalamus is involved in different daily activities like eating or drinking, in the control of the body’s temperature and energy maintenance, and in the process of memorizing. It also modulates the endocrine system through its connections with the pituitary gland. Precise anatomical description along with a correct characterization of the component structures is essential for understanding its functions.",book:{id:"6331",slug:"hypothalamus-in-health-and-diseases",title:"Hypothalamus in Health and Diseases",fullTitle:"Hypothalamus in Health and Diseases"},signatures:"Miana Gabriela Pop, Carmen Crivii and Iulian Opincariu",authors:null},{id:"57103",title:"GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets",slug:"gaba-and-glutamate-their-transmitter-role-in-the-cns-and-pancreatic-islets",totalDownloads:3478,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"Glutamate and gamma-aminobutyric acid (GABA) are the major neurotransmitters in the mammalian brain. Inhibitory GABA and excitatory glutamate work together to control many processes, including the brain’s overall level of excitation. The contributions of GABA and glutamate in extra-neuronal signaling are by far less widely recognized. In this chapter, we first discuss the role of both neurotransmitters during development, emphasizing the importance of the shift from excitatory to inhibitory GABAergic neurotransmission. The second part summarizes the biosynthesis and role of GABA and glutamate in neurotransmission in the mature brain, and major neurological disorders associated with glutamate and GABA receptors and GABA release mechanisms. The final part focuses on extra-neuronal glutamatergic and GABAergic signaling in pancreatic islets of Langerhans, and possible associations with type 1 diabetes mellitus.",book:{id:"6237",slug:"gaba-and-glutamate-new-developments-in-neurotransmission-research",title:"GABA And Glutamate",fullTitle:"GABA And Glutamate - New Developments In Neurotransmission Research"},signatures:"Christiane S. Hampe, Hiroshi Mitoma and Mario Manto",authors:[{id:"210220",title:"Prof.",name:"Christiane",middleName:null,surname:"Hampe",slug:"christiane-hampe",fullName:"Christiane Hampe"},{id:"210485",title:"Prof.",name:"Mario",middleName:null,surname:"Manto",slug:"mario-manto",fullName:"Mario Manto"},{id:"210486",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Mitoma",slug:"hiroshi-mitoma",fullName:"Hiroshi Mitoma"}]},{id:"35802",title:"Cross-Cultural/Linguistic Differences in the Prevalence of Developmental Dyslexia and the Hypothesis of Granularity and Transparency",slug:"cross-cultural-linguistic-differences-in-the-prevalence-of-developmental-dyslexia-and-the-hypothesis",totalDownloads:3601,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"673",slug:"dyslexia-a-comprehensive-and-international-approach",title:"Dyslexia",fullTitle:"Dyslexia - A Comprehensive and International Approach"},signatures:"Taeko N. Wydell",authors:[{id:"87489",title:"Prof.",name:"Taeko",middleName:"N.",surname:"Wydell",slug:"taeko-wydell",fullName:"Taeko Wydell"}]},{id:"58597",title:"Testosterone and Erectile Function: A Review of Evidence from Basic Research",slug:"testosterone-and-erectile-function-a-review-of-evidence-from-basic-research",totalDownloads:1331,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Androgens are essential for male physical activity and normal erectile function. Hence, age-related testosterone deficiency, known as late-onset hypogonadism (LOH), is considered a risk factor for erectile dysfunction (ED). This chapter summarizes relevant basic research reports examining the effects of testosterone on erectile function. Testosterone affects several organs and is especially active on the erectile tissue. The mechanism of testosterone deficiency effects on erectile function and the results of testosterone replacement therapy (TRT) have been well studied. Testosterone affects nitric oxide (NO) production and phosphodiesterase type 5 (PDE-5) expression in the corpus cavernosum through molecular pathways, preserves smooth muscle contractility by regulating both contraction and relaxation, and maintains the structure of the corpus cavernosum. Interestingly, testosterone deficiency has relationship to neurological diseases, which leads to ED. Testosterone replacement therapy is widely used to treat patients with testosterone deficiency; however, this treatment might also induce some problems. Basic research suggests that PDE-5 inhibitors, L-citrulline, and/or resveratrol therapy might be effective therapeutic options for testosterone deficiency-induced ED. Future research should confirm these findings through more specific experiments using molecular tools and may shed more light on endocrine-related ED and its possible treatments.",book:{id:"5994",slug:"sex-hormones-in-neurodegenerative-processes-and-diseases",title:"Sex Hormones in Neurodegenerative Processes and Diseases",fullTitle:"Sex Hormones in Neurodegenerative Processes and Diseases"},signatures:"Tomoya Kataoka and Kazunori Kimura",authors:[{id:"219042",title:"Ph.D.",name:"Tomoya",middleName:null,surname:"Kataoka",slug:"tomoya-kataoka",fullName:"Tomoya Kataoka"},{id:"229066",title:"Prof.",name:"Kazunori",middleName:null,surname:"Kimura",slug:"kazunori-kimura",fullName:"Kazunori Kimura"}]}],onlineFirstChaptersFilter:{topicId:"18",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81646",title:"Cortical Plasticity under Ketamine: From Synapse to Map",slug:"cortical-plasticity-under-ketamine-from-synapse-to-map",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104787",abstract:"Sensory systems need to process signals in a highly dynamic way to efficiently respond to variations in the animal’s environment. For instance, several studies showed that the visual system is subject to neuroplasticity since the neurons’ firing changes according to stimulus properties. This dynamic information processing might be supported by a network reorganization. Since antidepressants influence neurotransmission, they can be used to explore synaptic plasticity sustaining cortical map reorganization. To this goal, we investigated in the primary visual cortex (V1 of mouse and cat), the impact of ketamine on neuroplasticity through changes in neuronal orientation selectivity and the functional connectivity between V1 cells, using cross correlation analyses. We found that ketamine affects cortical orientation selectivity and alters the functional connectivity within an assembly. These data clearly highlight the role of the antidepressant drugs in inducing or modeling short-term plasticity in V1 which suggests that cortical processing is optimized and adapted to the properties of the stimulus.",book:{id:"11374",title:"Sensory Nervous System - Computational Neuroimaging Investigations of Topographical Organization in Human Sensory Cortex",coverURL:"https://cdn.intechopen.com/books/images_new/11374.jpg"},signatures:"Ouelhazi Afef, Rudy Lussiez and Molotchnikoff Stephane"},{id:"81582",title:"The Role of Cognitive Reserve in Executive Functioning and Its Relationship to Cognitive Decline and Dementia",slug:"the-role-of-cognitive-reserve-in-executive-functioning-and-its-relationship-to-cognitive-decline-and",totalDownloads:23,totalDimensionsCites:0,doi:"10.5772/intechopen.104646",abstract:"In this chapter, we explore how cognitive reserve is implicated in coping with the negative consequences of brain pathology and age-related cognitive decline. Individual differences in cognitive performance are based on different brain mechanisms (neural reserve and neural compensation), and reflect, among others, the effect of education, occupational attainment, leisure activities, and social involvement. These cognitive reserve proxies have been extensively associated with efficient executive functioning. We discuss and focus particularly on the compensation mechanisms related to the frontal lobe and its protective role, in maintaining cognitive performance in old age or even mitigating the clinical expression of dementia.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Gabriela Álvares-Pereira, Carolina Maruta and Maria Vânia Silva-Nunes"},{id:"81488",title:"Aggression and Sexual Behavior: Overlapping or Distinct Roles of 5-HT1A and 5-HT1B Receptors",slug:"aggression-and-sexual-behavior-overlapping-or-distinct-roles-of-5-ht1a-and-5-ht1b-receptors",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.104872",abstract:"Distinct brain mechanisms for male aggressive and sexual behavior are present in mammalian species, including man. However, recent evidence suggests a strong connection and even overlap in the central nervous system (CNS) circuitry involved in aggressive and sexual behavior. The serotonergic system in the CNS is strongly involved in male aggressive and sexual behavior. In particular, 5-HT1A and 5-HT1B receptors seem to play a critical role in the modulation of these behaviors. The present chapter focuses on the effects of 5-HT1A- and 5-HT1B-receptor ligands in male rodent aggression and sexual behavior. Results indicate that 5-HT1B-heteroreceptors play a critical role in the modulation of male offensive behavior, although a definite role of 5-HT1A-auto- or heteroreceptors cannot be ruled out. 5-HT1A receptors are clearly involved in male sexual behavior, although it has to be yet unraveled whether 5-HT1A-auto- or heteroreceptors are important. Although several key nodes in the complex circuitry of aggression and sexual behavior are known, in particular in the medial hypothalamus, a clear link or connection to these critical structures and the serotonergic key receptors is yet to be determined. This information is urgently needed to detect and develop new selective anti-aggressive (serenic) and pro-sexual drugs for human applications.",book:{id:"10195",title:"Serotonin and the CNS - New Developments in Pharmacology and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/10195.jpg"},signatures:"Berend Olivier and Jocelien D.A. Olivier"},{id:"81093",title:"Prehospital and Emergency Room Airway Management in Traumatic Brain Injury",slug:"prehospital-and-emergency-room-airway-management-in-traumatic-brain-injury",totalDownloads:49,totalDimensionsCites:0,doi:"10.5772/intechopen.104173",abstract:"Airway management in trauma is critical and may impact patient outcomes. Particularly in traumatic brain injury (TBI), depressed level of consciousness may be associated with compromised protective airway reflexes or apnea, which can increase the risk of aspiration or result in hypoxemia and worsen the secondary brain damage. Therefore, patients with TBI and Glasgow Coma Scale (GCS) ≤ 8 have been traditionally managed by prehospital or emergency room (ER) endotracheal intubation. However, recent evidence challenged this practice and even suggested that routine intubation may be harmful. This chapter will address the indications and optimal method of securing the airway, prehospital and in the ER, in patients with traumatic brain injury.",book:{id:"11367",title:"Traumatic Brain Injury",coverURL:"https://cdn.intechopen.com/books/images_new/11367.jpg"},signatures:"Dominik A. Jakob, Jean-Cyrille Pitteloud and Demetrios Demetriades"},{id:"81011",title:"Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition as a Background for Future Clinical Applications",slug:"amino-acids-as-neurotransmitters-the-balance-between-excitation-and-inhibition-as-a-background-for-f",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.103760",abstract:"For more than 30 years, amino acids have been well-known (and essential) participants in neurotransmission. They act as both neuromediators and metabolites in nervous tissue. Glycine and glutamic acid (glutamate) are prominent examples. These amino acids are agonists of inhibitory and excitatory membrane receptors, respectively. Moreover, they play essential roles in metabolic pathways and energy transformation in neurons and astrocytes. Despite their obvious effects on the brain, their potential role in therapeutic methods remains uncertain in clinical practice. In the current chapter, a comparison of the crosstalk between these two systems, which are responsible for excitation and inhibition in neurons, is presented. The interactions are discussed at the metabolic, receptor, and transport levels. Reaction-diffusion and a convectional flow into the interstitial fluid create a balanced distribution of glycine and glutamate. Indeed, the neurons’ final physiological state is a result of a balance between the excitatory and inhibitory influences. However, changes to the glycine and/or glutamate pools under pathological conditions can alter the state of nervous tissue. Thus, new therapies for various diseases may be developed on the basis of amino acid medication.",book:{id:"10890",title:"Recent Advances in Neurochemistry",coverURL:"https://cdn.intechopen.com/books/images_new/10890.jpg"},signatures:"Yaroslav R. Nartsissov"},{id:"80821",title:"Neuroimmunology and Neurological Manifestations of COVID-19",slug:"neuroimmunology-and-neurological-manifestations-of-covid-19",totalDownloads:41,totalDimensionsCites:0,doi:"10.5772/intechopen.103026",abstract:"Infection with SARS-CoV-2 is causing coronavirus disease in 2019 (COVID-19). Besides respiratory symptoms due to an attack on the broncho-alveolar system, COVID-19, among others, can be accompanied by neurological symptoms because of the affection of the nervous system. These can be caused by intrusion by SARS-CoV-2 of the central nervous system (CNS) and peripheral nervous system (PNS) and direct infection of local cells. In addition, neurological deterioration mediated by molecular mimicry to virus antigens or bystander activation in the context of immunological anti-virus defense can lead to tissue damage in the CNS and PNS. In addition, cytokine storm caused by SARS-CoV-2 infection in COVID-19 can lead to nervous system related symptoms. Endotheliitis of CNS vessels can lead to vessel occlusion and stroke. COVID-19 can also result in cerebral hemorrhage and sinus thrombosis possibly related to changes in clotting behavior. Vaccination is most important to prevent COVID-19 in the nervous system. There are symptomatic or/and curative therapeutic approaches to combat COVID-19 related nervous system damage that are partly still under study.",book:{id:"10890",title:"Recent Advances in Neurochemistry",coverURL:"https://cdn.intechopen.com/books/images_new/10890.jpg"},signatures:"Robert Weissert"}],onlineFirstChaptersTotal:17},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:99,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:289,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He obtained a Master’s degree in Public Health and PhD in Public Health and Epidemiology. He has a background in Clinical Medicine and has taken courses at higher diploma levels in public health from University of Transkei, Republic of South Africa, and African Medical and Research Foundation (AMREF) in Nairobi, Kenya. Dr. Kasenga worked in different places in and outside Malawi, and has held various positions, such as Licensed Medical Officer, HIV/AIDS Programme Officer, HIV/AIDS resource person in the International Department of Diakonhjemet College, Oslo, Norway. He also managed an Integrated HIV/AIDS Prevention programme for over 5 years. He is currently working as a Director for the Health Ministries Department of Malawi Union of the Seventh Day Adventist Church. Dr. Kasenga has published over 5 articles on HIV/AIDS issues focusing on Prevention of Mother to Child Transmission of HIV (PMTCT), including a book chapter on HIV testing counseling (currently in press). 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