\r\n\tRNA therapies evolved as profitable and widely applicable individualized treatment solutions. Moreover, RNA-based therapeutic vaccines (e.g., against SARS-CoV-2 infection) have been proven to be safe and effective, and several of them are approved by the United States Food and Drug Administration (FDA). \r\n\tThis book aims to present distinct classes of RNA therapeutics, ranging from single-stranded antisense oligonucleotides (ASOs), and subclasses of RNA interferences (miRNAs and other RNAi), to in vitro transcribed mRNAs and RNA vaccines. Also, it will present some of the challenges in RNA drug engineering, delivery, and specificity. Additionally, the improvement of pharmacological effectiveness will be discussed. Monumental breakthroughs in molecular biology, computational chemistry, bioinformatics, and individualized genomics, which undoubtedly propelled RNA therapeutics through the commercialization stage, will also be examined in this book. \r\n\tRNA therapeutics have had a significant impact on medicine, the economy, and overall public health; they are becoming prescription drugs, and this holds great promise for modernizing healthcare.
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\n
1. Introduction
\n
Molds are ubiquitous micro-organisms with a high capacity to colonize different types of substrates and to proliferate under extreme environmental conditions [1]. They alter various types of foods namely cereals, nuts, oil seeds, legumes, spices, vegetables, fruits, etc. and some species produce mycotoxins. Of all mycotoxins, Aflatoxin B1 (AFB1) produced primarily by Aspergillus flavus and A. parasiticus is the most toxic form (hepatotoxic, teratogenic, mutagenic and carcinogenic) for humans and animals [2, 3, 4, 5]. The health impact of this compound has justified the introduction of a consumer protection measure by the establishment of maximum levels in certain food categories. However, the existence of these standards also has significant economic repercussions restricting trade from certain areas where the contamination is frequent and strongly decreasing the economic value of some productions in case of contamination. These losses are estimated by FAO (Food and Agriculture Organization of The United Nations) at about 1 billion tons a year. Therefore, it seems imperative to develop ways of combating contamination of food with these toxic compounds and/or to limit their harmful effects.
\n
Pesticides and fungicides have been widely used to prevent the development of fungal agents. However, because of their own toxicity, their use is subjected to certain restrictions. Biological control is also a possible option. Thus, antiaflatoxigenic bacterial and fungal strains were found effective in reducing the development of toxic strains of A. flavus. However, none of these strategies seems to be able to solve the problem of contamination of raw materials by aflatoxins, as evidenced by the numerous researches that show high levels of contamination, particularly in areas where the climate is favorable for the development of the toxigenic fungal species. At present, there is growing interest in identifying natural compounds able to limit the growth and/or the production of mycotoxins. Thus, the use of essential oils (EOs) of plants or spices could show their ability to limit food contamination. The aim of this review is to summarize the results from the literature on the effects of EOs against A. flavus growth and AFB1 production.
\n
\n
\n
2. Aflatoxins
\n
Aflatoxins are produced primarily by the common fungus Aspergillus flavus and the closely related species A. parasiticus, and they can be found in feedstuffs and foodstuffs throughout the world. These mycotoxins are a family of several molecules of which the most important are AFB1, B2, G1 and G2 (\nFigure 1\n). The letters refer to the fluorescence blue (B) or green (G) under UV and the numbers (1 or 2) refer to their relative chromatographic mobility. They are molecules with a polycyclic structure belonging to the furanocoumarin class. There are also other aflatoxins; there are in total more than a dozen (M1, P1, Q 1, B2a, G2a, etc.). The most are products resulting from the metabolic metabolism of the four molecules produced by mold in food [6]. For example, after ingestion of contaminated feed, AFB1 is transformed into the liver of mammals by cytochrome P450 into several metabolites, mainly AFM1 excreted in milk, which is produced by hydroxylation of the tertiary carbon of the difuranocoumarin cycle. The hydroxyl group formed makes AFM1 more soluble in water and therefore rapidly excreted in mammalian milk, urine, bile and feces. The AFM1 owes its name to its presence in Milk [7]. Aflatoxins are stable molecules and very resistant to the various processes of food processing such as roasting, extrusion and cooking [8]. Indeed, the decomposition of aflatoxins takes place at very high temperatures which are difficult to comply with the manufacturing or processing processes of food. A. flavus and A. parasiticus are the main aflatoxin producers; A. flavus is responsible for the production of type B aflatoxins, while A. parasiticus produces both type B and G [9]. Aflatoxins can contaminate cereals, oil seeds, nuts, spices, legumes, dried fruits, milk and milk products, posing a high risk to public health [10, 11, 12, 13]. Maize, peanuts and tree nuts (i.e. pistachios) are susceptible to aflatoxin contamination in the field, while other cereals, oilseeds and dried fruits are mostly contaminated at postharvest and during storage [14, 15, 16].
\n
Figure 1.
Chemical structures of AFB1, B2, M1, G1 and G2.
\n
\n
\n
3. Methods of aflatoxin decontamination
\n
Foodstuffs should not be hazardous to consumer health; as consequence, elimination of mycotoxin from products is a challenge for the food industry. Concerns have been directed towards aflatoxins because of their global threat and toxicity. Most of the factors obtained from studies on aflatoxins can be applied to other mycotoxins. Although prevention is the most effective intervention, chemical, physical and biological methods have been investigated to eliminate aflatoxins or reduce them (\nFigure 2\n). However, these techniques are not completely safe, are expensive and not well preferred by consumers.
\n
Figure 2.
Some commonly used physical, chemical and biological methods of aflatoxin detoxification.
\n
\n
\n
4. Essential oils: an alternative strategy for control against aflatoxin contamination
\n
The frequency of contamination of world crops by aflatoxins shows that the strategies currently used are insufficient to guarantee the security of the foods and that it is necessary to develop others, as a complement or substitution of those already existing. In this context, strategies based on the use of compounds naturally recognized as not harmful to the environment and to health, seem interesting. Indeed, plants produce different secondary metabolites (terpenoids, phenolic compounds, etc.) for their protection against external agents (mechanical, biological or climatic). These compounds could possibly be used as a means of combating fungal contamination and/or mycotoxins [17].
\n
\n
4.1 Essential oils
\n
\n
4.1.1 Overview
\n
EOs are a mixture of volatile compounds (secondary metabolites) isolated from plants mainly by hydro-distillation. They are mostly consisting of mono- and sesquiterpenes but may also contain non-terpenoid hydrocarbons, phenylpropanoids, esters, lactones, phthalides, nitrogen or sulfurized structures and isothiocyanates. They are lipophilic compounds which are distinguished by their aromatic properties, hence their use as flavorings or perfumes [18]. In addition, certain compounds are also used for their many biological activities: bactericide, fungicide and antioxidant [19].
\n
\n
\n
4.1.2 Mechanism of cellular action of essential oils
\n
The mode of action of EOs has not been completely understood yet [20, 21]. In general, EOs actions are described in three phases. Firstly, EOs spreading on the cell wall of fungi changes the membrane permeability resulting in the loss of cellular components. Secondly, an acidification inside the cell that blocks the production of cellular energy (ATP) due to ion loss, the collapse of proton pumps, the reduction of membrane potential, and destruction of genetic materials that leads to the death of fungus. Furthermore, some reports have indicated that EOs can also coagulate the cytoplasm and damage lipids, proteins, cell walls and membranes that can lead to the leakage of macromolecules and the lysis [22, 23, 24, 25, 26, 27].
\n
Phenolic compounds are known to affect microbial cell permeability, allowing the loss of macromolecules from the interior. They could also interact with membrane proteins, causing a deformation in their structure and functionality [28].
\n
\n
\n
4.1.3 Use of essential oils as antifungal and antiaflatoxigenic agents
\n
In view of their different biological properties, EOs have been tested as alternative strategy for combating mycotoxins, especially aflatoxins [29, 30, 31, 32, 33, 34] (\nTable 1\n). EOs are molecules of natural origin, biodegradable, and are therefore considered as a possible alternative to synthetic pesticides [35]. Their use as food additives or flavorings has recently been authorized in the USA [36]. As their active components are highly volatile, they are mainly used as fumigants for products after harvest. A number of commercially available EOs can be used in crops produced according to the specifications such as E-Rase™ (jojoba EO, Simmondsia californica), Sporan™ (rosemary EO, Rosmarinus officinalis), Promax™ (thyme EO, Thymus vulgaris) [37], Cinnamite™ and Valero™ (cinnamon EO, Cinnamomum verum) [19], Talent® (based on carvone, EO of cumin or dill) and eugenol-Tween® [38].
Inhibition effect of some EOs on the growth of A. flavus and the production of AFB1.
\n
The antifungal activity of EOs of T. vulgaris and camphor (Eucalyptus rostrata L.) was tested on A. flavus. They completely inhibited mycelial growth of the fungus at 1000 and 2000 ppm (mg/kg), and aflatoxin production at 500 and 1000 ppm, respectively [39].
\n
The EO of Satureja hortensis was assessed for antifungal activity against A. flavus in vitro on solid and liquid culture, and under storage conditions. The EO showed strong antifungal activity based on the inhibition zone and minimal inhibitory concentration (MIC) values on solid culture. The very low concentrations of EOs also reduced wet and dry mycelium weight of A. flavus in liquid culture [40]. The antifungal potential of EOs of leaves and seeds of Aframomum daniellii, Aframomum melegueta and Aframomum latifolium and those of husk of A. latifolium was evaluated against A. flavus. Results showed that the inhibition of tested EOs were between 28.06 and 100%, respectively for EOs of seeds of A. melegueta and EO of the husk of A. latifolium at 500 ppm. EO of leaves of A. melegueta and husk of A. latifolium exhibited the most effective inhibition [41]. EOs extracted from Mentha arvensis (0.5 mg/mL) caused total inhibition of A. flavus growth and of AFB1 production [42]. Cymbopogon martinii, Foeniculum vulgare and Trachyspermum ammi EOs were tested against A. flavus. The MIC was recorded at 1 μL/mL for T. ammi EO and 4 μL/mL for C. martinii and F. vulgare. At these concentrations, the EOs completely inhibited the growth of A. flavus [43].
\n
\nAgeratum conyzoides EO inhibited A. flavus growth and reduced AFB1 production at 0.10 μg/mL. The ultra-structural changes in A. flavus cell under transmission electron microscopy (TEM) were observed on the endomembrane system, mainly the mitochondria. The plasma membrane cells lost its linear aspect. The fibrillar layers lost their building and failed to deposit on the cell wall. The mitochondria in treated cells suffered a disruption of the internal structure [1]. Ocimum sanctum EO was evaluated to inhibit A. flavus growth and AFB1 production. The MIC of O. sanctum against A. flavus was found at 0.3 μL/mL while AFB1 production was recorded at 0.2 μL/mL [44]. The efficacy of boldo (Peumus boldus Mol.), poleo (Lippia turbinata var. integrifolia (Griseb.), clove (Syzygium aromaticum L.), anise (Pimpinella anisum), and thyme (T. vulgaris) EOs was tested against A. flavus and A. parasiticus growth and AFB1 at different water activity (aW) levels (0.98, 0.95, 0.93). Inhibition was estimated at 75, 83, and 100% at 0.98, 0.95, and 0.93 aW, respectively [45].
\n
The effects of EOs of Ocimum gratissimum and Plectranthus glandulosus leaves on growth and AFB1 production by A. flavus were assessed at five levels (200, 400, 600, 800 and 1000 mg/L). Growth of A. flavus was completely inhibited by 800 mg/L of O. gratissimum EO and by 1000 mg/L of P. glandulosus EO. The AFB1 production was inhibited by 1000 mg/L of both EOs of O. gratissimum and P. glandulous [46]. Cinnamomum camphora and Alpinia galanga EOs inhibited A. flavus at 1000 ppm and the AFB1 production at 500 ppm for A. galanga and 750 ppm for C. camphora. The combination of the two EOs was more effective than the individual ones. The mixture showed total inhibition of the mycelium growth at 750 ppm and AFB1 production starting from 250 ppm [47]. Lippia rugosa EO was effective against fungal growth and production of AFB1 from A. flavus was totally inhibited at 1000 mg/L. The inhibition was attributed to the presence of geraniol [48].
\n
Both A. flavus growth and AFB1 production were inhibited by EOs of Citrus maxima Burm, Citrus sinensis (L.) Osbeck, and their combination. DL-Limonene inhibited AFB1 productionat a concentration of 250 ppm that is lower than the individual EOs and the combination. It has been suggested that remaining constituents in the EO would mask the efficacy of DL-limonene and they may act in negatively. Furthermore, the authors declared that there was no synergism between the EO constituents when the two EOs were mixed at the same concentration, attaining aflatoxin inhibition at 500 ppm [49].
\n
Similar types of results were also found in the case of Piper betle var. magahi EO, where eugenol was more effective as inhibitor of fungal growth and aflatoxin production than the whole EO. It was suggested that the components of the EO acted synergistically in negative direction and diminished the activity of eugenol [3]. The effect of basil, fennel, coriander, caraway, peppermint and rosemary EOs on A. flavus growth and AFB1 production at 500, 750 and 1000 ppm was also studied. The complete inhibition of A. flavus growth was observed at 1000 ppm concentrations of basil, coriander, caraway and rosemary EOs. While, EOs of basil and coriander showed interesting inhibition of AFB1 at all concentrations [50].
\n
\nCicuta virosa L. EO inhibited the growth of A. flavus and AFB1 production at 4 μL/mL of EO. The AFB1 was reduced to about half compared to the control at 2 μL/mL [51]. Similar type of results was found with Cinnamomum jensenianum EO, which reduced AFB1 to about half compared to the control at 2 μL/mL. At this concentration of the EO, the plasma membrane of A. flavus became rough with continuous folding into the cytoplasm and festooned with small lomasomes. A decreased cytoplasmic matrix was also observed. They showed that some mitochondria suffered extensive disruption of the internal structure with a decrease in mitochondrial cristae. The cell ultrastructure damage was aggravated when the EO concentration was doubled. Major alterations were observed, including massive vacuolation of cytoplasm with vacuole fusion, appearance of numerous lomasomes with folding, and detachment of plasma membrane from the cell wall. The fibrillar layers gradually lost their integrity, becoming thinner, and eventually failing to deposit on the cell wall. The plasma membrane was also folded at many sites. The cytoplasmic matrix and some cytoplasmic organelles were absent. Moreover, the mitochondria suffered a severe disruption of the internal structure with complete lysis. The antifungal mode of action of EO was evaluated by quantification of the ergosterol production in cells. At concentration of 2 μL/mL, the ergosterol content in the plasma membrane of A. flavus was significantly reduced by the different concentrations of EO. A dose dependent decrease in ergosterol production was observed when isolates were grown in the presence of the EO. Therefore, this EO exerts its effect directly on the plasma membrane without any obvious damage to the cell wall. This emphasizes that the antimicrobial components of the EOs cross the cell membrane, interact with the enzymes and proteins of the membrane, thus producing a flux of protons towards the cell exterior which induces disruption to the fungal cell organization and, ultimately, their death [34].
\n
The EO of Anethum graveolens was evaluated on A. flavus. Morphological changes in the cells of A. flavus and a reduction in the ergosterol quantity was caused by A. graveolens EO. An augmentation of mitochondrial membrane potential (MMP), and the suppression of the glucose-induced decrease in external pH were observed at concentration of 4 mL/mL. A decrease of the activities of ATPase and dehydrogenase in A. flavus cells were also observed. The authors attributed the dysfunctions of the mitochondria to the reactive oxygen species (ROS) accumulation in A. flavus. The addition of L-cysteine caused a reduction in cell viability, which indicates that ROS is an interesting mediator of the antifungal activity of A. graveolens EO [52].
\n
The Callistemon lanceolatus (Sm.) Sweet EO inhibited AFB1 production at concentrations lower than its fungitoxic concentration [53]. As well, the EO of Lantana indica showed in vitro antifungal and antiaflatoxigenic activities against A. flavus. The antifungal activity of the L. indica EO, tested by disk diffusion test and by SMKY liquid culture, completely inhibited mycelia growth and AFB1 production at 1.5 and 0.75 μg/mL, respectively [54]. The antifungal and antiaflatoxigenic activities of Litsea cubeba EO were tested on A. flavus. The EO showed a high activity against three toxigenic isolates of A. flavus. Under the scanning electron microscopy (SEM), the EO showed alterations of the hyphae and conidiophores structures. The results exhibited that L. cubeba EO could inhibit fungal growth and AFB1 production [55]. Caesulia axillaris Roxb EO showed complete inhibition of the fungal growth at 1.0 μL/mL and AFB1 at 0.8 μL/mL. Thus, the EO showed antiaflatoxigenic effects at concentration lower than their fungitoxic concentrations indicating two different mode of action for inhibition of fungal growth and AFB1 production [56]. Jamrosa EO (Cymbopogon khasans) showed antifungal activity and inhibition of AFB1 production at 0.4 μL/mL. The authors indicated that inhibition of AFB1 production was secondary to inhibition of fungal growth [57]. The capacity of 14 EO components and their combinations to inhibit fungal growth and AFB1 production revealed that thymol, eugenol, menthol, and their combinations were more effective for inhibition of fungal growth and AFB1 was completely inhibited at 1.0 μL/mL. Geranyl acetate, linalool, β-asarone, 1, 8-cineol, and E-citral were moderately antifungal between 1.0 and 5.0 μL/mL [58].
\n
The inhibition of AFB1 production by A. flavus was observed at 1.0 and 42.7 μL/mL, respectively, for the samples treated with the EO of Curcuma longa L. and curcumin at a concentration of 0.5%. The authors suggested that the antiaflatoxigenic activity might be attributed to phenolic compounds that inhibit lipid peroxidation. Thus, the antioxidant activity of C. longa could be important for the inhibition of AFB1 production [59]. The Boswellia carterii Birdw EO inhibited A. flavus growth and AFB1 production at 1.75 and 1.25 μL/mL, respectively. The EO caused reduction in ergosterol content of plasma membrane of A. flavus [60]. This observation showed that plasma membrane is an interesting site for the mechanism of EO supporting the findings of other authors [51]. The Cuminum cyminum L. EO was tested on A. flavus growth and AFB1 production. The EO inhibited the fungal growth and AFB1 production at 0.6 and 0.5 μL/mL, respectively. The EO totally reduced the ergosterol content at 0.6 μL/mL [31]. T. vulgaris L. EO was tested against A. flavus growth and AFB1 production. Total inhibition of fungal growth was observed at 250 μg/mL. The T. vulgaris EO reduced ergosterol production by A. flavus. The morphological structure of A. flavus was analyzed by SEM, alterations in conidiophore characteristics were observed. Conidial head size varied between 71.3 and 20.5 μm at concentrations between 50 and 500 μg/mL. A decrease of cytoplasmic content and modifications of membrane integrity were observed. The results were proportional to ergosterol production, which decreased with each EO concentration. Such modifications induced by the EO might be related to the interference caused by its constituents in cell wall synthesis, which affects A. flavus growth and morphology. Complete inhibition of AFB1 production was recorded at 150 μg/mL. T. vulgaris EO exhibited antiaflatoxigenic activity, as AFB1 biosynthesis inhibition occurred at lower concentration (50 μg/mL) than that required for inhibition of ergosterol production (100 μg/mL) and for morphological alterations of hyphae, conidiophores and conidia (100 μg/mL) [61].
\n
On the other hand, cinnamaldehyde was assessed on AFB1 production of A. flavus. The results demonstrated that with cinnamaldehyde treatment, ROS formation reduction was associated with AFB1 production inhibition, which indicate that AFB1 inhibition induced by cinnamaldehyde is related to ROS reduction. Lipid peroxidation is the consequence of ROS formation and has been shown to be involved in AFB1 biosynthesis [62].
\n
Ben Miri et al. [74] reported that Citrus limon EO at 1.75 mg/mL and Citrus sinensis at 2 mg/mL could totally inhibit fungal growth as well as AFB1 production. Additionally, the EOs showed notable antioxidant activity and were non phytotoxic to wheat seeds.
\n
\n
\n
\n
\n
5. In vivo assays of essential oils
\n
Although in vitro assays of EOs is an important first step in determination of the strong activity of plants, in vivo confirmation of activity is important because food models may interact with the bioactive compounds, decreasing their efficacy. Generally, to obtain the same effect in food items as those found in vitro experiences, higher concentrations of EOs must be applied. Thyme, summer savory and clove EOs was tested in tomato paste and all inhibited the mycelia growth of A. flavus. The thyme and summer savory EOs, exhibited the strongest inhibition at concentrations of 350 and 500 ppm, respectively. Taste panel evaluations were carried out in a tomato ketchup base, and the percent of inhibition of each EO in tomato paste was lower than in culture medium. Panelists accepted the results of taste panel with concentration of 500 ppm of thyme EO [69]. Under storage conditions, lemon fruits were completely prevented of A. flavus by S. hortensis at concentrations of 25, 12.5 and 6.25 μL/mL [40].
\n
The effect of hemlock (Cicuta virosa L. var. latisecta Celak) EO on inhibition of decay development in cherry tomatoes was assessed by exposing them to EO vapor at 200 μL/mL. Results showed that the C. virosa var. latisecta EO has potential to control food spoilage [51]. Mentha viridis EO can reduce A. flavus and aflatoxin production in stored corn. The authors showed that this of 300 μL of the EO in 100 g of corn is enough to control the fungal growth and the aflatoxin synthesis [70].
\n
EOs of Origanum majorana L., Coriandrum sativum L., Hedychium spicatum Ham. ex Smith, Commiphora myrrha (Nees) Engl., and Cananga odorata Hook.f. and Thomson, were tested in vivo at different concentration against A. flavus in chickpea seed. During the investigations in food system all EOs exhibited above 50% protection of chickpea seed from A. flavus contamination [71]. The holy basil O. sanctum EO reduced the number of A. flavus up to 62.94, 67.87 and 74.01% when fumigated at concentrations of 0.3, 0.5 and 1.0 μL/mL, respectively, on Rauvolfia serpentina medicinal plant during storage [44]. Boswellia carterii Birdw EO showed protection of the fumigated black pepper fruits up to 65.38% from A. flavus contamination after 6 months of storage [60]. The efficacy of the combined application of chitosan (CH) and Locust Bean Gum (LBG) in combination with bergamot and bitter orange EOs was evaluated to inhibit A. flavus on artificially infected dates. In fruit decay assays coatings based on CH incorporating Citrus, EOs were capable to reduce fungal decay between 52 and 62%. Furthermore, the complete absence of off-flavors and off-odors demonstrated the potential of CH coatings carrying bergamot and bitter orange EOs at sub-inhibitory concentrations to control postharvest growth of A. flavus in dates [72].
\n
\n
\n
6. Limitations of the use of EOs in food systems
\n
In spite of the great potential of EOs against fungal growth and mycotoxin production, their large scale utilization is limited because of volatile nature, organoleptic effect in food systems and susceptibility to oxidation under light, heat, oxygen and moisture. To develop stability, control the release and enhance the efficacy of EOs in food systems, it is necessary for the current research to develop some structural barriers to enclose these bioactive compounds. In this regards, encapsulation of EOs by different physical, physico-chemical and mechanical methods with the assistance of carrier matrices is a trending area of research.
\n
Thus, although the use of EOs can be an interesting strategy, it faces several constraints:
\n
\nPhytotoxicity: The alteration of the integrity of the cell membrane following exposure to EO (responsible for their anti-fungal effect) could also affect plants and induce phytotoxicity at slightly higher than those used to control fungi [19]. It should also be noted that the most effective EOs are generally the most phytotoxic [21].
\n
\nToxicity to mammals: exposure to EOs or their components may be toxic to mammals. For instance, EO with a high content of furanocoumarins may cause dermal irritation and burns during exposure to light due to photosensitization. The linalool, present in the EO of thyme and lavender is also toxic to human dermal cells [73].
\n
\nRapid volatilization: Compounds of EO are highly volatile and may also be oxidatively degraded following exposure to light or temperature rise. This loss of activity would therefore require their reintroduction continuously to maintain the protective effect [35].
\n
\nAlteration of organoleptic qualities: EOs consists of substances aromatic and are often used in cosmetics industry for their pleasant scent. Their application to foods could change their organoleptic qualities altering the taste [54]. To mitigate this effect, strategies such as encapsulation of EOs have been designed to strengthen the prospective use of EOs in the food industry.
\n
The present review has focused on the antifungal and antiaflatoxigenic activity of essential oils. Additionally, other plant extracts possess potential antifungal activities against A. flavus and AFB1 production, but they are generally similar to those observed with the EOs. However, it would seem interesting to further explore the potential of these extracts and their bioactive compounds as they may have several advantages over EOs, such as less sensorial impact on the food.
\n
\n
\n
7. Conclusion
\n
In view of the potential of EOs as inhibitory of A. flavus growth and AFB1 production and their efficacy in food system in controlling fungal contamination, the EOs may be recommended for the formulation of plant based preservatives for enhancement of shelf life and safety of foodstuffs during post-harvest processing because consumers are looking for food with natural characteristics.
\n
\n
Acknowledgments
\n
Thanks to the Government of Aragón and FEDER 2014-2020 (Grant Grupo de Investigación A06_17R) and the Ministry of Higher Education and Scientific Research of Algeria (Project number: PRFU/D00L01UN150120180002) for financial support.
\n
Conflict of interest
The authors declare that there are no conflicts of interest.
\n',keywords:"Aspergillus flavus, aflatoxin B1 (AFB1), essential oils, food system",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68377.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68377.xml",downloadPdfUrl:"/chapter/pdf-download/68377",previewPdfUrl:"/chapter/pdf-preview/68377",totalDownloads:528,totalViews:0,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:47,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"April 21st 2019",dateReviewed:"June 26th 2019",datePrePublished:"July 31st 2019",datePublished:"June 3rd 2020",dateFinished:"July 31st 2019",readingETA:"0",abstract:"Aspergillus flavus has been reported to be one of the most common fungal species in foods. Under conditions of high humidity and moderate temperature, this fungus may synthetize the mycotoxin Aflatoxin B1 (AFB1), which is reported to be hepatotoxic, teratogenic, mutagenic and immunosuppressive to human beings and livestock and it is classified as carcinogenic to humans (Group 1 by IARC). AFB1 affects cereals, oilseeds, nuts, spices, legumes, and dried fruits, while Aflatoxin M1 is a metabolite of AFB1 that can occur in milk and milk products. Current control is aimed at controlling fungal growth and AFB1 production in food by eco-friendly, biodegradable and safer alternatives, in contrast to synthetic chemicals that can be toxic to humans and cause adverse environmental effects. Recently, considerable attention has been directed towards natural compounds, such as essential oils (EOs) as a promising approach for controlling AFB1 production in food. The main reason for supporting the application of natural products is the consumer’s preference for natural methods to preserve foods. The aim of the present review is to summarize knowledge of EOs and AFB1 production from the literature.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68377",risUrl:"/chapter/ris/68377",book:{id:"8094",slug:"aflatoxin-b1-occurrence-detection-and-toxicological-effects"},signatures:"Yamina Ben Miri, Azem Belasli, Djamel Djenane and Agustín Ariño",authors:[{id:"58638",title:"Dr.",name:"Agustin",middleName:null,surname:"Ariño",fullName:"Agustin Ariño",slug:"agustin-arino",email:"aarino@unizar.es",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"245549",title:"Prof.",name:"Djamel",middleName:null,surname:"Djenane",fullName:"Djamel Djenane",slug:"djamel-djenane",email:"djenane6@yahoo.es",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"302571",title:"Ph.D.",name:"Yamina",middleName:null,surname:"Ben Miri",fullName:"Yamina Ben Miri",slug:"yamina-ben-miri",email:"sys_yamina@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Mouloud Mammeri University of Tizi-Ouzou",institutionURL:null,country:{name:"Algeria"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Aflatoxins",level:"1"},{id:"sec_3",title:"3. Methods of aflatoxin decontamination",level:"1"},{id:"sec_4",title:"4. Essential oils: an alternative strategy for control against aflatoxin contamination",level:"1"},{id:"sec_4_2",title:"4.1 Essential oils",level:"2"},{id:"sec_4_3",title:"4.1.1 Overview",level:"3"},{id:"sec_5_3",title:"4.1.2 Mechanism of cellular action of essential oils",level:"3"},{id:"sec_6_3",title:"Table 1.",level:"3"},{id:"sec_9",title:"5. In vivo assays of essential oils",level:"1"},{id:"sec_10",title:"6. Limitations of the use of EOs in food systems",level:"1"},{id:"sec_11",title:"7. Conclusion",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"},{id:"sec_15",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nNogueira JHC, Gonçalez E, Galleti SR, Facanali R, Marques MOM, Felício JD. Ageratum conyzoides essential oil as aflatoxin suppressor of Aspergillus flavus. 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In Vitro inhibition of growth and Aflatoxin B1 production of Aspergillus flavus strain (ATCC 16872) by various medicinal plant essential oils. Macedonian Journal of Medical Sciences. 2011;4(4):345-350\n'},{id:"B51",body:'\nTian J, Ban X, Zeng H, He J, Huang B, Wang Y. Chemical composition and antifungal activity of essential oil from Cicuta virosa L. var. latisecta Celak. International Journal of Food Microbiology. 2011;145:464-470\n'},{id:"B52",body:'\nTian J, Ban X, Zeng H, He J, Chen Y, Wang Y. The mechanism of antifungal action of essential oil from dill (Anethum graveolens L.) on Aspergillus flavus. PLoS One. 2012;7(1):e30147\n'},{id:"B53",body:'\nShukla R, Singh P, Prakash B, Dubey NK. Antifungal, aflatoxin inhibition and antioxidant activity of Callistemon lanceolatus (Sm.) sweet essential oil and its major component 1,8-cineole against fungal isolates from chickpea seeds. Food Control. 2012;25:27-33\n'},{id:"B54",body:'\nKumar A, Shukla R, Singh P, Anuradha, Dubey NK. Efficacy of extract and essential oil of Lantana indica Roxb. Against food contaminating moulds and aflatoxin B1 production. International Journal of Food Science and Technology. 2010;45:179-185\n'},{id:"B55",body:'\nLi Y, Kong W, Li M, Liu H, Zhao X, Yang S, et al. Litsea cubeba essential oil as the potential natural fumigant: Inhibitionof Aspergillus flavus and AFB1 production in licorice. Industrial Crops and Products. 2016;80:186-193\n'},{id:"B56",body:'\nMishra PK, Shukla R, Singh P, Prakash B, Dubey NK. Antifungal and antiaflatoxigenic efficacy of Caesulia axillaris Roxb. Essential oil against fungi deteriorating some herbal raw materials, and its antioxidant activity. Industrial Crops and Products. 2012;36:74-80\n'},{id:"B57",body:'\nMishra PK, Shukla R, Singh P, Prakash B, Kedia A, Dubey NK. Antifungal, anti-aflatoxigenic, and antioxidant efficacy of Jamrosa essential oil for preservation of herbal raw materials. International Biodeterioration and Biodegradation. 2012;74:11-16\n'},{id:"B58",body:'\nMishra PK, Singh P, Prakash B, Kedia A, Dubey NK. Assessing essential oil components as plant-based preservatives against fungi that deteriorate herbal raw materials. International Biodeterioration and Biodegradation. 2013;80:16-21\n'},{id:"B59",body:'\nFerreira FD, Kemmelmeier C, Arrotéia CC, da Costa LC, Mallmann CA, Janeiro V, et al. Inhibitory effect of the essential oil of Curcuma longa L. and curcumin on aflatoxin production by Aspergillus flavus link. Food Chemistry. 2013;136:789-793\n'},{id:"B60",body:'\nPrakash B, Mishra PK, Kedia A, Dubey NK. Antifungal, antiaflatoxin and antioxidant potential of chemically characterized Boswellia carterii Birdw essential oil and its in vivo practical applicability in preservation of Piper nigrum L. fruits. Food Science and Technology. 2014;56:240\n'},{id:"B61",body:'\nKohiyama CY, Ribeiro MMY, Mossini SAG, Bando E, Bomfim NDS, Nerilo SB, et al. Antifungal properties and inhibitory effects upon aflatoxin production of Thymus vulgaris L. by Aspergillus flavus link. Food Chemistry. 2015;173:1006-1010\n'},{id:"B62",body:'\nSun Q , Wang L, Lu Z, Liu Y. In vitro anti-aflatoxigenic effect and mode of action of cinnamaldehyde against aflatoxin B1. International Biodeterioration and Biodegradation. 2015;104:419-425\n'},{id:"B63",body:'\nKumar A, Shukla R, Singh P, Dubey NK. Chemical composition, antifungal and antiaflatoxigenic activities of Ocimum sanctum L. essential oil and its safety assessment as plant based antimicrobial. Food and Chemical Toxicology. 2010;48:539-543\n'},{id:"B64",body:'\nSingh P, Srivastava B, Kumar A, Kumar R, Dubey NK, Gupta R. Assessment of Pelargonium graveolens oil as plant-based antimicrobial and aflatoxin suppressor in food preservation. Journal of the Science of Food and Agriculture. 2008;88:2421-2425\n'},{id:"B65",body:'\nKedia A, Prakash B, Mishra PK, Chanotiya CS, Dubey NK. Antifungal, antiaflatoxigenic, and insecticidal efficacy of spearmint (Mentha spicata L.) essential oil. International Biodeterioration and Biodegradation. 2014;89:29-36\n'},{id:"B66",body:'\nMishra PK, Kedia A, Dubey NK. Chemically characterized Cymbopogon martinii (Roxb.) Wats. Essential oil for shelf life enhancer of herbal raw materials based on antifungal, antiaflatoxigenic, antioxidant activity, and favorable safety profile. Plant Biosystems. 2015;3504:1-10\n'},{id:"B67",body:'\nKumar A, Shukla R, Singh P, Prasad CS, Dubey NK. Assessment of Thymus vulgaris L. essential oil as a safe botanical preservative against post harvest fungal infestation of food commodities. Innovative Food Science and Emerging Technologies. 2008;9:575-580\n'},{id:"B68",body:'\nGorran A, Farzaneh M, Shivazad M, Rezaeian M, Ghassempour A. Aflatoxin B1-reduction of Aspergillus flavus by three medicinal plants (Lamiaceae). Food Control. 2013;31:218-223\n'},{id:"B69",body:'\nOmidbeygi M, Barzegar M, Hamidi Z, Naghdibadi H. Antifungal activity of thyme, summer savory and clove essential oils against Aspergillus flavus in liquid medium and tomato paste. Food Control. 2007;18:1518-1523\n'},{id:"B70",body:'\nGibriel YAY, Hamza AS, Gibriel AY, Mohsen SM. In vivo effect of mint (Mentha viridis) essential oil on growth and aflatoxin production by Aspergillus flavus isolated from stored corn. Journal of Food Safety. 2011;3:445-451\n'},{id:"B71",body:'\nPrakash B, Singh P, Kedia A, Dubey NK. Assessment of some essential oils as food preservatives based on antifungal, antiaflatoxin, antioxidant activities and in vivo efficacy in food system. Food Research International. 2012;49:201-208\n'},{id:"B72",body:'\nAloui H, Khwaldia K, Licciardello F, Mazzaglia A, Muratore G, Hamdi M, et al. Efficacy of the combined application of chitosan and locust bean gum with different citrus essential oils to control postharvest spoilage caused by Aspergillus flavus in dates. International Journal of Food Microbiology. 2014;170:21-28\n'},{id:"B73",body:'\nPrashar A, Locke IC, Evans CS. Cytotoxicity of lavender oil and its major components to human skin cells. Cell Proliferation. 2004;37:221-229\n'},{id:"B74",body:'\nBen Miri Y, Ariño A, Djenane D. Study of antifungal, anti-aflatoxigenic, antioxidant activity and phytotoxicity of Algerian Citrus limon var. Eureka and Citrus sinensis var. Valencia essential oils. Journal of Essential Oil-Bearing Plants. 2018;21(2):345-361\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Yamina Ben Miri",address:"sys_yamina@yahoo.com",affiliation:'
Laboratory of Food Quality and Food Safety, University Mouloud MAMMERI, Algeria
Veterinary Faculty, Instituto Agroalimentario de Aragón-IA2, Universidad de Zaragoza-CITA, Spain
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1. Introduction
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The renin-angiotensin system (RAS), in both its circulating and local tissue roles, is intertwined with multiple other regulatory and signalling mechanisms in various tissues and organ systems. It is thereby involved in a number of clinical disorders with complex pathophysiological mechanisms. This chapter aims at providing a brief overview of the most relevant conditions in clinical practice in which the RAS is important when considering its pathophysiological or therapeutic significance.
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2. RAS in hypertension
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Systemic arterial hypertension is the most crucial global modifiable risk factor for morbidity and mortality and clearly connected to cardiovascular disease development [1]. The RAS plays a central role in the normal regulation of blood pressure and in the development of hypertension [2]. RAS regulates blood pressure through its effector protein angiotensin II (Ang II), which causes the constriction of the efferent arteriole in the kidney glomerulus, as well as the vasoconstriction of arterioles in peripheral circulation [3]. In addition to the above, RAS achieves its effects by stimulating the secretion of aldosterone by adrenal glands and vasopressin by the posterior pituitary, which, through the synergistic effect of water retention and sodium absorption, ensures the stability or increase of the intravascular volume [3]. Abnormal RAS activity is present in conditions such as hypertension and diabetes, which causes slow, continuous damage to the renal parenchyma and leads to the development of chronic kidney disease (CKD) [4, 5].
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The pathophysiology of essential hypertension and other types of hypertension is extremely complex and not fully elucidated, with the RAS contributing only in part to the multifactorial pathophysiological mechanisms [1]. There is a pathophysiological interplay between the RAS, endothelial function/dysfunction, the role of the sympathetic nervous system, natriuretic peptides, inflammation and the immune system [1]. A dysfunction in the factors that contribute to blood pressure control may lead to the development of increases in mean blood pressure [1]. The genetic background/predisposition is of course very relevant. Furthermore, the RAS may play a completely different role depending on the type of hypertension. For instance, in primary aldosteronism, the most common type of secondary hypertension, there is an inappropriate increase in aldosterone synthesis in the setting of low plasma renin [6].
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In addition to its main hemodynamic, fluid volume and vascular tone-changing effects, RAS can participate in stimulating immune cell infiltration, inflammation and fibrosis that is present in conditions such as renal ischemia, myocardial infarction and systemic hypertension [7]. Because of the connection of angiotensin II to endothelial dysfunction, proinflammatory and profibrotic actions and oxidative stress, it is associated with renal, cardiac and vascular injury and thereby directly linked to target organ damage in hypertension [7].
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Besides the most largely know effector arm of the RAS, which includes angiotensin II and the angiotensin II type 1 receptor (AT1R), the RAS system is much more complex and features other important components, including angiotensin-(1–7) (Ang-(1–7), which exerts opposite effects than angiotensin II—it leads to vasodilation, and it has antifibrotic and antiproliferative effects [8]. Angiotensin-(1–7) is being extensively studied, including for its potential antihypertensive effects. Its potentially favourable cardiovascular actions are elicited through Mas G protein-coupled receptors that are expressed in various tissues essential to blood pressure regulation such as the brain, kidneys, blood vessels and heart [9]. However, the clinical potential and role of angiotensin-(1–7) in the pathophysiology and treatment is not yet clear because of a lack of adequate clinical studies and data [9].
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From a therapeutic standpoint, there are several important groups of pharmacological agents targeting the RAS in hypertension. These include already clinically well-established antihypertensive drugs such as inhibitors of the angiotensin-converting enzyme (ACE inhibitors), AT1R blockers or direct renin inhibitors [2]. However, novel potential drugs targeting the RAS are also being developed, including agents seeking to upregulate the ACE2/angiotensin-(1–7)/Mas axis—counteracting the unwanted actions of the ACE/angiotensin II/AT1R axis—or agents such as new small molecule inhibitors, recombinant ACE2 protein, as well as gene therapy suppressing angiotensinogen at the RNA level [2].
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3. Role in heart failure
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3.1 Introduction
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Heart failure is a progressive condition defined by the inability of the heart to pump enough blood to meet the body requirements for nutrients and oxygen.
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It develops when the heart fails to pump enough blood to meet the requirements of metabolizing tissues, which is caused by conditions like ischaemic heart disease, arrhythmias, etc., and produces different symptoms and signs. Some of the symptoms and signs include the following: exertional dyspnoea and/or dyspnoea at rest, orthopnoea, acute pulmonary oedema, chest pain, tachycardia, fatigue and weakness, distention of neck veins, rales, wheezing, S gallop or pulsus alternans, etc. [7].
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Heart failure is one of the most challenging pathophysiologic states with increasing prevalence in the Western world, affecting 1–2% of the total population [10].
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The neurohumoral basis of heart failure is complex and includes interaction between components of the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system and counterregulatory mediators (i.e., the natriuretic peptides).
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Activation of neurohumoral mechanisms (i.e., the renin-angiotensin-aldosterone system) initially improves cardiac output, but despite this, counterregulatory mechanisms finally lead to heart failure syndrome with different signs and symptoms [11].
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3.1.1 The neurohumoral pathophysiology of heart failure
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The renin-angiotensin-aldosterone system (RAAS) plays a major role in the pathogenesis of heart failure, and the impact of treatment that targets RAAS is significant.
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The neurohumoral basis of heart failure includes activation of RAAS by renal hypoperfusion (caused by hypotension or hypovolemia) and sympathetic activation [12].
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Production of angiotensin II leads to vasoconstriction of arterioles and an increase in blood pressure, leads to antidiuretic hormone secretion, and stimulates the release of aldosterone and consequently salt and water retention [12] (\nFigure 1\n).
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Figure 1.
A summary of the key pathogenesis of RAAS in heart failure. RAAS, renin-angiotensin-aldosterone system; ADH, antidiuretic hormone.
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All of the above temporarily improve cardiac output but finally propagate the heart failure syndrome via overwhelming the opposing vasodilators and natriuretic mediators (i.e., A-type natriuretic peptide and B-type natriuretic peptide) which are mainly secreted form heart in response to the degree of ventricular stretch [13].
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An imbalance between regulatory and counterregulatory mechanisms is the major pathophysiological target in heart failure treatment.
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Therefore drugs that modulate RAAS (i.e., ACE inhibitors, beta-blockers, angiotensin receptor blockers and mineralocorticoid receptor antagonists) represent the core of treatment augmented by angiotensin receptor neprilysin inhibitors as a novel therapy [14].
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4. Role in kidney failure
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Chronic kidney disease (CKD) is a disease whose prevalence is constantly increasing in the elderly in the current, modern age [15]. CKD has multiple causes, where different organ dysfunctions lead to the reduction of the glomerular filtration rate, a disorder of excretory and endocrine function of the kidney and a significant diminishment of quality of life of such patients [16, 17]. End-stage renal failure, where glomerular filtration rate falls to less than 15 ml/min, requires treating the patient suffering from CKD with haemodialysis, which is a process in which blood is filtered through a semipermeable membrane, intended to replace the excretory function of the kidney [18]. Considering the high costs of treatment of patients with CKD, much research has been dedicated to studying the pathophysiological mechanisms that contribute to its development and exacerbation with the intention of developing new medications and procedures in an attempt to slow down the increase in the prevalence of patients with CKD. Abnormal activity of the renin-angiotensin system (RAS), regardless of the primary cause of CKD, has an immense value in the results of many studies [19].
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In patients with CKD, RAS activity is increased in the central and peripheral circulation, which is indirectly confirmed by the fact that the activity and expression of the angiotensin-converting enzyme (ACE) linearly increases as the glomerular filtration rate decreases in patients with CKD [20]. Although ACE is the main enzyme that leads to RAS activation in patients with CKD by converting angiotensin I (Ang I) into angiotensin II, certain studies have shown that in particular types of acute renal failure, such as the one caused by aristolochic acid, there is a more significant RAS activation through chymases and a relatively mild ACE activation [21]. Chymase inhibition causes the slowing of the progression of fibrotic and inflammatory changes in the renal parenchyma, which makes it possible to talk about the synergistic effect of ACE and chymases in the activation of RAS effectors [21]. The role of chymase is also crucial for RAS activation in patients with stage five CKD treated with haemodialysis [22]. Considering the lower-than-normal levels of ACE and high chymase levels in such patients than those in patients with the same stage of CKD who are undergoing conservative treatment, it is clear that in such patients, the high levels of angiotensin in the renal parenchyma are a consequence of the increased chymase activity [22]. Increased chymase and angiotensin II activity leads to faster development of renal fibrosis in patients treated with haemodialysis than that in patients with the same stage of CKD who are not treated with dialysis [22].
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According to new findings, nearly all RAS components may have a big effect on the development of CKD and its predisposing factors, such as hypertension. The activity of the prorenin receptors (PRR), which is found in the collecting duct cells of the kidney and increases the affinity of renin for angiotensinogen, is significant for RAS activation [23]. PRR blockade in animal models causes the decrease of RAS activity, which indirectly decreases levels of proteinuria, macroscopic signs of interstitial fibrosis and renal fibrosis. Although the increased activity of the systemic RAS plays a large role in the development of CKD, new findings place greater emphasis on the role of the local RAS in the renal and brain parenchyma and their synergistic effects. Prolonged activation of the local RAS in the renal parenchyma causes the production of inflammatory cytokines IL-6 and TNF-alpha, which lead to the infiltration of inflammatory cells into renal tissue, tissue damage and fibrosis [24] (\nTable 1\n).
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Component of RAS system whose activation or inhibition is involved in the development of CKD
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Explanation of mechanism
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References (author, year and title of study)
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Prorenin receptor placed in collecting duct cells of kidney
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PRR increases the affinity of prorenin and renin for angiotensin, and blockade of this receptor decreases activity of components of RAS and reduces laboratory markers of CKD
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[23] (Fang et al., 2018, Role of (pro)renin receptor in albumin overload-induced nephropathy in rats)
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Wnt/β catenin signalling pathway as the main pathway for expression of RAS components in kidney and brain tissue (hypothalamic paraventricular nucleus )
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Wnt/β catenin signalling pathway is the main pathway of molecular expression of RAS components in brain and kidney tissue; local brain RAS and renal RAS communicate through the sympathetic nervous system
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[26] (Zhou et al., 2019, The regulation effect of WNT-RAS signalling in hypothalamic paraventricular nucleus on renal fibrosis [25] (Xiao et al., 2019, Wnt/β-catenin regulates blood pressure and kidney injury in rats)
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Angiotensin-converting enzyme in systemic circulation
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Activity of ACE in systemic circulation increases with an increase of severity of CKD and in that way leads to further deterioration of kidney function
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[20] (Wolke et al., 2017, Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort)
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Chymase enzyme as an alternative pathway of activation of angiotensin II
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Chymase, as an alternative pathway of RAS activation, converts angiotensin I to angiotensin II; blockade of this enzyme prevents CKD progression
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[21] (Hsieh et al., 2017, Renal chymase-dependent pathway for angiotensin II formation mediated acute kidney injury in a mouse model of aristolochic acid I-induced acute nephropathy)
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Neprilysin as an secondary enzymatic pathway for activation of angiotensin-(1–7)
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Neprilysin, similar to ACE2 enzyme, converts angiotensin II to angiotensin-(1–7) which binds to Mas receptors and causes vasodilatory and renoprotective effects; prevents CKD
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[31] (Domenig et al., 2016, Neprilysin is a mediator of alternative renin-angiotensin-system activation in the murine and human kidney)
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Angiotensin receptor-associated protein (ATRAP), which is associated with AT1 receptor
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ATRAP inhibits expression of AT1 receptor with circulating angiotensin II; it disables RAS activity in the development and progression of CKD
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[32] (Kobayashi et al., 2017, An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model)
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Table 1.
RAS in the pathophysiology of renal failure.
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Recent studies have identified the Wnt/β catenin signalling pathway as the main pathway for expression of RAS components in renal tissue, and its blockade in animal models of CKD was connected to significant clinical improvement and reduction of proteinuria and creatininaemia [25]. The Wnt/β catenin signalling pathway is the main pathway for RAS expression in the hypothalamic paraventricular nucleus which indirectly affects the renal tissue RAS through activation of the sympathetic nervous system [26]. Blocking the central Wnt/β catenin signalling pathway leads to the inhibition of expression of the renal RAS components and to the slowing of the progression of renal fibrosis; it is thus clear that in the tissue, local RAS is regulated by the central nervous system [5, 26]. Inhibition of RAS through intraventricular injection of losartan leads to a decrease in peripheral sympathetic nervous system activity and renal RAS activity, which potentially makes the sympathetic nervous system one of the possible pathways of communication between renal RAS and brain RAS [5]. In animal models of CKD, where a strong expression of RAS components was noticed after incubation of renal cells with inhibitors of the Wnt/β catenin signalling pathway, there is mainly a reduced expression of profibrotic factors in the renal parenchyma. In one such model, positive feedback was noticed between RAS and the Wnt/β catenin signalling pathway, where angiotensin II increases the expression of proteins of that signalling pathway, which is probably also the mechanism used by the central and circulating RAS to stimulate the activity of local RAS [25].
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The role of the Wnt/β catenin signalling pathway in RAS activation and local fibrosis is also confirmed by research done on its inhibitors. The Klotho gene, which plays a significant role in slowing the process of ageing, encodes the protein which inhibits the components of the Wnt/β catenin signalling pathway [27]. In renal tissue of animal models of CKD, the Klotho level is inversely associated with the levels of RAS components, and the Klotho expression level showed a negative correlation with the degree of renal fibrosis [27]. Experimental studies on animal models that proved the effect of vitamin D on the decreased level of CKD and renal fibrosis measure an increased Klotho level, decreased activation of the Wnt/β catenin signalling pathway and low tissue RAS activity in in vitro conditions [28]. Multiple experimental studies have demonstrated the connection between the Wnt/β catenin signalling pathway and harmful RAS activation in CKD and renal fibrosis, which paves the way for new research with the aim of finding efficient medications that would slow the development and progression of CKD by affecting the above components [24, 26].
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Local renal RAS may be activated by the effects of free radicals, which stimulate the expression of RAS components at the molecular level of signalling pathways. The above factor is one of the main mechanisms examined in harmful RAS activation in diabetic nephropathy, which is one of the leading causes of CKD [5]. The effect of free radicals on the development of CKD was demonstrated in studies examining strong antioxidants, such as melatonin. The application of melatonin in animal models of CKD leads to a reduced expression of all RAS components, decreased levels of markers of interstitial fibrosis and increased expression of antioxidant enzymes, such as superoxide dismutase [29]. The role of RAS in CKD has also been examined at the level of angiotensin receptors. Angiotensin II mainly produces its effect by activating the AT1 receptor, through which it causes vasoconstriction and has a proinflammatory and profibrotic effect on renal parenchyma. In addition to the AT1 receptor, there is also the AT2 receptor, which is presumed to have a vasodilatory and renoprotective effect. In experiments on animal models of CKD using resveratrol, which is a selective AT1 receptor antagonist and AT2 receptor agonist, increased expression of antioxidant enzymes was demonstrated, as was a reduced expression of fibronectin and type IV collagen—which are markers of tissue fibrosis [30].
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A similar role, but with another agonist as the AT2 receptor, is played by the Mas receptor, which is also a part of RAS that contributes to local vasodilatation and has renoprotective effects. It is also known that, in normal circumstances, the Mas receptor is activated by angiotensin-(1–7), which is synthesized by the action of angiotensin-converting enzyme 2 (ACE2) on angiotensin II [31]. More recent studies of animal models with ACE2 enzyme blocking have determined the existence of stable levels of angiotensin-(1–7), and neprilysin was found to be the secondary enzymatic pathway contributing to its increase [31].
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The AT1 receptor activity is regulated by a special associated protein, which regulates its expression and thus indirectly also regulates RAS activity. ATRAP inhibits the expression of the AT1 receptor and thus decreases the effect that circulating angiotensin II has on blood pressure levels, while also having a long-term effect by inhibiting the secretion of TNF-alpha, whose inflammatory factors contribute to the development of CKD [32].
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The results of the latest studies confirm the essential role that RAS plays in the development and progression of CKD, which emphasizes the need and paves the way for new research on the subject of medications and therapeutic procedures that could efficiently decrease the growing epidemic of patients with CKD by affecting RAS components [32].
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5. Role in diabetes
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The RAS has been implicated in the human pathophysiology of numerous diseases, of particular importance in the development and onset of complications of diabetes as one of the most lethal non-communicable metabolic diseases [33]. The major intracellular mechanisms responsible for the adverse effects of diabetes are excessive production of advanced glycation end-products (AGEs), activation of the hexosamine biosynthetic pathway, activation of protein kinase C (PKC), lipotoxicity, mitochondrial dysfunction, enhanced oxidative stress and activation of intracellular RAS [34]. Because of hyperglycaemia in diabetes, intracellular accumulation of glucose that is not oxidised by glycolysis (because of inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by reactive oxygen species (ROS)) is already being diverted to other metabolic pathways [34]. The result of GAPDH inhibition is the increased flux of glucose metabolites through four other metabolic pathways. These are the aldose reductase or polyol pathway, the formation of advanced glycation end-products, the formation of diacylglycerol (DAG), resulting in protein kinase C activation and increased flux via the hexosamine biosynthesis pathway (HBP), and generation of the end product uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a substrate used for protein glycosylation [35]. The polyol pathway leads to NADPH and glutathione deficiency resulting in massive ROS formation [34]. On the other hand, in addition to leading to the development of insulin resistance, hyperlipidaemia also has a lipotoxic effect on cells [34]. Excessive fatty acid (FFA) inflow leads to increased and inefficient oxidation of FFA in the mitochondria with consequent generation of reactive oxygen radicals and exacerbation of mitochondrial dysfunction [34]. In diabetes, mitochondrial function decreases, and mitochondrial mass decreases, which is most likely connected to a decrease in OxPhos protein expression [34]. Excessive amounts of ROS, AGEs, DAG and activated PKCs and post-translational O-GlcNAcylation of transcription factors jointly lead to activation of intracellular synthesis of AGT, renin and chymase and thus activation of intracellular RAS. In addition, AGEs act via RAGE receptors that, through activation of inflammatory signalling pathways (TGF β, MAPK, JNK and NF-κB), lead to enhanced expression of collagen proteins and other extracellular matrix proteins. Together with activated RAS and activated PKCs isoforms by DAGs and by some lipid intermediates (e.g., ceramide, diacylglycerol and acylcarnitine), there is increased inflammation, fibrosis and apoptosis of cells attacked by hyperglycaemia [34] (\nFigure 2\n).
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Figure 2.
Intracellular mechanism of activation and deleterious action of RAS in diabetes. ACE, angiotensin-converting enzyme; AGEs, advanced glycation end-products; Ang, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; ARB, angiotensin receptor blocker; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; DAG, diacylglycerol; FFA, free fatty acid; GAD-3P, glyceraldehyde 3-phosphate; iAng, intracellular angiotensin; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa beta; PKC, protein kinase C; RAGE, receptor for advanced glycation end-products; TCA cycle, tricarboxylic acid cycle; TGF-β, transforming growth factor beta.
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6. The role of intracellular Ang II (iAngII)
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In addition to the commonly known circulating RAS, there is a local tissue intracellular RAS that occurs in all cells that produce peptides [36]. Activation of the transcription factors and gene expression described in the previous paragraph results in the synthesis of intracellular angiotensinogen, which is converted to angiotensin I by renin, and becomes the intracellular angiotensin II by the proteolytic action of chymase [34]. Chymase is a key proteolytic enzyme that completely replaces the role of extracellular angiotensin-converting enzyme within the cell and, unlike other alternative enzymes (tonin and cathepsin), has the highest substrate specificity. Intracellular Ang II levels are three times higher in diabetic patients than those in nondiabetic patients [37]. Intracellular Ang II has intracrine, autocrine, paracrine and endocrine functions [38]. iAngII by direct unidentified mechanisms, independent of global circulating RAS, causes an increase in oxidative stress and cell apoptosis and enhances the expression of intracellular components of RAS. Activation of AT1R via iAng II can trigger the MAPK signalling pathway (p38-MAPK), promoting inflammation, cell proliferation and thrombosis [37]. The study showed that an increase in phosphorylated p53 was associated with an increase in iAngII, enhanced activation of AT1R and RAS-independent O-glycosylation [39]. Also, iAng II enhances AT1R expression and decreases extracellular ACE2 expression in diabetic patients [37]. Increased expression of AT1R leads to stronger and negative effects of activation of AG1R [40]. ACE2 activation and AT2R activation are known to have protective effects on cells [38]. Direct inhibition, glycosylation or some other forms of protein modification leads to impaired ACE2 activity [41]. ACE2 catalyses the breakdown of Ang II to produce angiotensin-(1–7), which has an anti-inflammatory and antioxidant role [41]. In an animal model, it has been shown that oral administration of the recombinant-rich bacterium Lactobacillus paracasei (LP) can express and deliver human ACE2 to the circulation, which prevents the development of diabetic retinopathy and probably other forms of diabetes complication [41]. This potent protective effect of AT2R is prevented by the activation of AT1R by either iAngII or eAngII which results in the direct inhibition of AT2R activity or reduced expression of AT2R[38]. On the other hand, eAngII acts through AT1R and AG2R, and activation of a particular receptor depends on their balance regulated by the indicated intracellular mechanisms [38]. Thus, activation of AT1R by extracellular or intracellular Ang II leads to activation of several signalling pathways, activation of growth factor receptors, promotion of ROS synthesis and other apoptotic and fibrotic responses [37]. Patients with diabetes have 10 times higher levels of prorenin than renin than healthy subjects, and prorenin is thought to contribute more to the pathogenesis of diabetic complications [40]. Also, hyperglycaemia induces an increase in aldosterone by activation of AT1R and an increase in local Ang II whose pathophysiological effects in diabetes are unknown, but are thought to synergize with Ang II causing inflammation, apoptosis and fibrosis [42].
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7. Influence of the RAS on pancreatic tissue, muscle tissue and adipose tissue
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Chymase is found in all cells, and predominantly in mast cells, so we can also associate inflammation with the activation of RAS [43]. Activated intracellular RAS is thought to induce growth factor and cytokine synthesis by acting directly on other cells, which explains proteinuria in patients with diabetes with ACE inhibitors, resistance to antihypertensives in diabetics with hypertension and higher cardiovascular mortality in diabetics with hypertension [44]. Ang II reduces blood flow through beta Langerhans cells [45]. Ang II is thought to directly affect beta cell function and mass, promoting inflammation, oxidative stress and fibrosis [45]. All these effects finally lead to a decrease in insulin secretion and thus at least partially participate in the development of diabetes when it comes to beta cells [45]. Since muscle tissue accounts for about 80% of insulin-stimulated glucose disposal, the decrease in tissue perfusion caused by RAS directly contributes to the decreased glucose uptake into muscle cells [45]. On the other hand, it also leads to microvascular dysfunction, but all of this needs to be explored in more detail in the future [46]. Blockade of RAS causes overexpression of the GLUT4 transporter in skeletal muscle and accumulation of bradykinin that stimulates glucose uptake into skeletal muscle [47]. Long-term valsartan treatment reduced oxidative stress, NF-κB activation and TNF-alpha expression in skeletal muscle [48]. iAngII synthesized in adipose tissue (AT) leads to adipocyte hypertrophy, increased lipid synthesis and storage and inhibition of lipolysis, thereby modulating the lipid capacity of adipocytes to develop and worsen insulin resistance [49]. Also, Ang II promotes AT gene expression by enhancing the synthesis of proinflammatory adipokines and thus macrophage infiltration [49]. In female mice lacking the angiotensin II type 2 receptor (AT2R), decreased insulin sensitivity to adipose tissue leads to compensatory adiponectinaemia [50]. Animal model research has shown that RAS in diabetic rats leads to remodelling of the sympathetic nervous system, increased oxidative stress and increased norepinephrine levels in the myocardium itself [51]. In addition to its role in controlling electrolytes, blood pressure and vascular tone, RAS is involved in the development of inflammation, oxidative stress, metabolic syndrome, diabetes and its complications [49, 52, 53, 54, 55].
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8. Use of RAS inhibitors in patients with diabetes
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Therapy with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is a mainstay of treatment for diabetes mellitus (DM) because they prevent the development of diabetic complications [56]. Also, these drugs reduce the incidence of newly acquired DM II by 22% in the high-risk population by improving insulin sensitivity and insulin secretion [49]. Unfortunately, ARB and ACE inhibitors do not block iAngII, but only the autocrine and paracrine effects of extracellular Ang II, while the renin inhibitor aliskiren blocks extracellular and intracellular Ang II synthesis; therefore, aliskiren of all RAS inhibitors tested has the most potent effect in inhibiting fibrosis and apoptosis of cells exposed [49]. Insulin treatment showed no pronounced effect on the inhibition of iAngII synthesis [57]. Numerous meta-analyses state that many RAS blockers in use today will not have an additional benefit for diabetics over nondiabetics [38]. Today, attention is increasingly focused on the pharmacological activation of angiotensin II type 2 receptor and angiotensin-converting enzyme 2, which has been shown to reduce oxidative stress, inflammation, fibrosis and cell apoptosis in diabetics [57]. The protective effect has been demonstrated in combination therapy with activator neprilysin inhibitors (NEPi) with angiotensin-converting enzyme 2 [57]. This combination in diabetic rats significantly contributes to the inhibition of inflammatory, profibrotic and apoptotic signalling and thus prevents the development of diabetic cardiomyopathy and nephropathy [58]. Concomitant activation of the angiotensin II type 1 receptor (AT1) and activation of glucagon-like peptide-1 (GLP-1) receptor in insulin resistance leads to a decrease in oxidative damage to renal function and a significant decrease in albuminuria [59]. Urinary angiotensinogen may serve as an important marker of RAS activity, which may help in the decision to initiate treatment with RAS inhibitors and prevent the development and progression of complications in patients with diabetes [59, 60]. Numerous studies are based on uncontrolled studies of RAS inhibition; therefore, some studies discuss the beneficial effects on insulin sensitivity [61, 62, 63, 64, 65], and controversial studies report conflicting data [66, 67, 68, 69]. Dosage and duration of treatment can be important factors that can create controversy, and in the future, they present us with a challenge in discovering the beneficial effects of inhibiting potent RAS [49].
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9. Role in other clinical conditions
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The local renin-angiotensin system in blood vessels of the brain parenchyma plays a significant role in regulating blood flow. The central nervous system RAS is separated from the systemic circulation by the blood-brain barrier, which enables the homeostasis of vasoconstriction and vasodilation of blood vessels in the brain, independent of blood pressure changes. Components of local RAS, such as renin, angiotensin II, ACE and AT1 receptor, participate in the cascade that results in vasoconstriction and anti-inflammatory effects, while activation of the AT2 receptor by angiotensin II and activation of the Mas receptor by angiotensin (1–7) cause vasodilation and increase local brain tissue perfusion; the above has been demonstrated in experimental animal models [70]. Reduced levels of angiotensin-converting enzyme 2, which produces vasoprotective angiotensin (1–7), have been found in clinical trials of patients with acute ischemic stroke; its levels normalise only in the post-acute phase of the stroke [71, 72]. As regards the above, the most sensational research conducted is the research on experimental animal models in which a reduction in the size of the ischemic penumbra after a stroke was found upon the use of the AT1R antagonist and the AT2R agonist; this represents a new treatment option for patients with ischemic stroke [71, 73]. Apart from the effect it has on regulating cerebral circulation, RAS also has a great effect on learning and memory acquisition through the activation of the AT2 receptor within the hippocampus and the cortex [74]. In animal models of dementia induced by scopolamine, simultaneous oral treatment of mice with ACE and ARB inhibitors slows cognitive decline [75]. It has been confirmed in clinical trials that ACE inhibitors and ARBs have an effect on slowing the progression of dementia caused by Alzheimer’s disease, cerebrovascular disease and other diseases [70].
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Local RAS in the retina, which is also part of the central nervous system, plays a significant role in the development and progression of diabetic retinopathy. The effect of angiotensin II on the production of free radicals and inhibition of antioxidant enzymes, which causes an increase in VEGF production, which in turn leads to the development of diabetic retinopathy by stimulating angiogenesis, has been confirmed in experimental animal models [76].
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RAS plays a significant, though as yet insufficiently explored, role in the regulation of physiological processes in the lung parenchyma, which is evident in the fact that long-term treatment by ACE inhibitors and ARBs decreases the incidence of inflammatory, infectious and structural diseases of the lung parenchyma [77].
\n
Coronavirus disease 2019 (COVID-19) caused a serious pandemic, with cardiovascular disease (10.5%) having the highest mortality rate, especially if over 70 years of age [78]. The hypothesis of an association between the use of ACE inhibitors and COVID-19 is based on the fact that the COVID-19 agent (also known as SARS-CoV-2) uses the SARS-CoV receptor angiotensin-converting enzyme 2 for entry into target alveolar epithelial cells causing pneumonia [79]. ACE2 is found in endothelial cells, type I and II alveolar cells of the lungs, enterocytes, basal epidermal cells of the skin and epithelium of the nose, oral mucosa and nasopharynx, and ACE2 levels decline with age and are lower in patients with chronic diseases [80]. Cardiovascular patients taking ACE inhibitors or AT blockers significantly increase mRNA expression and activity of cardiac ACE2 [81]. By binding SARS-CoV-2, ACE2 is depleted, which inhibits the protective axis and may cause imbalances between the ACE/Ang II/AT1R pathway and the ACE2/Ang-(1–7)/Mas receptor in RAS, which may result in an increase in ACE activity and exacerbation of acute severe pneumonia by an increase in proinflammatory factors [82]. Animal models have also shown that acute ACE-induced lung injury results in increased ACE activity and Ang II expression, whereas ACE2 and Ang- (1–7) activities are reduced. In patients undergoing ACEi therapy, there is an increase in renin whose cascade response is directed towards the formation of ACE2 as an important balancing factor [83]. The binding of SARS-CoV-2 may decrease ACE2 function, leading to increased neutrophil infiltration into the lungs and resulting in excessive inflammation and injury [84]. The progression of inflammation could lead to hypoxia-induced enhanced expression of renin synthesis, which closes the vicious cycle, and it is clear that hypertension is an important risk factor in patients with COVID-19 [85, 86]. A meta-analysis conducted by Caldeira et al. did not highlight the protective effect of ACEi and ARBs [87]. A 5-year study showed that ACE administration had a higher risk of pneumonia than ARB administration. Low-dose lisinopril in neurological dysphagia does not reduce pneumonia but increases mortality. Compared to calcium channel blockers, ACE inhibitors showed a lower mortality rate in patients with viral pneumonia [88]. Paradoxically, some authors report that chronic administration of ACE inhibitors or ARBs leads to an increase in ACE2 activity, which reduces the risk of infection because ACE2 dysregulation is triggered by the binding of a virus that increases the production of protective angiotensin-(1–7) [89]. This is based on the knowledge that ACEI/ARBs have shown an anti-inflammatory effect in the lungs, and it is suggested that they reduce the risk of pneumonia in elderly patients with hypertension with Parkinson’s disease, in patients after CVI and in patients with chronic obstructive pulmonary disease (COPD) [90]. Patients with viral pneumonia who retained ACE and ARB had lower mortality rates and the need for intubation [91]. A major Chinese study has reported that ACE2 expression level is not crucial for the severity of COVID-19 infection but also plays an important role in the immune response and viral particle count and that, given pressure control, ACEi and ARBs can be used in patients with new types of coronavirus pneumonia to reduce pulmonary inflammation and reduce patient mortality rates [80]. No information is currently available on the number of hospitalized COVID-19 patients with hypotension, but it can be considered as an important limiting factor for the use of ACE inhibitors or ARBs in the treatment of COVID-19 patients [89]. Thus, we do not yet have the most accurate information on the real impact of ACEi and ARBs on infectious diseases such as pneumonia. Research should be conducted as soon as possible to prove the hypotheses and thus reduce the risk of mortality in patients taking ACE inhibitors and/or AT blockers.
\n
At its molecular level, vitamin D is a prorenin molecule transcription antagonist. In animal models with knockout genes for vitamin D receptors, this is reflected in an elevated transcription of renin-angiotensin system components, development of hypertension and chronic cardiac and renal failure [92]. Data obtained through clinical studies that investigated possible therapeutic uses of vitamin D supplementations on RAS was inconsistent. Exogenous application of vitamin D has a distinct effect on local kidney tissue RAS. It causes a reduction in angiotensin excretion in patients with chronic renal failure and/or in renal transplant recipients [93, 94]. However, in prospective studies, the simultaneous application of vitamin D and drugs that affect RAS on patients with arterial hypertension or in normotensive patients did not result in a decrease in arterial pressure or the difference in RAS component concentrations [95, 96]. The exception with regard to the previous statements is the prospective study carried out by Wu et al., in which a decrease in blood pressure values was noted after 6 months of perioral administration of high doses of vitamin D, as well as a decrease in atherosclerotic plaque circumference and thickness on epicardial blood vessels of test subjects that underwent a coronarography [97]. The latest data points out an evident need for supplementary studies that must include a sufficient period for observation and a sufficiently large dose of vitamin D supplementations that would achieve a clearly notable effect on the observed variables.
\n
Ghrelin, which is a peptide hormone secreted by the stomach, fulfils its physiological role by binding to target receptors in the central nervous system in which it triggers the feeling of hunger or the need for sleep by regulating hormone levels [98]. However, according to newly acquired data, the acylated form of this enzyme plays a significant, opposite role in the cardiovascular system, namely, in the area of the heart ventricle and aorta. Unlike RAS, which causes ischemic expansion and tissue degradation in cases of acute myocardial infarction, ghrelin has an opposite effect that is realized through its receptors. It causes a reduction in angiotensin-converting and proapoptotic enzyme expression, along with a reduction in oxidative stress [99].
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10. Therapy targeting the RAS
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Knowledge of the physiology of RAS and participation in the pathophysiology of cardiovascular and other diseases has led to the development of drugs that have an effect on numerous stages of the synthesis of RAS components and their action on known RAS receptors. Blocking of RAS is achieved by direct inhibitors of the enzyme responsible for the synthesis of RAS component (renin-angiotensin-converting enzyme) and inhibition of receptors through which they exert their effects (angiotensin receptor blockers) [100]. In recent years, new RAAS components have been discovered whose pathways have protective effects, which have enabled the development of new therapeutic targets [101]. One of the most impressive approaches in the study of novel therapeutic methods is the selective deletion of hepatic angiotensinogen [102].
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10.1 Direct renin inhibitors
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A low molecular weight non-peptide renin inhibitor that is well tolerated and has clinical utility is called aliskiren [103]. Clinical trials have demonstrated a strong antihypertensive and organoprotective (cardioprotective, renoprotective) role for the renin inhibitor [104, 105]. It has been shown to be very good at regulating blood pressure in hyperthyroid rats [106]. The use of aliskiren showed a decrease in the antidiuretic effect of renin [107]. This drug has a potent antifibrotic activity mediated by the reduction of oxidative stress and fibrogenic cytokines in all tissues [108].
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10.2 ACE inhibitors
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ACE is a multifunctional enzyme with numerous biological substrates. These classic drugs directly inhibit the vasoconstrictive and proliferative effects of the already known ACE/Ang II/AT1R axis and indirectly stimulate the production of the vasoprotective and antiproliferative peptide Ang-(1–7) [100].
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10.3 Angiotensin I receptor antagonists/blockers (ARBs)
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Selective AT1 receptor blockers inhibit the effects of Ang II on AT1R. The main effect is the inhibition of vasoconstriction, i.e., the reduction of peripheral vascular resistance, without significantly affecting the heart rate [109]. Administration of these drugs significantly reduces cardiovascular mortality, stroke, myocardial infarction and the onset and development of complications of diabetes [110]. The consequence of AT1R blockade is an increase in the secretion of renin, ACE and consequently Ang II [109].
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10.4 Other therapeutic compounds
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10.4.1 β1 blockers
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Blocking the sympathetic β1 receptor in plasma cells of the dense macula results in a decrease in plasma renin levels. An effect on the reduction of Ang II has been demonstrated. β1 blockers also reduce the conversion of prorenin to renin [111].
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10.4.2 Prorenin receptor antagonist/blocker
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The newly discovered prorenin receptor blocker is a decoy peptide for the handle region of the prorenin average (HRP) [112]. It binds competitively to the non-proteolytic domain of prorenin, thereby preventing its activation [113]. Studies have shown that its administration reduces renal and cardiac impairment without affecting blood glucose levels in diabetic and antihypertensive rats [112]. Transgenic rat models with overexpression of the prorenin receptor showed massive proteinuria and glomerulosclerosis, but administration of HRP significantly suppressed the production of proteinuria and glomerulosclerosis, but without affecting the level of circulating Ang II [114]. Another study questions the use of HRP in which there was no reduction in target organ damage in hypertensive rats, nor did the blockade affect the expression of the prorenin receptor. It is thought that HRP cannot block extracellular signal-regulated kinases (ERKs) that induce prorenin and renin and that its positive effect depends on an undefined mechanism and not on the antagonism of the prorenin receptor. Clearly, this receptor plays a major role in the human body, but its cellular biology and its impact on the cardiovascular system need further investigation [112].
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10.4.3 Chymase inhibitors
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The chymase enzyme is only active in damaged tissues resulting from the activation of intracellular RAS [115]. The chymase can convert TGF-beta and MMP-9 precursors into their active forms that induce inflammation and fibrosis. To date, there are no specific results from human studies, but animal models have shown that inhibitors of chymase enzyme prevent vascular proliferation, myocardial fibrosis after cardiac infarction, development of diabetic complications, development of skin keloid and the occurrence of abdominal aortic aneurysm [116].
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10.4.4 Angiotensin II receptor agonist
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The first synthesized oral agonist was called Compound 21 (C21), which showed organoprotective, anti-inflammatory, antithrombotic, antifibrotic and antiapoptotic effects in an animal model. It has a very high affinity for AT2R and a low affinity for AT1R [103]. C21 lowers mean arterial pressure and improves ventricular function after myocardial infarction [117]. It significantly stimulates the growth of the hippocampal neurons, and its role mediated through AT2R in enhancing congenital functions is further investigated [118].
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10.4.5 Activation angiotensin-converting enzyme 2 and Mas receptor agonist
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Activation of the protective axis of RAS by ACE2, Ang-(1–7) and Mas receptors achieves beneficial vascular effects. The aim of this therapeutic target is to enhance the effect of ACE2, reduce the level of circulating Ang II and redirect the formation of Ang-(1–7), which by acting on AT2R and Mas receptors, achieves its protective effect. For the time being, the administration of human recombinant ACE2 is known to have an antihypertensive effect. ACE2 diminazene aceturate (DIZE) activator also reduces body weight and markers of adipogenesis and improves plasma lipid profile. They have a protective and pancreatic effect because it increases proliferation and decreases β-cell apoptosis and promotes glucose-stimulated insulin secretion. Overexpression or expression of ACE2 enhances basal and insulin-stimulated glucose uptake into cells, especially hepatocytes and adipocytes. Another tested ACE2 activator is 1-[[2-(dimethylamino) ethyl] amino]-4-(hydroxymethyl)-7-[[(4-methylphenyl) sulfonyl] oxy] -9H-xanthone-9 (XNT), which, through 2 weeks of continuous treatment, led to an improvement in endothelial function in hypertensive and diabetic rats by reducing oxidative stress. It also causes Mas receptor-mediated vasodilation [119]. In diabetic rats, it reduced pulmonary hypertension and significantly improved function and reduced myocardial fibrosis [120]. Therefore, in addition to the antihypertensive effect, the use of ACE2 activator leads to beneficial metabolic effects that reduce the possibility of diabetes and its complications [119]. Deficiency of Mas receptor genes or blockade of Mas receptors in male mice results in a metabolic syndrome that includes hyperlipidaemia, hyperglycaemia, hyperinsulinaemia, increased insulin resistance, increased glucose intolerance and adiposity [121]. The use of Mas agonists AVE0991 in animal models showed mild cardioprotective effects and an effect on lowering glucose and lipid levels in the blood [122]. Another Mas agonist of hydroxypropyl-p-cyclodextrin (HPβCD), in addition to increasing the half-life of Ang-(1–7), reduced the adverse effects and magnitude of myocardial infarction, myocardial hypertrophy and isoproterenol-induced heart damage. The remaining two agonists CGEM856 and CGEM857 cause vasodilation and cardioprotection [123]. In addition to Mas receptors, there are probably other receptors through which Ang-(1–7) exerts its effects, but this needs to be revealed in the future [119]. Virus-mediated ACE2 gene expression, i.e., gene therapy, has shown cardioprotective and antihypertensive effects in animal models. ACE2 overexpression by gene therapy is not limited to the heart but shows effects in brain and lung tissue where it exhibits antihypertensive effects [123].
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10.4.6 Analogue of Ang-(1–7)
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Although it is a very attractive therapeutic target, there are very limited studies today because of the short lifespan of this hormone. The clinical studies conducted focused on the intra-arterial or intravenous administration of infusions of the Ang-(1–7) analogue, which exerts its immediate vasodilatory effects. ACE inhibitors and angiotensin receptor antagonists, by their action, indirectly redirect the metabolic pathway of RAS towards the formation of increased levels of Ang-(1–7) [124].
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10.4.7 Vaccines
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The Ang I vaccine showed no antihypertensive effect, probably due to low antibody levels. Ang II vaccine, on the other hand, has proven to be very effective with a half-life of about 4 months. It was formed by covalent attachment of virus-like particles derived from the bacteriophage Qb envelope and modified Ang II. The antihypertensive effect manifested on systolic and diastolic pressures mostly in the early morning hours compared to placebo [125]. In addition to preclinical, it has also been tested in clinical trials with mild side effects such as flu symptoms. The more recent divalent vaccine HBcAg-CE12-CQ10 has shown antihypertensive and renoprotective properties without immune or electrophysiological adverse effects and has specific binding to AT1R and L-type calcium channels [126].
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10.4.8 Alamandine
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Recently, a new member of the RAS family named alamandine was discovered on animal models. It acts on MrgD receptors and exerts vasodilatory and cardioprotective effects similar to Ang-(1–7) [127]. Deletion of the MrgD gene at an early age resulted in the development of gender-independent dilated cardiomyopathy [128]. Endogenous alamandine is known to reduce leptin synthesis and secretion by activating the c-Src/p38 MAP kinase pathways, which is contrary to the action of Ang-(1–7) [129]. To date, no studies have been conducted on the administration of drugs that modulate this newly discovered component of RAS, so there is an opportunity to discover new therapeutic strategies in the future [127].
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10.5 Perspectives
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The use of RAS-A blockers to date has not been shown to be sufficient to achieve the desired effects on the cardiovascular system [130]. With the realization that there is a protective axis within RAS, pharmacotherapy and gene therapy are increasingly focused on the activation of the protective components of RAS. The greatest challenge in the future remains to unravel the mutual mechanisms of regulation of the vasoconstrictive and vasoprotective axis. It is important to explore whether the expression of one enzyme/receptor induces the expression or inhibition of another, which are the mechanisms of action of the protective axis at the cellular level, which are the consequences of prolonged activation or inhibition of RAS, whether we can act more selectively on RAS and are there additional undetected roles and consequences of deleterious action therapies on RAS. We also need to further investigate the impact of gender, organ function, dosage and timing of administration on the targeted effect of therapy [123]. Discoveries and the complex modulation of RAS add a great challenge to the treatment of the most common diseases of humanity [130] (\nFigure 3\n).
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Figure 3.
Influence of specific therapeutic strategies on components of the RAS. ACE, angiotensin-converting enzyme; AMPA, aminopeptidase A; AMPM, aminopeptidase M; Ang, angiotensin; ARBs, angiotensin receptor blockers; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; AVE0991, orally active Mas receptor agonist; C21, Compound 21 (AT2R agonist); CGEM856 and CGEM857, orally active Mas receptor agonists; DIZE, ACE2 activator diminazene aceturate; HPβCD, Mas agonist hydroxypropyl-p-cyclodextrin; HRP, decoy peptide for handle region of the prorenin prosegment; IRAP, insulin-regulated aminopeptidase receptor; MasR, angiotensin-(1–7) Mas receptor; MrgD, Mas-related G protein-coupled receptor; NEP, neprilysin; POP, prolyl oligopeptidase; PRR, prorenin receptor; TOP, thimet oligopeptidase; XNT, ACE2 activator xanthenone.
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Conflicts of interest
The authors have no conflict of interest to declare.
\n',keywords:"renin-angiotensin system, hypertension, heart failure, angiotensin-converting enzyme inhibitors, diabetes mellitus",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72192.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72192.xml",downloadPdfUrl:"/chapter/pdf-download/72192",previewPdfUrl:"/chapter/pdf-preview/72192",totalDownloads:707,totalViews:0,totalCrossrefCites:1,dateSubmitted:"January 10th 2020",dateReviewed:"March 30th 2020",datePrePublished:"May 16th 2020",datePublished:"August 19th 2020",dateFinished:"May 16th 2020",readingETA:"0",abstract:"The renin-angiotensin system, in both its circulating and local tissue roles, is intertwined with multiple other regulatory and signalling mechanisms in various tissues and organ systems. It plays a central role in the normal regulation of arterial blood pressure and in the development of hypertension, which is an immense global public health burden and a crucial modifiable risk factor in the development of cardiovascular diseases. The renin-angiotensin system plays also important roles in a range of other clinical conditions such as heart failure, kidney failure, diabetes mellitus and others. Therapeutic interventions within the renin-angiotensin system include the use of medications such as angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, which are well established and have been invaluable as clinically effective tools during many years of practical use. Additionally, numerous other therapeutic approaches targeting components of the renin-angiotensin system have been developed or are currently in development. This chapter will discuss details of the roles of this system in the most relevant clinical conditions.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72192",risUrl:"/chapter/ris/72192",signatures:"Vedran Đambić, Đorđe Pojatić, Anto Stažić and Aleksandar Kibel",book:{id:"7848",type:"book",title:"Selected Chapters from the Renin-Angiotensin System",subtitle:null,fullTitle:"Selected Chapters from the Renin-Angiotensin System",slug:"selected-chapters-from-the-renin-angiotensin-system",publishedDate:"August 19th 2020",bookSignature:"Aleksandar Kibel",coverURL:"https://cdn.intechopen.com/books/images_new/7848.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-422-0",printIsbn:"978-1-78985-421-3",pdfIsbn:"978-1-78985-554-8",isAvailableForWebshopOrdering:!0,editors:[{id:"183303",title:"Dr.",name:"Aleksandar",middleName:null,surname:"Kibel",slug:"aleksandar-kibel",fullName:"Aleksandar Kibel"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. RAS in hypertension",level:"1"},{id:"sec_3",title:"3. Role in heart failure",level:"1"},{id:"sec_3_2",title:"3.1 Introduction",level:"2"},{id:"sec_3_3",title:"3.1.1 The neurohumoral pathophysiology of heart failure",level:"3"},{id:"sec_6",title:"4. Role in kidney failure",level:"1"},{id:"sec_7",title:"5. Role in diabetes",level:"1"},{id:"sec_8",title:"6. The role of intracellular Ang II (iAngII)",level:"1"},{id:"sec_9",title:"7. Influence of the RAS on pancreatic tissue, muscle tissue and adipose tissue",level:"1"},{id:"sec_10",title:"8. Use of RAS inhibitors in patients with diabetes",level:"1"},{id:"sec_11",title:"9. Role in other clinical conditions",level:"1"},{id:"sec_12",title:"10. Therapy targeting the RAS",level:"1"},{id:"sec_12_2",title:"10.1 Direct renin inhibitors",level:"2"},{id:"sec_13_2",title:"10.2 ACE inhibitors",level:"2"},{id:"sec_14_2",title:"10.3 Angiotensin I receptor antagonists/blockers (ARBs)",level:"2"},{id:"sec_15_2",title:"10.4 Other therapeutic compounds",level:"2"},{id:"sec_15_3",title:"10.4.1 β1 blockers",level:"3"},{id:"sec_16_3",title:"10.4.2 Prorenin receptor antagonist/blocker",level:"3"},{id:"sec_17_3",title:"10.4.3 Chymase inhibitors",level:"3"},{id:"sec_18_3",title:"10.4.4 Angiotensin II receptor agonist",level:"3"},{id:"sec_19_3",title:"10.4.5 Activation angiotensin-converting enzyme 2 and Mas receptor agonist",level:"3"},{id:"sec_20_3",title:"10.4.6 Analogue of Ang-(1–7)",level:"3"},{id:"sec_21_3",title:"10.4.7 Vaccines",level:"3"},{id:"sec_22_3",title:"10.4.8 Alamandine",level:"3"},{id:"sec_24_2",title:"10.5 Perspectives",level:"2"},{id:"sec_29",title:"Conflicts of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nOparil S, Acelajado MC, Bakris GL, Berlowitz DR, Cífková R, Dominiczak AF, et al. Hypertension. Nature Reviews. Disease Primers. 2018;4:18014. DOI: 10.1038/nrdp.2018.14\n'},{id:"B2",body:'\nArendse LB, Danser AHJ, Poglitsch M, Touyz RM, Burnett JC Jr, Llorens-Cortes C, et al. Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure. Pharmacological Reviews. 2019;71(4):539-570. DOI: 10.1124/pr.118.017129\n'},{id:"B3",body:'\nMirabito Colafella KM, Bovée DM, Danser AHJ. The renin-angiotensin-aldosterone system and its therapeutic targets. Experimental Eye Research. 2019;186(May):107680\n'},{id:"B4",body:'\nGant CM, Laverman GD, Vogt L, Slagman MCJ, Heerspink HJL, Waanders F, et al. Renoprotective RAAS inhibition does not affect the association between worse renal function and higher plasma aldosterone levels. BMC Nephrology. 2017;18(1):1-8\n'},{id:"B5",body:'\nLiu Y, Li L, Qiu M, Tan L, Zhang M, Li J, et al. Renal and cerebral ras interaction contributes to diabetic kidney disease. American Journal of Translational Research. 2019;11(5):2925-2939\n'},{id:"B6",body:'\nByrd JB, Turcu AF, Auchus RJ. Primary aldosteronism. Circulation. 2018;138(8):823-835. DOI: 10.1161/CIRCULATIONAHA\n'},{id:"B7",body:'\nAmes MK, Atkins CE, Pitt B. The renin-angiotensin-aldosterone system and its suppression. Journal of Veterinary Internal Medicine. 2019;33(2):363-382. DOI: 10.1111/jvim.15454\n'},{id:"B8",body:'\nKibel A, Novak S, Cosic A, Mihaljevic Z, Falck JR, Drenjancevic I. Hyperbaric oxygenation modulates vascular reactivity to angiotensin-(1-7) in diabetic rats: Potential role of epoxyeicosatrienoic acids. Diabetes & Vascular Disease Research. 2015;12(1):33-45. DOI: 10.1177/1479164114553424\n'},{id:"B9",body:'\nMedina D, Arnold AC. Angiotensin-(1-7): Translational avenues in cardiovascular control. American Journal of Hypertension. 2019;32(12):1133-1142. DOI: 10.1093/ajh/hpz146\n'},{id:"B10",body:'\nMosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93:1137-1146\n'},{id:"B11",body:'\nBroqvist M, Dahlstrom U, Karlberg BE, et al. Neuroendocrine response in acute heart failure and the influence of treatment. European Heart Journal. 1989;10(12):1075-1083\n'},{id:"B12",body:'\nChaggar PS, Malkin CJ, Shaw SM, et al. Neuroendocrine effects on the heart and targets for therapeutic manipulation in heart failure. Cardiovascular Therapeutics. 2009;27:187-193\n'},{id:"B13",body:'\nMcMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England Journal of Medicine. 2014;371:993-1004\n'},{id:"B14",body:'\nOrsborne C, Chaggar PS, Shaw SM, et al. The renin-angiotensin-aldosterone system in heart failure for the non-specialist: The past, the present and the future. Postgraduate Medical Journal. 2017;93:29-37\n'},{id:"B15",body:'\nKaratas A, Canakci E, Turkmen E. Sociodemographic characteristics in patients with chronic kidney disease. Nigerian Journal of Clinical Practice. 2018;21(11):1461-1467\n'},{id:"B16",body:'\nAfsar B, Elsurer R. Association between serum bicarbonate and pH with depression, cognition and sleep quality in hemodialysis patients. Renal Failure. 2015;37(6):1-4\n'},{id:"B17",body:'\nHe S, Zhu J, Jiang W, Ma J, Li G, He Y. Sleep disturbance, negative affect and health-related quality of life in patients with maintenance hemodialysis. Psychology, Health & Medicine. 2019;24(3):294-304\n'},{id:"B18",body:'\nHrvačević R. Savremene metode dijalize-knjiga. 2012. pp. 1-227\n'},{id:"B19",body:'\nMurakami T, Iwamoto T, Yasuda G, Taniguchi M, Fujiwara A, Hirawa N, et al. Role of renin angiotensin system inhibitors in retardation of progression of end-stage renal failure: A retrospective study. Clinical and Experimental Nephrology. 2016;20(4):603-610\n'},{id:"B20",body:'\nWolke C, Teumer A, Endlich K, Endlich N, Rettig R, Stracke S, et al. Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort. Experimental Biology and Medicine. 2017;242(5):554-563\n'},{id:"B21",body:'\nHsieh WY, Chang TH, Chang HF, Chuang WH, Lu LC, Yang CW, et al. Renal chymase-dependent pathway for angiotensin II formation mediated acute kidney injury in a mouse model of aristolochic acid I-induced acute nephropathy. PLoS One. 2019;14(1):1-15\n'},{id:"B22",body:'\nOhashi N, Isobe S, Ishigaki S, Suzuki T, Ono M, Fujikura T, et al. Intrarenal renin-angiotensin system activity is augmented after initiation of dialysis. Hypertension Research. 2017;40(4):364-370\n'},{id:"B23",body:'\nFang H, Deng M, Zhang L, Lu A, Su J, Xu C, et al. Role of (pro)renin receptor in albumin overload-induced nephropathy in rats. American Journal of Physiology—Renal Physiology. 2018;315(6):1759-1768\n'},{id:"B24",body:'\nBian X, Bai Y, Su X, Zhao G, Sun G, Li D. Knockdown of periostin attenuates 5/6 nephrectomy induced intrarenal renin–angiotensin system activation, fibrosis, and inflammation in rats. Journal of Cellular Physiology. 2019;234(12):22857-22873\n'},{id:"B25",body:'\nXiao L, Xu B, Zhou L, Tan RJ, Zhou D, Fu H, et al. Wnt/β-catenin regulates blood pressure and kidney injury in rats. Biochimica et Biophysica Acta, Molecular Basis of Disease. 2019;1865(6):1313-1322\n'},{id:"B26",body:'\nZhou G, Li J, Zeng T, Yang P, Li A. The regulation effect of WNT-RAS signaling in hypothalamic paraventricular nucleus on renal fibrosis. Journal of Nephrology. Apr 2020;33(2):289-297\n'},{id:"B27",body:'\nZhou L, Mo H, Miao J, Zhou D, Tan RJ, Hou F, et al. Klotho ameliorates kidney injury and fibrosis and normalizes blood pressure by targeting the renin-angiotensin system. The American Journal of Pathology. 2015;185(12):3211-3223\n'},{id:"B28",body:'\nEltablawy N, Ashour H, Rashed LA, Hamza WM. Vitamin D protection from rat diabetic nephropathy is partly mediated through Klotho expression and renin–angiotensin inhibition. Archives of Physiology and Biochemistry. 2018;124(5):461-467\n'},{id:"B29",body:'\nIshigaki S, Ohashi N, Matsuyama T, Isobe S, Tsuji N, Iwakura T, et al. Melatonin ameliorates intrarenal renin–angiotensin system in a 5/6 nephrectomy rat model. Clinical and Experimental Nephrology. 2018;22(3):53949\n'},{id:"B30",body:'\nJang IA, Kim EN, Lim JH, Kim MY, Ban TH, Yoon HE, et al. Effects of resveratrol on the renin-angiotensin system in the aging kidney. Nutrients. 2018;10(11):1-15\n'},{id:"B31",body:'\nDomenig O, Manzel A, Grobe N, Königshausen E, Kaltenecker CC, Kovarik JJ, et al. Neprilysin is a mediator of alternative renin-angiotensin-system activation in the murine and human kidney. Scientific Reports. 2016;6(August):1-11\n'},{id:"B32",body:'\nKobayashi R, Wakui H, Azushima K, Uneda K, Haku S, Ohki K, et al. An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model. Kidney International. 2017;91(5):1115-1125\n'},{id:"B33",body:'\nConnelly KA, Boyle AJ, Kelly DJ. Angiotensin II and the cardiac complications of diabetes mellitus. Current Pharmaceutical Design. 2007;13(26):2721-2729\n'},{id:"B34",body:'\nZamora M, Villena JA. Contribution of impaired insulin signaling to the pathogenesis of diabetic cardiomyopathy. International Journal of Molecular Science. 2019;20(11):2833. DOI: 10.3390/ijms20112833\n'},{id:"B35",body:'\nSchaefer CF. Pathway databases. Annals of the New York Academy of Sciences. 2004;1020:77-91\n'},{id:"B36",body:'\nBader M, Ganten D. Update on tissue renin-angiotensin systems. Journal of Molecular Medicine (Berlin, Germany). 2008;86:615-621\n'},{id:"B37",body:'\nMandavia CH, Aroor AR, Demarco VG, Sowers JR. Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sciences. 2013;92(11):601-608\n'},{id:"B38",body:'\nSingh VP, Le B, Bhat VB, Baker KM, Kumar R. High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes. American Journal of Physiology. Heart and Circulatory Physiology. 2007;293(2):H939-H948\n'},{id:"B39",body:'\nFiordaliso F, Leri A, Cesselli D, Limana F, Safai B, et al. Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes. 2001;50(10):2363-2375\n'},{id:"B40",body:'\nBernardi S, Michelli A, Zuolo G, Candido R, Fabris B. Update on RAAS modulation for the treatment of diabetic cardiovascular disease. Journal of Diabetes Research. 2016;2016:8917578. DOI: 10.1155/2016/8917578\n'},{id:"B41",body:'\nVerma A, Xu K, Du T, et al. Expression of human ACE2 in Lactobacillus and beneficial effects in diabetic retinopathy in mice. Molecular Therapy—Methods & Clinical Development. 2019;14:161-170\n'},{id:"B42",body:'\nGiacchetti G, Sechi LA, Rilli S, Carey RM. The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends in Endocrinology and Metabolism, 126. 2005;16(3):120\n'},{id:"B43",body:'\nHuynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacology & Therapeutics. 2014;142(3):375-415\n'},{id:"B44",body:'\nBarrett EJ, Eggleston EM, Inyard AC, Wang H, Li G, Chai W, et al. The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action. Diabetologia. 2009;52:752-764\n'},{id:"B45",body:'\nChu KY, Lau T, Carlsson PO, Leung PS. Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes. 2006;55:367-374\n'},{id:"B46",body:'\nClerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006;55:1436-1442\n'},{id:"B47",body:'\nMiyata T, Taguchi T, Uehara M, Isami S, Kishikawa H, Kaneko K, et al. Bradykinin potentiates insulin-stimulated glucose uptake and enhances insulin signal through the bradykinin B2 receptor in dog skeletal muscle and rat L6 myoblasts. European Journal of Endocrinology. 1998;138:344-352\n'},{id:"B48",body:'\nWei Y, Sowers JR, Clark SE, Li W, Ferrario CM, Stump CS. Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. American Journal of Physiology. Endocrinology and Metabolism. 2008;294:E345-E351\n'},{id:"B49",body:'\nGoossens GH. The renin-angiotensin system in the pathophysiology of type 2 diabetes. Obesity Facts. 2012;5(4):611-624\n'},{id:"B50",body:'\nQuiroga DT, Miquet JG, Gonzalez L, Sotelo AI, Muñoz MC, et al. Mice lacking angiotensin type 2 receptor exhibit a sex-specific attenuation of insulin sensitivity. Molecular and Cellular Endocrinology. 2019;498:110587\n'},{id:"B51",body:'\nYehya YM, Hussein AM, Ezam K, Eid EA, Ibraheim EM, et al. Blockade of renin angiotensin system ameliorates the cardiac arrythmias and sympathetic neural remodeling in hearts of type 2 DM rat model. Endocrine, Metabolic & Immune Disorders Drug Targets. 2019;20:464-478\n'},{id:"B52",body:'\nSjølie AK. Prospects for angiotensin receptor blockers in diabetic retinopathy. Diabetes Research and Clinical Practice. 2007;76(Suppl 1):S31-S39\n'},{id:"B53",body:'\nGhattas A, Lip PL, Lip GY. Renin-angiotensin blockade in diabetic retinopathy. International Journal of Clinical Practice. 2011;65:113-116\n'},{id:"B54",body:'\nFletcher EL, Phipps JA, Ward MM, Vessey KA, Wilkinson-Berka JL. The renin-angiotensin system in retinal health and disease: Its influence on neurons, glia and the vasculature. Progress in Retinal and Eye Research. 2010;29:284-311\n'},{id:"B55",body:'\nKalupahana NS, Moustaid-Moussa N. The renin-angiotensin system: A link between obesity, inflammation and insulin resistance. Obesity Reviews. 2012;13:136-149\n'},{id:"B56",body:'\nMark PB, Papworth R, Ramparsad N, Tomlinson LA, Sawhney S, et al. Risk factors associated with biochemically detected and hospitalised acute kidney injury in patients prescribed renin angiotensin system inhibitors. British Journal of Clinical Pharmacology. Jan 2019;86:121-131\n'},{id:"B57",body:'\nSharma N, Malek V, Mulay SR, Gaikwad AB. Angiotensin II type 2 receptor and angiotensin-converting enzyme 2 mediate ischemic renal injury in diabetic and non-diabetic rats. Life Sciences. 2019;235:116796\n'},{id:"B58",body:'\nMalek V, Sharma N, Gaikwad AB. Simultaneous inhibition of neprilysin and activation of ACE2 prevented diabetic cardiomyopathy. Pharmacological Reports. 2019;71(5):958-967\n'},{id:"B59",body:'\nRodriguez R, Escobedo B, Lee AY, Thorwald M, Godoy-Lugo JA, et al. Simultaneous angiotensin receptor blockade and glucagon-like peptide-1 receptor activation ameliorate albuminuria in obese insulin-resistant rats. Clinical and Experimental Pharmacology & Physiology. Mar 2020;47(3):422-431\n'},{id:"B60",body:'\nBa Aqeel S, Ye M, Wysocki J, et al. Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus. Physiological Reports. 2019;7(19):e14242\n'},{id:"B61",body:'\nHanley AJ, Zinman B, Sheridan P, Yusuf S, Gerstein HC. Effect of rosiglitazone and ramipril on β-cell function in people with impaired glucose tolerance or impaired fasting glucose: The DREAM trial. Diabetes Care. 2010;33:608-613\n'},{id:"B62",body:'\nMorel Y, Gadient A, Keller U, Vadas L, Golay A. Insulin sensitivity in obese hypertensive dyslipidemic patients treated with enalapril or atenolol. Journal of Cardiovascular Pharmacology. 1995;26:306-311\n'},{id:"B63",body:'\nLender D, Arauz-Pacheco C, Breen L, Mora-Mora P, Ramirez LC, Raskin P. A double blind comparison of the effects of amlodipine and enalapril on insulin sensitivity in hypertensive patients. American Journal of Hypertension. 1999;12:298-303\n'},{id:"B64",body:'\nShamiss A, Carroll J, Peleg E, Grossman E, Rosenthal T. The effect of enalapril with and without hydrochlorothiazide on insulin sensitivity and other metabolic abnormalities of hypertensive patients with NIDDM. American Journal of Hypertension. 1995;8:276-281\n'},{id:"B65",body:'\nSuzuki M, Ikebuchi M, Yokota C, Shinozaki K, Harano Y. Normalization of insulin resistance in non-obese essential hypertension by cilazapril treatment. Clinical and Experimental Hypertension. 1995;17:1257-1268\n'},{id:"B66",body:'\nHeinemann L, Heise T, Ampudia J, Sawicki P, Sindelka G, Brunner G, et al. Four week administration of an ACE inhibitor and a cardioselective beta-blocker in healthy volunteers: No influence on insulin sensitivity. European Journal of Clinical Investigation. 1995;25:595-600\n'},{id:"B67",body:'\nPetrie JR, Morris AD, Ueda S, Small M, Donnelly R, Connell JM, et al. Trandolapril does not improve insulin sensitivity in patients with hypertension and type 2 diabetes: A double-blind, placebo-controlled crossover trial. The Journal of Clinical Endocrinology and Metabolism. 2000;85:1882-1889\n'},{id:"B68",body:'\nPratt MC, Lewis-Barned NJ, Walker RJ. A comparison between enalapril and captopril on insulin sensitivity in normotensive healthy volunteers. Australian and New Zealand Journal of Medicine. 1993;23:652-655\n'},{id:"B69",body:'\nReaven GM, Clinkingbeard C, Jeppesen J, Maheux P, Pei D, Foote J, et al. Comparison of the hemodynamic and metabolic effects of low-dose hydrochlorothiazide and lisinopril treatment in obese patients with high blood pressure. American Journal of Hypertension. 1995;8:461-466\n'},{id:"B70",body:'\nFouda AY, Artham S, El-Remessy AB, Fagan SC. Renin-angiotensin system as a potential therapeutic target in stroke and retinopathy: Experimental and clinical evidence. Clinical Science. 2016;130(4):221-238\n'},{id:"B71",body:'\nBennion DM, Rosado CA, Haltigan EA, Regenhardt RW, Sumners C, Waters MF. Serum activity of angiotensin converting enzyme 2 is decreased in patients with acute ischemic stroke. Journal of the Renin-Angiotensin-Aldosterone System. 2016;17(3):1-7\n'},{id:"B72",body:'\nKozak A, Ergul A, El-remessy AB, Johnson MH, Machado LS, Elewa HF, et al. Candesartan augments ischemia-induced proangiogenic state and results in sustained improvement after stroke. Stroke. 2009;40(5):18707\n'},{id:"B73",body:'\nAlhusban A et al. Compound 21 is pro-angiogenic in the brain and results in sustained recovery after ischemic stroke. Journal of Hypertension. 2015;33(1):170-180\n'},{id:"B74",body:'\nJackson L, Eldahshan W, Fagan SC, Ergul A. Within the brain: The renin angiotensin system. International Journal of Molecular Sciences. 2018;19(3):1-23\n'},{id:"B75",body:'\nAbabei DC, Bild V, Ciobică A, Lefter RM, Rusu RN, Bild W. A comparative study on the memory enhancing actions of oral renin-angiotensin system altering drugs in scopolamine treated mice. American Journal of Alzheimer’s Disease and Other Dementias. 2019;34(5):329-336\n'},{id:"B76",body:'\nMiller AG, Tan G, Binger KJ, Pickering RJ, Thomas MC, Nagaraj RH, et al. Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function. Diabetes. 2010;59(12):3208-3215\n'},{id:"B77",body:'\nSoto M, Bang SI, McCombs J, Rodgers KE. Renin angiotensin system-modifying therapies are associated with improved pulmonary health. Clinical Diabetes and Endocrinology. 2017;3(1):1-9\n'},{id:"B78",body:'\nThe Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)—China, 2020. China CDC Weekly. 2020;2(8):113-122\n'},{id:"B79",body:'\nHoffmann M et al. The new 2019 coronavirus (2019-nCoV) uses the SARS coronavirus receptor ACE2 and the cellular protease TMPRSS2 to enter target cells. bioRxiv. 2020. 2020.01.31.929042\n'},{id:"B80",body:'\nSantos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, et al. The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: Focus on angiotensin-(1-7). Physiological Reviews. 2018;98(1):505-553\n'},{id:"B81",body:'\nZheng Y-Y, Ma Y-T, Zhang J-Y, Xie X. COVID-19 and the cardiovascular system. Nature Reviews Cardiology. May 2020;17(5):259-260\n'},{id:"B82",body:'\nSun ML, Yang JM, Sun YP, Su GH. Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(0):E014\n'},{id:"B83",body:'\nFerrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605-2610\n'},{id:"B84",body:'\nSodhi CP, Wohlford-Lenane C, Yamaguchi Y, Prindle T, Fulton WB, Wang S, et al. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2018;314(1):L17-L31\n'},{id:"B85",body:'\nKrämer BK et al. Effects of hypoxia on renin secretion and renal gene expression. Kidney International. 1998;54(67):S155-S158\n'},{id:"B86",body:'\nA top coronavirus doctor in Wuhan says high blood pressure is a major risk of death. Bloomberg News 9:00 PM GMT on 09 March 2020\n'},{id:"B87",body:'\nCaldeira D, Alarcão J, Vaz-Carneiro A, Costa J. Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: Systematic review and meta-analysis. BMJ. 2012;345:e4260. DOI: 10.1136/bmj.e4260\n'},{id:"B88",body:'\nArai T, Yasuda Y, Takaya T, Toshima S, Kashiki Y, Yoshimi N, et al. ACE inhibitors and reduction of the risk of pneumonia in elderly people. American Journal of Hypertension. 2000;13(9):1050-1051\n'},{id:"B89",body:'\nGurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Developmental Research. 2020:1-4\n'},{id:"B90",body:'\nKang JH, Kao LT, Lin HC, Wang TJ, Yang TY. Do outpatient statins and ACEIs/ARBs have synergistic effects in reducing the risk of pneumonia? A population-based case-control study. PLoS One. 2018;13(6):e0199981\n'},{id:"B91",body:'\nHenry C, Zaizafoun M, Stock E, Ghamande S, Arroliga AC, White HD. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proceedings (Baylor University. Medical Center). 2018;31(4):419-423\n'},{id:"B92",body:'\nLegarth C, Grimm D, Wehland M, Bauer J, Krüger M. The impact of vitamin D in the treatment of essential hypertension. International Journal of Molecular Sciences. 2018;19(2):1-14\n'},{id:"B93",body:'\nTiryaki O, Usalan C, Tarakcioglu M, Coban S. Calcitriol reduces albuminuria and urinary angiotensinogen level in renal transplant recipients. Transplantation Proceedings. 2018;50(5):1342-1347\n'},{id:"B94",body:'\nTiryaki Ö, Usalan C, Sayiner ZA. Vitamin D receptor activation with calcitriol for reducing urinary angiotensinogen in patients with type 2 diabetic chronic kidney disease. Renal Failure. 2016;38(2):222-227\n'},{id:"B95",body:'\nMcMullan CJ, Borgi L, Curhan GC, Fisher N, Forman JP. The effect of vitamin D on renin angiotensin system activation and blood pressure: A randomized control trial. Journal of Hypertension. 2017;35(4):822-829\n'},{id:"B96",body:'\nZaheer S, Taquechel K, Brown JM, Adler GK, Williams JS, Vaidya A. A randomized intervention study to evaluate the effect of calcitriol therapy on the renin-angiotensin system in diabetes. Journal of the Renin-Angiotensin-Aldosterone System. 2018;19(1):1-8\n'},{id:"B97",body:'\nWu Z, Wang T, Zhu S, Li L. Effects of vitamin D supplementation as an adjuvant therapy in coronary artery disease patients. Scandinavian Cardiovascular Journal. 2016;50(1):9-16\n'},{id:"B98",body:'\nOberbach A, Schlichting N, Kullnick Y, Heinrich M, Lehmann S. Gastric mucosal devitalization improves blood pressure, renin and cardiovascular lipid deposition in a rat model of obesity. Endoscopy International Open. 2019;7(12):1605-1615\n'},{id:"B99",body:'\nEid RA, El-Kott AF, Samir M, Zaki A, Eldeen MA, Al-hashem FH, et al. Acylated ghrelin protects aorta damage post-MI via activation of eNOS and inhibition of angiotensin-converting enzyme induced activation of NAD(P) H-dependent oxidase. Ultrastructural Pathology. 2018;42(5):416-429\n'},{id:"B100",body:'\nAtlas SA. The renin-angiotensin aldosterone system: Pathophysiological role and pharmacologic inhibition. Journal of Managed Care Pharmacy. 2007;13:S9-S20\n'},{id:"B101",body:'\nRavandi A, Teo KK. Blocking the renin-angiotensin system: Dual-versus mono-therapy. Expert Review of Cardiovascular Therapy. 2009;7(6):667-674. DOI: 10.1586/erc.09.47\n'},{id:"B102",body:'\nLu H, Cassis LA, Kooi CWV, Daugherty A. Structure and functions of angiotensinogen. Hypertension Research. 2016;39:492-500\n'},{id:"B103",body:'\nSteckelings UM, Rompe F, Kaschina E, et al. The past, present and future of angiotensin II type 2 receptor stimulation. Journal of the Renin-Angiotensin-Aldosterone System. 2010;11:67-73\n'},{id:"B104",body:'\nParving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, Avoid Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. The New England Journal of Medicine. 2008;358:2433-2446\n'},{id:"B105",body:'\nMcMurray JJ, Pitt B, Latini R, et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circulation. Heart Failure. 2008;1:17-24\n'},{id:"B106",body:'\nFarhadi SAS, Dizaye KF. Aliskiren, fosinopril, and their outcome on renin-angiotensin-aldosterone system (RAAS) in rats with thyroid dysfunction. International Journal of Endocrinology. 2019;2019:5960563\n'},{id:"B107",body:'\nYamashita S, Biswas KB, Nabi AHMN, Nakagawa T, Suzuki F, Ebihara A. Aliskiren reduces the release of soluble (pro)renin receptor from human umbilical vein endothelial cells. Biomedical Reports. 2018;9(3):247-252\n'},{id:"B108",body:'\nAltarejo Marin T, Machado Bertassoli B, Alves de Siqueira de Carvalho A, Feder D. The use of aliskiren as an antifibrotic drug in experimental models: A systematic review. Drug Development Research. 2019;81(1):114-126\n'},{id:"B109",body:'\nBrenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. The New England Journal of Medicine. 2001;345:861-869\n'},{id:"B110",body:'\nDahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002;359:995-1003\n'},{id:"B111",body:'\nBlumenfeld JD, Sealey JE, Mann SJ, et al. β-Adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. American Journal of Hypertension. 1999;12:451-459\n'},{id:"B112",body:'\nMuller DN, Klanke B, Feldt S, Cordasic N, Hartner A, et al. (Pro)renin receptor peptide inhibitor “handle-region” peptide does not affect hypertensive nephrosclerosis in Goldblatt rats. Hypertension. 2008;51:676-681\n'},{id:"B113",body:'\nIchihara A, Hayashi M, Kaneshiro Y, Suzuki F, Nakagawa T, Tada Y, et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. The Journal of Clinical Investigation. 2004;114:1128-1135\n'},{id:"B114",body:'\nKaneshiro Y, Ichihara A, Sakoda M, Takemitsu T, Nabi AH, Uddin MN, et al. Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. Journal of the American Society of Nephrology. 2007;18:1789-1795\n'},{id:"B115",body:'\nMiyazaki M, Takai S, Jin D, Muramatsu M. Pathological roles of angiotensin II produced by mast cell chymase and the effects of chymase inhibition in animal models. Pharmacology & Therapeutics. 2006;112:668-676\n'},{id:"B116",body:'\nTakai S, Jin D, Miyazaki M. New approaches to blockade of the renin-angiotensin-aldosterone system: Chymase as an important target to prevent organ damage. Journal of Pharmacological Sciences. 2010;113:301-309\n'},{id:"B117",body:'\nWan Y, Wallinder C, Plouffe B, Beaudry H, Mahalingam AK, Wu X, et al. Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist. Journal of Medicinal Chemistry. 2004;47:5995-6008. DOI: 10.1021/jm049715t\n'},{id:"B118",body:'\nLi JM, Mogi M, Tsukuda K, Tomochika H, Iwanami J, Min LJ, et al. Angiotensin II-induced neural differentiation via angiotensin II type 2 (AT2) receptor-MMS2 cascade involving interaction between AT2 receptor-interacting protein and Src homology 2 domain-containing protein-tyrosine phosphatase 1. Molecular Endocrinology. 2007;21:499-511. DOI: 10.1210/me.2007-0111\n'},{id:"B119",body:'\nFraga-Silva RA, Costa-Fraga FP, Murça TM, et al. Angiotensin-converting enzyme 2 activation improves endothelial function. Hypertension. 2013;61(6):1233-1238\n'},{id:"B120",body:'\nFerreira AJ, Shenoy V, Qi Y, Fraga-Silva RA, Santos RAS, Katovich MJ, et al. Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases. Experimental Physiology. 2011;96:287-294\n'},{id:"B121",body:'\nSantos SH, Fernandes LR, Mario EG, Ferreira AV, Pôrto LC, Alvarez-Leite JI, et al. Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism. Diabetes. 2008;57(2):340-347\n'},{id:"B122",body:'\nEbermann L, Spillmann F, Sidiropoulos M, Escher F, Heringer-Walther S, Schultheiss HP, et al. The angiotensin-(1-7) receptor agonist AVE0991 is cardioprotective in diabetic rats. European Journal of Pharmacology. 2008;590(1-3):276-280. DOI: 10.1016/j.ejphar.2008.05.024\n'},{id:"B123",body:'\nFerreira AJ, Santos RA, Bradford CN, et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension. 2010;55(2):207-213\n'},{id:"B124",body:'\nSchindler C, Bramlage P, Kirch W, Ferrario CM. Role of the vasodilator peptide angiotensin-(1-7) in cardiovascular drug therapy. Vascular Health and Risk Management. 2007;3(1):125-137\n'},{id:"B125",body:'\nMaurer P, Bachmann MF. Immunization against angiotensins for the treatment of hypertension. Clinical Immunology. 2010;134:89-95\n'},{id:"B126",body:'\nWu H, Wang Y, Wang G, Qiu Z, Hu X, et al. A bivalent antihypertensive vaccine targeting L-type calcium channel and angiotensin II type 1 receptor. British Journal of Pharmacology. 2020;177:402-419\n'},{id:"B127",body:'\nVillela DC, Passos-Silva DG, Santos RA. Alamandine: A new member of the angiotensin family. Current Opinion in Nephrology and Hypertension. 2014;23(2):130-134. DOI: 10.1097/01.mnh.0000441052.44406.92\n'},{id:"B128",body:'\nOliveira AC, Melo MB, Motta-Santos D, Peluso AA, Souza-Neto F, et al. Genetic deletion of the alamandine receptor MRGD leads to dilated cardiomyopathy in mice. American Journal of Physiology. Heart and Circulatory Physiology. 2019;316(1):H123-H133. DOI: 10.1152/ajpheart.00075.2018\n'},{id:"B129",body:'\nUchiyama T, Okajima F, Mogi C, Tobo A, Tomono S, Sato K. Alamandine reduces leptin expression through the c-Src/p38 MAP kinase pathway in adipose tissue. PLoS One. 2017;12(6):e0178769. DOI: 10.1371/journal.pone.0178769\n'},{id:"B130",body:'\nSchmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet. 2007;369:1208-1219\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Vedran Đambić",address:null,affiliation:'
Department for Emergency Medical Services of the Osijek-Baranja County, Croatia
Department for Heart and Vascular Diseases, Osijek University Hospital, Croatia
Department of Physiology and Immunology, Faculty of Medicine, University J.J. Strossmayer in Osijek, Croatia
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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Consequently, melatonin has beneficial effects including stimulation of antioxidant enzymes, inhibition of lipid peroxidation, and so it contributes to protection from oxidative damages.",book:{id:"7328",slug:"melatonin-molecular-biology-clinical-and-pharmaceutical-approaches",title:"Melatonin",fullTitle:"Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches"},signatures:"Aysun Hacışevki and Burcu Baba",authors:[{id:"248612",title:"Associate Prof.",name:"Aysun",middleName:null,surname:"Hacışevki",slug:"aysun-hacisevki",fullName:"Aysun Hacışevki"},{id:"248614",title:"Ph.D.",name:"Burcu",middleName:null,surname:"Baba",slug:"burcu-baba",fullName:"Burcu Baba"}]},{id:"42117",doi:"10.5772/51819",title:"The Role of Copper as a Modifier of Lipid Metabolism",slug:"the-role-of-copper-as-a-modifier-of-lipid-metabolism",totalDownloads:4416,totalCrossrefCites:9,totalDimensionsCites:38,abstract:null,book:{id:"2552",slug:"lipid-metabolism",title:"Lipid Metabolism",fullTitle:"Lipid Metabolism"},signatures:"Jason L. 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Consequently, melatonin has beneficial effects including stimulation of antioxidant enzymes, inhibition of lipid peroxidation, and so it contributes to protection from oxidative damages.",book:{id:"7328",slug:"melatonin-molecular-biology-clinical-and-pharmaceutical-approaches",title:"Melatonin",fullTitle:"Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches"},signatures:"Aysun Hacışevki and Burcu Baba",authors:[{id:"248612",title:"Associate Prof.",name:"Aysun",middleName:null,surname:"Hacışevki",slug:"aysun-hacisevki",fullName:"Aysun Hacışevki"},{id:"248614",title:"Ph.D.",name:"Burcu",middleName:null,surname:"Baba",slug:"burcu-baba",fullName:"Burcu Baba"}]},{id:"75377",title:"Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020",slug:"pathophysiologic-approach-to-type-2-diabetes-management-one-centre-experience-1980-2020",totalDownloads:777,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This overview summarizes the evolution of pathophysiologic treatment of diabetes type 2 (T2D) in the period of the last 40 years. Randomized Controlled Trials (RCT) and Real World Evidence (RWE) studies resulted in recent Statements of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) in the year 2020. Case reports and studies of a single-centre in Czech Republic are reported. The authors demonstrate the impact of (1) multiple doses of rapid insulin, (2) multiple doses of rapid or ultrarapid insulin analogs (3) continuous subcutaneous insulin infusion (CSII) (4) incretin receptor agonists, (5) fixed combination of insulin degludec with liraglutide (IDegLira) and (6) SGLT2 inhibitor dapagliflozin, on plasma glucose concentration, HbA1c, body mass and patient satisfaction. The importance of therapeutic patients’ education and technology (personal glucometers, continuous/flash glucose monitors, insulin pens/pumps) is emphasized. Most of the observations were already published. Hence, individually adopted education, lifstyle, technical equipment, incretin receptor agonists and/or metformin and/or gliflozins and/or insulin analogs appear to be the core of an effective pathophysiologic approach. Scientific conclusions from RCTs, RWE trials and own clinical case reports may prevail over clinical inertia and induce early implementation of effective methods into routine T2D treatment.",book:{id:"9517",slug:"type-2-diabetes-from-pathophysiology-to-cyber-systems",title:"Type 2 Diabetes",fullTitle:"Type 2 Diabetes - From Pathophysiology to Cyber Systems"},signatures:"Rudolf Chlup, Richard Kaňa, Lada Hanáčková, Hana Zálešáková and Blanka Doubravová",authors:[{id:"278357",title:"Prof.",name:"Rudolf",middleName:null,surname:"Chlup",slug:"rudolf-chlup",fullName:"Rudolf Chlup"},{id:"346119",title:"Dr.",name:"Richard",middleName:null,surname:"Kaňa",slug:"richard-kana",fullName:"Richard Kaňa"},{id:"346120",title:"BSc.",name:"Lada",middleName:null,surname:"Hanáčková",slug:"lada-hanackova",fullName:"Lada Hanáčková"},{id:"346121",title:"BSc.",name:"Hana",middleName:null,surname:"Zálešáková",slug:"hana-zalesakova",fullName:"Hana Zálešáková"},{id:"346122",title:"Dr.",name:"Blanka",middleName:null,surname:"Doubravová",slug:"blanka-doubravova",fullName:"Blanka Doubravová"}]},{id:"61064",title:"Secretions of Human Salivary Gland",slug:"secretions-of-human-salivary-gland",totalDownloads:2766,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"The salivary glands play an important role in our body by the virtue of its ability to secrete saliva. Saliva has a role to play in maintaining the health of the oral cavity and for carrying out physiological functions like mastication, taste perception, speech etc. It also acts as a mirror to the systemic status of an individual owing to its ability to act as a diagnostic fluid for detecting a number of conditions and diseases. Saliva is a potential noninvasive diagnostic fluid for detection of a number of biomarkers of disease and health. Advancement in diagnostic methods has helped in identifying biomarkers of disease in saliva. In order to understand and diagnose pathological changes, a thorough understanding of the salivary gland anatomy, physiology and regulation of its secretion is warranted. This chapter aims to provide the basic understanding of the secretions of saliva.",book:{id:"6246",slug:"salivary-glands-new-approaches-in-diagnostics-and-treatment",title:"Salivary Glands",fullTitle:"Salivary Glands - New Approaches in Diagnostics and Treatment"},signatures:"Anahita Punj",authors:[{id:"226076",title:"Dr.",name:"Anahita",middleName:null,surname:"Punj",slug:"anahita-punj",fullName:"Anahita Punj"}]},{id:"63301",title:"Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake",slug:"role-of-pi3k-akt-pathway-in-insulin-mediated-glucose-uptake",totalDownloads:3541,totalCrossrefCites:11,totalDimensionsCites:27,abstract:"Glucose uptake is regulated by several mechanisms, where insulin plays the most prominent role. This powerful anabolic hormone regulates the transport of glucose into the cell through translocation of glucose transporter from an intracellular pool to the plasma membrane mainly in metabolically active tissues like skeletal muscles, adipose tissue, or liver (GLUT4). This translocation occurs through multiple steps of PI3K/AKT signaling pathway. In this chapter, we will focus on molecular events leading to GLUT4 translocation, starting with activation of insulin receptors through signaling cascade involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) and finally, the action of their effectors. We will present regulatory mechanisms and modulators of insulin-mediated glucose uptake.",book:{id:"7061",slug:"blood-glucose-levels",title:"Blood Glucose Levels",fullTitle:"Blood Glucose Levels"},signatures:"Ewa Świderska, Justyna Strycharz, Adam Wróblewski, Janusz Szemraj, Józef Drzewoski and Agnieszka Śliwińska",authors:null},{id:"70711",title:"Fetal Growth Restriction",slug:"fetal-growth-restriction",totalDownloads:3104,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Fetal growth defect is classified into intrauterine growth restriction (IUGR) and small-for-gestational-age (SGA) fetus based on the estimated fetal weight percentile and Doppler hemodynamic parameters. IUGR pathophysiology and etiology are complex and diverse, highlighting placental insufficiency as a paradigm, which explains its association with other entities of great clinical importance such as preeclampsia. 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Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",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. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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