A well-balanced diet is the basis for a healthy life. Both the western diet and special diets can have a relevant impact on the microbiome and promote the development of various diseases. There has been an increase in food-related disorders in recent years, largely associated with dramatic changes in food consumption trends and main nutrients. A major response to food intolerances has been the adoption of new dietary trends involving the reduction or exclusion of specific food ingredients. Especially gluten-containing, but also gluten-free cereals are in the cross-fire. Supporters of the gluten-free diet argue that gluten triggers inflammation and related diseases, while followers of the Paleo diet drastically impeach all cereals as dangerous for human health. To date, no controlled studies support or reject a positive health effect of a gluten-free or cereal-free diet. Future large-scale studies need to evaluate the effect of gluten-containing and gluten-free cereals and the various diets on human health, inflammatory parameters, clinical symptoms, and the gut microbiota . Dietary-associated changes in compositional and functional microbiota traits should be correlated with the health status for the future development of dietary recommendations and potential clinical interventions. A healthy and well-balanced diet is the basis for a healthy life and mental well-being. In the past 50–100 years, Westernized communities have seen dramatic changes in the physiological and psychological relationship with food, which have challenged our long-term adaptation to nutrients. On the one hand, the intake of finished products strongly increased, together with the consumption of novel chemical compounds present in the nutritional formulation. For example, a variety of additives, including preservative agents, emulsifiers, colorants, and flavor enhancers, are now commonly used in the food industry and sourdough is mainly replaced by yeast fermentation. On the other hand, novel forms of nutrition, including vegetarian and vegan diets, low-carb and low-fat diets, and a gluten-free diet (GFD) or cereal-free Paleo diet, have gained popularity. While these “elimination diets” are assumed to be healthier, up to date there are no randomized and controlled studies which confirm their constitutional effect for healthy individuals. In contrast, several studies have shown that healthy people who consume elimination diets typically face an increased risk of malnutrition, including deficiencies in minerals and vitamins .The surge of elimination diets has been mostly justified by mild or severe clinical intolerances to common nutritional ingredients. However, most of the claimed intolerances are not clinically verified. The spectrum of nutrients known to trigger intolerances and their related symptoms is wide: sugar can cause gastrointestinal complaints in affected individuals , gluten In recent years, the importance of the intestinal microbiota and its interaction with the host has become evident. The intestinal immune system plays a central role in stabilizing the host defense by protecting against microorganisms. If this system collapses, there will be a risk of immune-mediated diseases, e.g., autoimmune reactions. The microbiota proved to be a very complex and well-balanced intestinal ecosystem that influences gut homeostasis and delivers valuable food metabolites, for instance, vitamins, or short-chain fatty acids, which are essential fuels for the host. Studies on mice have shown that gut microbes are responsible for an increased energy uptake through the fermentation of complex fibers that are otherwise indigestible for the host. It is speculated that in humans eating a Western diet nearly 10% of the energy uptake originates from short-chain fatty acids that are derived from fiber degradation by gut bacteria . A growiBifidobacterium species (spp). The feeding of mice with prebiotic oligofructose causes a change in the gut microbiota and an increased expression of the proglucagon-derived peptide GLP-2 which results in lower intestinal permeability and improved epithelial integrity [Despite the wide differences in gut microbiota, human and mice harbor beneficial bacteria mainly belonging to phylum Firmicutes and Bacteroidetes. A dramatic reduction in Bacteroidetes and increase in Firmicutes has been observed in obese mice compared to lean siblings, and it is suggested that obesity alters the diversity of gut microbiota . In accontegrity . Recent ntegrity . Furtherntegrity ,21.Clostridium difficile infections [A dysbiotic status can be driven by infections, antibiotics, genetics, and environmental changes, but also specific diets. While causation/correlation patterns in clinical results are not always clear, meaning that dysbiosis could be regarded as a symptom rather than a trigger, restoration of a balanced microbiota through fecal transplants was shown to cure 98% of patients affected by fections , and wasfections . This laSeveral studies showed that changes in food intake significantly altered the gut microbiota. In fact, the availability of distinct food components favors the selective enrichment of microorganisms capable of exploiting these nutrients and supports microbial metabolic cross-feeding, leading to the maintenance of a diverse and balanced community . Even shClostridium species, which are mainly butyrate-producing bacteria. In comparison, vegetarians tend to accumulate the groups of Bacteroides and Prevotella [The diet of people living in Western countries is rather low in fiber and provides a high amount of fat and refined carbohydrates compared with the diet of people in non-industrialized countries . The difevotella .Bifidobacteria, Lactobacillus, and Enterococcus were elevated in the subjects’ stool [Diverse studies have investigated the influence of whole-wheat flakes on the composition of the gut microbiota . For exas’ stool , but thes’ stool .Akkermansia and the production of propionic acid, whereas β-glycan or insoluble arabinoxylan favored butyrate producers, e.g., Lactobacillus, Blautia, and Allobaculum [Faecalibacterium and Prevotella but a reduced proportion of Bacteroides spp. in comparison to white wheat bread intake. A positive association of Prevotella with plasma levels of the brain-derived neurotrophic factor is noticed, but further studies are necessary to explore a possible protective effect of Prevotella on neurodegenerative processes [Already minimal variations in dietary fiber composition promote environmental conditions for specialized microorganisms. Rat studies have displayed a relation between soluble arabinoxylan and obaculum . Even a rocesses .Bifidobacterium spp. in the stool of volunteers [Myrciaria dubia), so that the antioxidative properties of fruit may unfold with the change in the microbiota [In several studies, the influence of fruit on the composition of the intestinal microbiota was investigated. Vendrame et al., for instance, studied the influence of a wild blueberry drink in a placebo-controlled study and found an increased amount of lunteers . Anhe etcrobiota .Clostridium clusters XIVa and IV. Therefore, the proposed health effect of walnuts may be partly due to the microbiota [With regard to nuts, the influence of almonds and pistachios was investigated on the composition of the human intestinal microbiota in randomized controlled trials . The piscrobiota .Clostridium clusters without any effect on SCFA concentrations [Only a few studies examined the influence between the consumption of vegetables and the composition of intestinal microbiota. After eating chickpeas, fewer subjects were positive for trations . Anothertrations . In additrations .Clostridium spp. were reduced in the fiber group, but there were no differences in the concentrations of SCFA [Bifidobacterium after inulin administration compared to maltodextrin, even when no differences in SCFA concentrations were present [Several studies examined the influence of inulin on human gut microbiota. For example, one study investigated the effect of a mixture of inulin and partially hydrolyzed guar gum (I-PHGG) or maltodextrin on intestinal microbiota. The total numbers of  of SCFA . Another present . On the  present . Singh e present .The more a diet is enriched by a particular macronutrient, the greater the shift in the levels of the other macronutrients is. For example, high-fat diets are usually low in carbohydrates and have a lack of complex carbohydrates. This shift in nutritive compounds, as well as the absorbed fat quantity and quality, can influence the composition of the intestinal microbiota in a highly relevant fashion. Preliminary data suggest that ingested fat levels modulate the community of intestinal microbiota via their effect on bile acid secretion and bile acid composition. Due to their selective antimicrobial activity, bile acids can significantly alter the intestinal microbiota under a high-fat diet .Bacteroides enterotype but a reduction of the Prevotella enterotype [So far, little is known about the quality of fat and its effect on bile acid composition and thus on the gut microbiota pattern. Wu et al. reported an altered intestinal microbiome depending on the intake of saturated fats with an increase in the terotype . In anotterotype . Just etterotype . These rRoseburia and Eubacterium counts [Enterococcus but diminished proportions of Ruminoccoccus and Lactobacilli. Golden Syrian hamsters had reduced levels of Bacteroidetes but enriched Bifidobacteriaceae, Clostridiales, and Deferribacteriacea after three weeks supplementation with soy protein concentrates [The effect of protein on the human microbiota composition has been studied only to a limited extent. A high-protein and low-carbohydrate diet has been shown to affect gut microbiota in overweight men. After a four-week period, the high protein diet resulted in an increase in branched-chain fatty acids, a decrease in butyrate concentrations, and a decrease in m counts . In addim counts . Digesteentrates . Althougentrates .As mentioned above, elimination diets are necessary for some patients. Gluten, in particular, has become a main intolerance factor. For patients with celiac disease (CD), a strict lifelong gluten-free diet is mandatory and the only available therapy. In patients with a genetic predisposition (HLA DQ2 or DQ8), dietary gluten triggers the activation of gluten-specific T cells and results in the remodeling and destruction of the intestinal mucosa with crypt hyperplasia and villi atrophy . In receThe amino acid sequence of gluten is unique, with high amounts of proline and glutamine. This special primary structure is the reason why human gastric, pancreatic, or small intestinal proteinases cannot completely degrade gluten and up to 33-mer gluten fragments are found in the intestine. These long fragments displayed a potent T cell stimulation without the need of further processing by antigen-presenting cells . The gluBifidobacterium lactis is able to inhibit gluten-induced increased epithelial cell permeability of in vitro cultured colon carcinoma cell lines (CaCo2). However, it remains unclear, whether this is a direct effect of the Bifidobacterium on CaCo2 cells or caused by the degradation of gluten by bacterial proteases [Interestingly, breeding and culture of more profitable wheat species, as well as variations in bread formulation, are thought to be responsible for the increasing incidence in CD. In this context, studies with ancient wheat species displayed less toxicity in in vitro assays , and theroteases .Bifidobacterium spp., especially Bifidobacterium longum, but a high abundance of Bacillus fragilis and Staphlyococcus spp., both belonging to Firmicutes. Interestingly, breastfeeding modified the microbiota pattern and resulted in a shift to beneficial bacteria with increased numbers of Bifidobacterium spp. but lower numbers of B. fragilis [Bacteroides, and Escherichia coli that were normalized under a gluten-free diet [It was noticed that antibiotic use in childhood correlated with the onset of CD, and especially cephalosporin strongly increased the risk of CD. It is speculated that gastrointestinal infections and the use of antibiotics alter the gut microbiota, which may influence the development of CD . Feces ffragilis . It is sree diet .Neisseria flavescens was the most abundant Neisseria species in duodenum samples of patients with active CD and was able to induce an inflammatory response in dendritic cells and ex vivo mucosal samples. The dysbiosis and increase in microbiota with inflammatory potential are suggested to contribute to the maintenance of clinical symptoms in celiac disease [Furthermore, the intestinal microbiota seem to play a crucial role in the manifestation of CD. In this context, it was shown that adult patients with CD and persisting gastrointestinal symptoms or anemia possess a reduced microbial diversity, which is dominated by Proteobacteria . Another disease .Bifidobacterium spp., combined with an increase in Enterobacteriacea and Escherichia coli [Bifidobacterium longum CECT 7347 in addition to a gluten-free diet, this resulted in an improved health status compared to children that received the placebo compound [Bifidobacterium infantis alleviated gastrointestinal symptoms in newly diagnosed adult patients with CD, but the probiotic was not able to affect the abnormal intestinal permeability in these patients. Further studies must prove the beneficial effect of probiotics in the recovery of gut microbiota in CD and on the gut mucosal barrier [Remarkably, several studies demonstrated that a gluten-free diet also caused a reduction in the proportion of hia coli ,67. The compound . Further barrier .Non-celiac gluten-sensitivity is now considered as a separate clinical entity. Although the clinical symptoms resemble the complaints in CD and strongly correlate with the intake of gluten, NCGS is clearly distinguishable from CD or wheat allergy. To date, no disease-specific serological parameters are known and only a moderate stimulation of the intestinal immune system with elevated intraepithelial cells was described. Currently, a GFD is the only adequate therapy, although some studies have cast doubt on gluten as the main or sole culprit in NCGS ,71. OtheIn addition, amylase trypsin inhibitors (ATI) that are found in high amounts in cereals and are very stable to digestion or cooking, received much attention because of their ability to activate the naive immune system and maintain inflammatory processes . ATIs frLachnospiraceae and Bifidobacteriaceae, and the GFD diet caused an increase in Bacteroidaceae in NCGS patients, thus adapting to the values of healthy controls. There were significant differences in bacterial families between NCGS patients and healthy controls. Genus analysis revealed much more significant variations caused by diets in NCGS than healthy controls. As expected, the changes in intestinal bacteria also showed an effect on metabolism concerning the ability of dehalogenation, ammonia oxidizing, sulfate reducing, and xylan and cellulose degradation, especially under GFD. Hence, a variation in diet had a curative effect on clinical symptoms and well-being in NCGS and displayed a huge impact on microbial pattern and metabolisms. Although a GFD resolves the clinical symptoms in NCGS, the role of gluten is still unclear and provokes further research. A multi-stage process with the involvement of carbohydrates and gluten in the course of NCGS is suggested [Our own data has shown that NCGS patients profited with partial symptom improvement while consuming a low FODMAP diet and completely normalized under GFD in regard to all clinical symptoms, stool consistency, and psychological well-being . Most inuggested .New dietary trends include the Paleo diet, which is free of all cereals. Supporters of this diet argue that especially gluten but also gluten-free cereals were absent in the ancient hunters and gatherers’ diet. It is thought that the inclusion of cereals in the human diet started with the rise of agriculture, about 10,000 years ago, but that there has been no adequate adaptation of the human gut or microbiota to this drastic dietary change, although this argument is still controversially debated. Recent fecal metabolome analysis of Hadza hunter-gatherers from Tanzania, which should mirror our ancient gut microbiota before the inclusion of gluten, has clearly shown the main differences in microbial pattern and intestinal metabolites compared to urban-living Italians. Stool samples from Hadza hunters have been collected during the rainy season, when the dominant food is plant-based , and game meat is rare. Most of the tubers contain a high moisture content and indigestible fibers, which are expectorated during chewing, thus the Hadza diet is enriched in monosaccharides, starch, and protein, but low in fat. The nutrition of the Italian comparison group has been adapted to the Mediterranean diet, with plenty of plant foods, fresh fruit, pasta, bread, and olive oil and moderate amounts of dairy and meat. Only a minor proportion of carbohydrates is derived from fibers .Prevotella (Bacteroidetes), Treponema (Spirochaetes), and unclassified Bacteroidetes in Hadza feces, but an absence of Bifidobacteria. The genus Prevotella and Treponema possess the ability for xylan degradation, and the phylum Firmicutes also harbors several fiber-degrading species. Thus, it is suggested that these microbiota are the prerequisite for proper digestion of the glycan and fiber-rich diet consumed by Hadza [The gut microbiota from Hadza show a higher microbial richness and biodiversity compared to microbiota from Italian controls. The Hadza microbiota is dominated by phylum Firmicutes (72%), Bacteroidetes (17%), Proteobacteria (6%), and Spirochaetes (3%). The high proportions of Proteobacteria and Spirochaetes in Hadza feces, especially, are considerably distinct from very low levels of these phyla in the Italian control group. The determination of the genus level reveals increased quantities of by Hadza .Clostridium clusters IV and XIV, which are considered to be beneficial bacteria, and Hadza microbiota also possess distinct enrichment of opportunistic bacteria, e.g., Proteobacteria, or Treponema. In addition, the absence of Bifidobacteria in Hadza gut microbiota is of special interest because these bacteria are found in 1–10% of Western adults’ gut microbiota and Bifidobacteria are considered as valuable probiotic agents for gastrointestinal disorders [Interestingly, Hadza feces show an unusual pattern of Clostridiales with a reduction of butyrate-producing isorders .When investigating metabolic activity, there is striking evidence for the increased concentration of hexoses in Hadza feces compared to the Italian control samples (50.5% vs. 16.3%). The hexoses may be enriched because the Hadza diet is dominated by indigestible polysaccharides and fibers that pass through the small intestine, reach the colon, and are processed by local microorganisms. There is also a surplus of sphingolipids and glycerophosholipids but a strong depletion of amino acids and biogenic amines in the Hadza metabolome. The original source for sphingolipids and glycerophospholipids in feces is not known, because sphingo- and phospholipids are found in phylum Bacteroidetes but are also naturally present in host membranes. The metabolism of sphingolipids is further influenced by bile degradation, and since a typical high-fiber diet from Hadza hunters reduces the excretion of bile acid, this may promote higher concentrations of sphingolipids. Independent of the origin, sphingolipids and glycerophosholipids have been reported to exert an anti-inflammatory effect and may be responsible for the low immune stress in Hadza hunters . InteresIn summary, the remarkable microbial community with an altered metabolome from Hadza feces may be an adaptation and precondition for the specialized form of nutrition and may yield a benefit for this atypical lifestyle. However, further studies are necessary to clarify the impact of a Paleo diet on gut microbiota and health outcomes in the context of Western genetic and environmental conditions.In the course of life, the microbiome changes constantly. Even before birth, the flora of the mother may affect the microbial composition of the placenta. Afterwards, the type of delivery , the influence of diet as a baby (breast milk vs. milk replacement products), genetics, age, educational status, health status, and diet in adulthood influence the microbial composition. At an advanced age, decreasing physical activity, altered eating habits, inflammatory conditions, and taking medications can alter the intestinal flora ,82,83,84Nutrition has a very special influence on the microbiome as it is an important factor throughout age. Food components that are indigestible to human enzymes  provide substrates for microbial metabolism in the gut. Because bacteria are specialized in the fermentation of various substrates, complex diets can lead to a number of metabolic products, especially vitamins and SCFAs, which are vital to human health .Bacteroides and Prevotella. These organisms have the ability to utilize a wide variety of substrates and are major producers of propionate [Information on the composition of the colon microbiota comes mainly from the analysis of stool samples. Based on molecular analysis, most bacteria belong to the phyla Bacteroidetes and Firmicutes . The Graopionate . Firmicuopionate  and specopionate .Recently, it has been suggested that cereals and especially glutens are responsible for triggering the pathophysiology of many illnesses, including autoimmune diseases. This is the reason why the consumption of gluten-free products gains great popularity and the trade of gluten-free products achieves a big economical market. In view of the inflammatory capacity of gluten, one cannot completely rule out a fundamental effect of cereals on gut health or microbiota composition. However, conflicting results have come from fecal analysis that reveal that consuming a GFD results in a decrease of beneficial and increase of unhealthy gut bacteria in healthy individuals, thus supporting a positive effect of gluten . The cer


Transport of drugs across biological barriers has been a subject of study for decades. The discovery and characterization of proteins that confer the barrier properties of endothelia and epithelia, including tight junction proteins and membrane transporters belonging to the ATP-binding cassette (ABC) and Solute Carrier (SLC) families, represented a significant step forward into understanding the mechanisms that govern drug disposition. Subsequently, numerous studies, including both pre-clinical approaches and clinical investigations, have been carried out to determine the influence of physiological and pathological states on drug disposition. Importantly, there has been increasing interest in gaining a better understanding of drug disposition during pregnancy, since epidemiological and clinical studies have demonstrated that the use of medications by pregnant women is significant and this condition embodies a series of significant anatomical and physiological modifications, particularly at excretory organs and barrier sites  expressing transporter proteins which influence pharmacokinetics. Currently, most of the research in this field has focused on the expression profiling of transporter proteins in trophoblasts and endothelial cells of the placenta, regulation of drug-resistance mechanisms in disease states and pharmacokinetic studies. However, little attention has been placed on the influence that the cerebrovascular dysfunction present in pregnancy-related disorders, such as preeclampsia, might exert on drug disposition in the mother’s brain. This issue is particularly important since recent findings have demonstrated that preeclamptic women suffer from long-term alterations in the integrity of the blood-brain barrier (BBB). In this review we aim to analyze the available evidence regarding the influence of pregnancy on the expression of transporters and TJ proteins in brain endothelial cells, as well the mechanisms that govern the pathophysiological alterations in the BBB of women who experience preeclampsia. Future research efforts should be focused not only on achieving a better understanding of the influence of preeclampsia-associated endothelial dysfunction on drug disposition, but also in optimizing the pharmacological treatments of women suffering pregnancy-related disorders, its comorbidities and to develop new therapies aiming to restore the integrity of the BBB. Worldwide, there has been an increase in the number of prescribed and over-the-counter medications taken by pregnant women . In LatiTreatment of chronic diseases within pregnancy carries a risk for both the mother and fetus, as the administered drug could cross the placenta and reach the fetus circulation, with deleterious consequences . PharmacPregnant women suffering from psychiatric disorders and other central nervous system (CNS) diseases often require pharmacotherapy to stabilize their symptoms, which are likely to continue after labor due to their chronic nature. Clinical studies of pregnant women receiving antiepileptic and antidepressive pharmacotherapy demonstrated that the reduced drug exposure, due to increased clearance, is associated with an increase in the seizure rate  and decrFurthermore, women under pharmacological treatment for epilepsy  or deprePreeclampsia is associated with impaired systemic endothelial function  and, in While the function of the BBB and transport of molecules across brain endothelial cells (BECs) has been extensively studied in non-pregnant populations, much less is known about BBB physiology during pregnancy and pregnancy-related disorders. Therefore, this review will summarize the findings related to the effect of pregnancy and preeclampsia on the expression and activity of proteins involved in the transport of drugs at the BBB.The BBB Figure  is a higUnlike other vascular beds, the endothelial cells of the BBB express a unique phenotype Figure  with higin vitro and animal models have consistently demonstrated that the transport of molecules across the BBB is strongly regulated by membrane transporters and TJ proteins  activity at the BBB in both healthy  form complex strands that interact between cells, reducing paracellular diffusion . HoweverSince the discovery that the permeability of the BBB could be regulated through reversible disruption of TJs, this principle has served as an approach for the delivery of therapeutics that would not cross this barrier by conventional means, e.g., passive diffusion, carrier-mediated transport .in vitro and animal models have helped establish which membrane transporters impact brain drug disposition. Furthermore, the Data from ABCB1 gene in human and the abcb1a/abcb1b genes in rodent. This protein is located at the luminal side of BECs and is described as a phenotypical marker  (The MRP transporters are encoded by the athione) . Membersathione)  and tranathione)  analysesathione) .The OATPs, a group of SLC transporters belonging to the SLCO subfamily, are ubiquitously expressed throughout the body, and at the human BBB, luminal expression of OATP1A2  and OATPDuring normal pregnancy there is an increase in blood levels of several endogenous mediators including hormones and their metabolites, pro-inflammatory cytokines, chemokines, matrix metalloproteinases and growth factors . For exaThe influence of pregnancy on the integrity of TJs has primarily been studied in endothelial cells of the placenta , and to 11C-verapamil. However, the latter study did not confirm if this effect was a result of increased P-GP expression. No studies to date have reported the influence of pregnancy on the expression of SLC transporters in the maternal BBB, although it has been demonstrated expression of rodent Oatp1a4 (a rodent isoform that shows a high homology with human OATP1A2) in the BBB of the newborn increases with maturation , a protein found at high levels in plasma during pregnancy , has alsPregnancy alone can be considered as an inflammatory  state. One hallmark of pregnancy-related disorders, including preeclampsia, is the manifestation of endothelial dysfunction promoted by high levels of factors released from the placenta .In vitro studies have demonstrated that when rat cerebral vasculature was exposed to plasma from normal and preeclamptic human pregnancies, there was an increase in BBB permeability. Interestingly, this effect was more marked following treatment with preeclamptic plasma (The brain vasogenic edema present in later stages of preeclampsia is apparently the result of impaired autoregulation of cerebral blood flow and increased BBB permeability , but thec plasma . FurtherThe pro-inflammatory cytokine TNFα is also believed to contribute to the increased BBB permeability in preeclampsia. TNFα infusion in healthy pregnant rats at gestational day 19 increased the water content in the anterior cerebrum without increasing the BBB permeability . HoweverFindings from other studies conducted in the RUPP model have helped to elucidate how BECs respond to the circulating factors present in preeclampsia. When RUPP was performed in pregnant rats at gestational day 14, edema and increased maternal BBB permeability in the anterior cerebrum were observed, with increased expression of the protein aquaporin 4 and no changes in the expression of TJ proteins . HoweverThe increased BBB permeability reported by both Hypertension is one of the pathological features of preeclampsia and is routinely managed with the use of antihypertensive drugs including nifedipine, nicardipine, labetalol, hydralazine and methyldopa . AlthougThe mechanism of action by which magnesium sulfate exerts its effects is unknown, but despite this limitation, it is widely considered a neuroprotective agent capable of reducing BBB permeability in animal models of brain injury . FurtherTo date, as the specific effects of magnesium sulfate on the expression/functionality of BBB TJ proteins and drug transporters are unknown, future studies addressing this subject will prove crucial in identifying potential therapeutic targets and in developing treatment strategies.The effect of endothelial dysfunction elicited by preeclampsia on brain drug disposition is unknown. A preeclampsia-mediated increase in BBB permeability could potentially result in increased permeation of endogenous, blood-borne substances, including placental derived sFlt-1, and hormones, into the brain. Furthermore, a less restrictive BBB could allow more extensive penetration of therapeutic drugs into the CNS, resulting in increased side effects. In preeclamptic women, in addition to hypertension, which is treated with antihypertensive P-GP drug substrates, comorbidities, including epilepsy, depression and HIV infection, are often reported . Since tAlthough the precise mechanisms, and effects, of alterations in BBB permeability associated with preeclampsia have not yet been elucidated, it is possible to gain an insight into the potential consequences of BBB modification from clinical situations in which the expression of BBB drug transporters and BBB integrity are altered. In this regard, ischemic and hemorrhagic stroke are life-threatening conditions whose outcomes include severe BBB disruption . In rode11C-verapamil as tracer (Pathological similarities are observed in both ischemic stroke and preeclampsia, including neuroinflammation, vasogenic edema and increased BBB permeability Figure . To dates tracer . Future The BBB is a highly restrictive but dynamic system that regulates the transport of ions and molecules into and out of the brain. Consequently, alterations in its function could result in an increased CNS exposure to potentially toxic xenobiotics, including therapeutic drugs, and endogenous factors. Given the findings that preeclampsia is associated with increased BBB permeability, there is an urgent and fundamental need to characterize the functionality of BBB ABC and SLC transporter proteins involved in CNS drug disposition through the use of appropriate pre-clinical models and execution of clinical studies.A better understanding of preeclampsia-associated changes in BBB physiology would not only allow characterization of the processes responsible for pathophysiological changes, but could help improve the therapeutic management of women experiencing, or those who had experienced, preeclamptic pregnancies. Indeed, this knowledge will help to reduce the risk of acute and chronic complications caused by alterations in BBB function elicited by preeclampsia.PT-V designed and wrote the manuscript. CE and JP contributed to the writing of the manuscript and provided a critical revision of its contents.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In the last few years microfluidics and microfabrication technique principles have been extensively exploited for biomedical applications. In this framework, organs-on-a-chip represent promising tools to reproduce key features of functional tissue units within microscale culture chambers. These systems offer the possibility to investigate the effects of biochemical, mechanical, and electrical stimulations, which are usually applied to enhance the functionality of the engineered tissues. Since the functionality of muscle tissues relies on the 3D organization and on the perfect coupling between electrochemical stimulation and mechanical contraction, great efforts have been devoted to generate biomimetic skeletal and cardiac systems to allow high-throughput pathophysiological studies and drug screening. This review critically analyzes microfluidic platforms that were designed for skeletal and cardiac muscle tissue engineering. Our aim is to highlight which specific features of the engineered systems promoted a typical reorganization of the engineered construct and to discuss how promising design solutions exploited for skeletal muscle models could be applied to improve cardiac tissue models and vice versa. Why is microfluidics so appealing? The trend of publications containing the word microfluidics has continuously grown during the past years with a 55% net increase from 2010 to 2015 [Since the introduction of soft-lithography techniques based on poly-dimethyl-siloxane (PDMS)  and the Recently, a specific application of microfluidic technologies has led to the development of advanced in vitro cell culture platforms, so-called organs-on-a-chip. By recapitulating key features of the natural architecture and the multicellular arrangement of the native tissue, these platforms allow one to model and analyze at the molecular, cellular, and tissue level a wide range of interactions that traditional systems are not able to dissect . These pIn addition to the advantages offered by the microscale size, the presence of a 3D microenvironment allows to effectively mimic structure and function of in vivo-like tissues, overcoming limitations of conventional 2D culture systems. In particular, several efforts have been made to develop organs-on-a-chip mimicking the complexity of heart and skeletal muscle, whose functionality is based on the effective coupling between electrochemical stimulation and mechanical contraction. In this context, electrical stimulation has been reported to increase cardiomyocyte spreading and alignment  and induSince a growing body of literature is rapidly emerging, it is necessary to analyze the state of the art of existing organs-on-a-chip mimicking heart and skeletal muscle, and explore the challenges and future directions. This review critically summarizes microfluidic platforms for cardiac and skeletal muscle tissue engineering that were developed during the last five years, highlighting which system architectures promoted specific features of the engineered tissue, and suggesting future directions by emphasizing how specific design solutions exploited for the skeletal side of the muscle could be applied to the cardiac side and vice versa.In the human body muscles develop strength and body work, and allow blood pumping through the beating heart. Based on their specialization, muscle tissues may be classified into three types: skeletal, cardiac, and smooth. From a structural point of view, the muscle is characterized by a hierarchical organization. Moving from the inside out, skeletal muscle is composed by myofilaments, sarcomeres, myofibrils, muscle fibers, and fascicles . SarcomeThe myocardial structure presents similarities with the skeletal muscle  Figure . Myosin Many problems can affect skeletal muscles and cardiac tissues. Skeletal muscle pathologies include genetic disorders such as muscular dystrophy , inflammConsidering the aim of this review, it is fundamental to compare morphological differences and similarities between skeletal and cardiac muscle in order to design customized in vitro systems for their study. For this reason, we would like to highlight the following parameters characterizing skeletal and cardiac muscle, such as presence of gap junctions, contraction regulation, source of calcium ions, and stimulation systems (nervous/pacemaker cells) . Since mDifferent strategies have so far been developed for the generation of functional skeletal muscle tissue constructs, including mixed in vitro/in vivo approaches which were employed to engineer muscle flaps to reconstruct large tissue defects . MacroscIn the field of sub-cellular analyses of skeletal muscle myofiber regulation, the actin-myosin interaction represents a key aspect to understand the muscle contraction. The common setup for the protein-protein interaction study is the flow-through chamber in which buffers and proteins are sequentially perfused. These molecular analyses are extremely sensitive and the addition of reagents that could introduce shear stress would invalidate the measurements. Roman et al. developed a microfluidic device that allows to control chemical flows in a flow-through chamber while avoiding the creation of any bulk flow that could disturb the molecular mechanics analyses . The motoneuron work and the neuromuscular junction function involve cycles of necrosis and regeneration that, with time in the pathological condition, could lead to serious illness, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis. ALS is a disease involving the death of neurons that control voluntary muscles, SMA induces physical strength loose affecting the motor nerve cells in the spinal cord, and myasthenia gravis is related to a deficit in the acetylcholine function at the neuromuscular junction level. Modeling these degenerative processes is critical to understand the mechanisms underlying muscle contraction diseases. However, 2D cultures do not allow to reliably study these phenomena which involve the coupling of different tissues. Ionescu et al. developed a method to study the mechanisms of NMJ formation, maintenance and disruption in a 3D environment. Particularly, green fluorescent protein (GFP) labelled motoneurons from mice were introduced in one side of a microfluidic device and myotubes were plated on the other side. The motoneurons innervated the muscle fibers and formed functional NMJs. Furthermore, the described system was dedicated to the analysis of the NMJ biology thanks to the possibility to independently manipulate and observe the pre- and post-synaptic cell compartments . AdditioConsidering the muscle tissue physiology, vascularization has a central role for the generation of advanced in vitro muscle models. For these reasons several strategies have been developed to obtain complex vascular networks, such as vasculogenesis-based techniques  and biopThese models could pave the way for a new generation of microfluidic systems embedding vascularized and innervated muscle constructs better recapitulating different aspects of muscle tissues. To reach this milestone, researchers should consider physiological characteristics of in vivo muscle fibers. In particular, since the high metabolic activity of muscles, it is important to consider oxygen and nutrient consumption to develop reliable engineered models . FinallyDifferent strategies involving tissue engineering methods have been so far proposed to generate in vitro cardiac tissue models, aiming at reproducing myocardium intrinsic complexity and organization  to studyThe cardiac ventricle wall exhibits locally laminar anisotropic structures. Parker and co-workers designed a microfluidic platform where 2D muscular thin films (MTFs), formed by engineered anisotropic muscular tissue, are grown on top of fibronectin-patterned flexible elastomeric cantilevers  for analyzing the maturation and functionality of 2D cultured cardiomyocytes.To develop more realistic 3D biomimetic tissues, microfluidic devices were designed to culture under continuous perfusion, self-assembled aggregates of stem cells. For example, Bergstrom generated cardiac bodies (CBs) and captured them in “niches” arranged along a perfusion channel within a microfluidic device . The CBsIn order to evaluate the functionality of the cardiac tissue constructs, different microscale approaches were exploited to guide the formation of cell-laden hydrogels in specific zones and allow in situ real time measurements. Aung et al. developed 3D cardiac perfused cell-laden hydrogels within a microfluidic device with the possibility to quantify the contractile stress of microtissue in real-time and through in situ measurements . ExploitSince different studies highlighted important connections between cell mechanics and cell phenotype ,69, as wAll together, these platforms evidenced the importance to develop new systems with suitable structural and mechanical properties, promoting the generation of functional tissues.50 and EC50 values were more consistent with data at tissue-scale level compared to cellular-scale studies. These results demonstrated that the platform allowed cells to reach a minimal physiological level of reorganization, even without mechanical and electrical stimuli. Exploiting the recent organ-on-chip technology [Even if some specific cues of cardiac tissue were gained in the previously described systems, the complete set of microenvironmental parameters typical of the myocardial niche was not recapitulated. With this perspective, Mathur and colleagues developed a cardiac microphysiological system (MPS) to recapitulate the minimal organoid structure of the human myocardium. The authors designed a microfluidic device where the central channel, with its biomimetic dimension, forced the self-organization of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) into aligned 3D microtissues ,78. Nutrchnology . With thchnology . Indeed,chnology , perfusechnology . The cirAll of these platforms showed well how mechanical, electrical, and chemical stimulations can improve the properties of the cultured constructs. However, as previously shown in this review, more efforts should be performed to incorporate systems allowing real-time analyses of the tissue.The heart contains two types of cells: excitable and non-excitable. The first ones are involved in the electrical signal propagation, while the others contract following their pacing . CardiomWe have highlighted some of the similarities between cardiac and skeletal muscle tissues and we have discussed different approaches that were used to analyze their features at different levels, from actin-myosin interactions to the contraction of the whole tissue.In the field of cardiac tissue engineering two interesting strategies, aiming at studying in a high-throughput way the effect of different drugs, were developed. Cardiac 2D muscle strips  allowed Combining the advantages evidenced by Bergstrom et al.  in perfoFurthermore, although not belonging to the last five years of literature, and despite it employed rat and chicken embryo fibroblasts, we have included the work by Marquez et al. since the approach seemed promising to be translated in microfluidic devices for drug screening tests measuring the contractility of muscle fibers . ParticuMicrofluidic approaches were developed to study chemotaxis phenomena and the effect of ECM proteins on cellular migration  in tissuDespite being useful, all of these systems do not allow to fully recapitulate the architecture of the native muscle, since fiber-like constructs would better reproduce and mimic the hierarchical structure of this tissue.In this framework, Onoe introduced the fiber-based strategy which could be applied theoretically to engineer functional building blocks that can be assembled with different methods to reconstruct complex tissues  . FurtherAnother interesting method that can substitute the bending posts technique to investigate the mechanical properties of the construct is based on fluorescent beads. These particles were successfully employed in cardiac models to monitor the stress generated from 3D engineered tissues and to gain information about the maturation stage of the construct . This stAlthough not at the microscale and not in vitro, we would like to highlight the work by Cezar et al. who introduced the concept of differentiation and regeneration of the muscle fibers through mechanical compression in vivo. The mechanical compression could be inserted in microscale models as a stimulus conditioning the differentiation of both cardiac and skeletal muscle without the use of growth factors. Applying mechanotherapy may be an additive strategy to regenerate injured muscles in the patient treatment .The electrical stimulation has been shown to induce the differentiation, enhance the functionality and promote the contraction of cardiac muscle ,73 and sTo perform more relevant studies specially designed microfluidic platforms were developed in the last years to provide a highly controllable biomimetic microenvironment and to model physiological functions of tissues . In thisAnother important aspect which should be taken into account is the interaction between different cellular populations in a tissue, such as muscle cells and neurons. Several microfluidic platforms were designed to analyze formation, maintenance and disruption of engineered NMJs ,40. EvenFrom a reverse engineering point of view, it is important to understand which are the most critical features to fully recapitulate the functionality of a skeletal/cardiac tissue unit. In this context, we have highlighted that skeletal and cardiac muscles are characterized by unique properties, which have been successfully investigated by specific microfluidic models analyzing cell recruitment, cell-cell interactions or the effect of biophysical stimulations on the engineered tissue. Noteworthy, most of these models could be easily tailored for the study of both skeletal and cardiac muscle, by tuning specific parameters . The peculiar design features and the optimization of microfluidic models, originally developed for the highly specific study of myoblasts or cardiomyocytes, could lead to a general progress of our knowledge of the pathophysiology of both skeletal and cardiac muscle.


The development of natural phospholipids for nanostructured drug delivery systems has attracted much attention in the past decades. Lecithin that was derived from naturally occurring in soybeans (SL) has introduced some auspicious accomplishments to the drug carrying aspect, like effectual encapsulation, controlled release, and successful delivery of the curative factors to intracellular regions in which they procure these properties from their flexible physicochemical and biophysical properties, such as large aqueous center and biocompatible lipid, self-assembly, tunable properties, and high loading capacity. Despite the almost perfect properties as a drug carrier, liposome is known to be quite quickly eliminated from the body systems. The surface modification of liposomes has been investigated in many studies to overcome this drawback. In this review, we intensively discussed the surface-modified liposomes that enhancing the targeting, cellular uptake, and therapeutic response. Moreover, the recent applications of soy lecithin-derived liposome, focusing on cancer treatment, brain targeting, and vaccinology, are also summarized. The field of nanotechnology has provided the medical research fraternity with viable systems of delivering therapeutic substances, antioxidants, and nutrients to targeted areas of the body ,2. ConsePresented with these challenges, it has become a research priority to develop mechanisms of enhancing the stability of liposomes. Furthermore, liposomes are highly preferable as carriers of therapeutic substances due to their low toxicity profiles, flexibility in their encapsulation of a wide range of substances, and high biocompatibility ,24. ConsLecithin generally refers to the various triglycerides, phospholipids , and glycolipids  31]. Ho. Ho31]. On the other hand, lecithin that was extracted from soybeans is considered to be more economical, safer, and stable from a production point of view ,37. AparBudai et al. compared the efficiency of liposomes that were generated from both soy and egg lecithins in the delivery of caffeine to the skin for its antioxidant and soothing benefits in one of the various studies that have investigated the viability of soy lecithin liposome-based carrier systems . PreviouAzadirachta indica [C. sinensis CS1197 loaded nano-liposomes, liposomes stored at 4 and 25 °C showed stable after eight weeks [The use of liposomal formulations from soy lecithin for drug delivery to the skin has been studied further by Singh, Vengurlekar, and Rathod . Accordia indica ,45. Morea indica . These rht weeks . Muppidiht weeks . This isPlasmodium falciparum, in order to make the fight against malaria more effective. The study by Rajendran et al. aimed to evaluate the antimalarial activity of monensin in the context of its encapsulation in soy lecithin liposome-based drug delivery system. Therefore, the lipid formulations of phosphatidylcholine (PC) from soybean in combination with cholesterol containing either phosphatidic acid or stearyl amine were prepared together with varying densities of DSPE-mPEG-2000 . After the incorporation of monensin into the liposomes, in vitro determination of parasite killing capacity of monensin was achieved by using hypoxanthine incorporation assay. Additionally, in vivo evaluation of parasite killing was achieved using infected red blood cells that were Giemsa-stained. In terms of the physicochemical properties of the soy lecithin liposomes, the sizes of their spherical shapes ranged from 90 nm to 120 nm based on high-resolution electron microscopy and dynamic light scattering. The results of the antimalarial activity showed a heightened parasite killing capacity of monensin in liposomes containing DSPE-mPEG-2000 (5 mol%), stearyl amine, and free artemisinin. Furthermore, this combination resulted in improved survival of infected erythrocytes and the prevention of parasite recrudescence [Soy lecithin liposome-based carrier systems have also been developed for the delivery of antimalarial agents as described in one of the recent studies by Rajendran et al. . The resdescence . It is wdescence . As a redescence .Mycobacterium tuberculosis (WHO). Therefore, current research in the fight against TB is centered on devising means of formulating new antimicrobials and more efficient mechanisms of delivering the drugs at high concentration inside the macrophages of the lungs where TB bacteria are active [M. tuberculosis strains [M. tuberculosis rapidly multiply [Soy lecithin liposomes, as drug carriers, have been additionally studied in the treatment of tuberculosis (TB). According to the 2017 global report on tuberculosis by the World Health Organization, out of the 9 million new cases of TB reported in 2016, approximately 500,000 were attributed to multidrug-resistant (MDR) strains of  strains . Inhaledmultiply . Howevermultiply . When etmultiply .Despite the challenges of the aforementioned studies, more recent studies have shown the inherent potential of soy lecithin liposomes for the efficient encapsulation and deeper deposition of anti-TB aerosol therapy. One of these studies by Zaru et al. involved the use of liposomes that were formulated from soy lecithin to entrap rifampicin for the passive targeting of alveolar macrophages that were infected by Mycobacterium avium complex (MAC) . Using rResearch has demonstrated the need to overcome the challenge of loss of stability in the encapsulated drugs during the development of soy lecithin liposome-based drug delivery systems. In a bid to address this issue, some researchers have tested the role of pro-liposomes (a free-flowing combination of granular products comprising phospholipid precursors and the drug of interest) in promoting the stability of the entrapped drugs. Moreover, pro-liposomes are convenient to use, as they easily convert into highly stable liposomes upon hydration and subsequent reconstitution . One of Patil-Gadhe and Pokharkar reported a study that demonstrated the application of soy lecithin in the preparation of pro-liposomes using the QbD approach . The QbDMetronidazole is an important antiprotozoal and antibacterial agent that is often prescribed to treat bacterial vaginosis . MoreoveIn one of the studies, Patel and Patel formulated liposomes while using a combination of cholesterol and soy lecithin for purposes of encapsulating metronidazole and testing the drug’s stability and the efficiency of drug release from the liposomes . The lipProtein hydrolysates are valuable products for their nutritional applications, as they can be combined with various food formulations to enhance the nutritional value of food. Furthermore, certain protein hydrolysates can be used to improve the biological and physiological functions in the body in addition to reducing the risk of various diseases . It is aYokota et al. reported an experiment in which the peptide was microencapsulated in liposomes formulated using crude soy-lecithin in order to overcome these obstacles and ensure convenient and effective delivery of casein hydrolysate (CH) . The aimSome of the common problems that arise with liposomes are entrapment inefficiency and drug release with the required profile. However, literature has identified several strategies through which the issues can be solved. One method is loading liposomes with isoniazid. According to a study by Roy et al., liposomes of isoniazid, which are made by thin-layer film hydration, showed entrapment efficiency, which was determined by the particle sizes viewed from scanning electron microscopy (SEM) photographs . The proThe discussion on the use of soybean lecithin liposome-based drug delivery systems shows huge potential in the treatment of a wide range of diseases that affect the human population. From skin infections to metabolic disorders, such as phenylketonuria, the relevance of soy lecithin liposomes in the encapsulation and delivery of specific molecules has been proven.One of the limitations of conventional liposomes is their short time of circulation in the blood, as they are easily detected as foreign materials and degraded by components of the immune system A. Conseq2000 resulted in PEGylated formulations had smaller particle sizes and lower polydispersity indexes to conventional samples where a similar finding was also noted previous studies [As a way of managing this limitation, various researchers have investigated the effectiveness of liposomes that are coated with polyethylene glycol (PEG), which is a hydrophilic polymer B. The ro studies , confirm studies ,73,74.One of the studies that have tested the effectiveness of PEGylated liposomes is by Biswas et al. . In thisIn addition to surface modification of liposomes using PEG, liposomes have been modified and their functionalization enhanced through engineering techniques that facilitate the attachment of a targeting ligand such as antibodies, small molecules or peptides to the liposomes surface. The attached ligand is able to track the specific receptors that are overexpressed on the surfaces of the diseased cells. By attaching to the surface receptors, the ligands mediate the action of the drug that has been incorporated in the liposome ,84,85,86Among the advantages of modifying the surfaces of liposomes by using targeted ligands is that such liposomes are highly specific in terms of targeting the diseased cells. As a result, healthy tissues are spared from the off-target effects that are associated with certain therapies, such as chemotherapy in cancer treatment . ImmunolLCDX and DCDX) with polyethylene glycol molecules on the surface of liposomes for its possibility of biomedical applications in drug delivery systems for the brain [LCDX and its analog peptide DCDX in brain drug delivery is further supported by their ability to specifically bind to nicotinic acetylcholine receptors of lysosomes of brain capillary endothelial cells, which act as an enzymatic barrier for the transport of peptide ligands to the brain [LCDX and DCDX peptide were prepared while using thin-film hydration method. The immunogenicity of the respective liposomes was then evaluated by intraperitoneal injection of BALB/c mice with four weekly doses of the liposomes. The ELISA method was then used to determine the antibodies present in the blood samples while using the antigens LCDX-PEG3400-DSPE, DCDX-PEG3400-DSPE, or mPEG2000-DSPE. The outcomes of this analysis showed that liposomal surface modification with DCDX peptide elicited the strongest immune response as compared to the other liposomal formulations. Precisely, the amount of IgGs generated by DCDX-modified liposomes was 50 times higher than those that were generated by unmodified liposomes and 100 times higher than those generated by LCDX-modified liposomes. The researchers also noted that, after the fourth dose, much more IgMs against the polyethylene glycol coating on the liposome surfaces were produced in DCDX-modified liposomes than in non-peptide/plain and LCDX-modified liposomes [In 2010, Guan’s research developed targeted liposomes by attaching two peptide ligands  before joining it to PEG-DOPE conjugate to form Rh123-PEG-DOPE . The useiposomes .2C2(CO)2NH at the chain termini of PEG-DSPE in order to develop immunoliposomes. The conjugates of monoclonal antibody fragments  were then coincubated with doxorubicin-containing liposomes for half an hour at 55 degrees Celcius. Free drug and conjugates that had not been incorporated were separated from immunoliposomes by Sepharose CL-4B gel filtration. SDS-PAGE was then applied to estimate the efficiency of the incorporation of monoclobal antibody fragments. Using three mouse models , Wicki et al. tested the effect of the surface modification of liposomes with anti-VEGFR2 antibodies. The researchers noted a superior therapeutic efficacy in immunoliposomes whose surfaces had been modified by the incorporation of anti-VEGFR2 monoclonal antibodies when compared to pegylated liposomes containing doxorubicin, antibodies alone, empty liposomes, and anti-VEGFR2 immunoliposomes with no doxorubicin [Wicki et al. investigated the effectiveness of ligand targeted liposomes in the form of immunoliposomes (ILs) in disrupting the signaling axis between VEGF and VEGFR2 in tumor angiogenesis . In otheorubicin .Ligand targeted liposomes are created to facilitate the precise delivery of therapeutic agents to diseased tissues, which are tested through imaging techniques. One form of liposomes that is ligand targeted is CDX-modified stealth Liposomes, which are immunogenic. The liposomes are strengthened through the use of peptidomimetics, such as retro-inverso analogs used in targeted drug delivery. In the peptides or all-D retro, the amino acid is retained while the direction of the peptide bonds is reversed. Assembling D-amino acid residues in the reverse order in accordance with the original sequence completes the process. Notably, retro-inverso peptide analogs are stronger and stable as compared to the natural peptides. In brain-targeted drug delivery, CDX-modified liposomes, which are prepared while using the thin-film hydration method and their retro-inverso peptide analog CDX, possess a brain-targeting property by nicotinic acetylcholine receptors that makes them resistant to proteolysis . The metMultifunctional liposomes have been developed and extensively studied for their ability to perform multiple functions through surface modification techniques C. Moreov99mTc, as well as chemotherapeutic agents (doxorubicin), and therapeutic radionuclide (186Re/188Re). Additionally, the lipid formulation included DOTA-DSPE for the purposes of enabling the radionuclide labeling within the liposome membrane while using 64Cu and β+ decay for positron emission tomography imaging. The incorporation of Gd-DOTA-DSPE and DOTA ligand would impart the magnetic resonance imaging capability of the liposomes. The pre-manufactured liposomes were also modified by the insertion of a near-infrared lipidized fluorescent tracer (IRDye-DSPE), which would facilitate the mapping of near-infrared imaging of lymph nodes that are associated with tumors or the tumors [99mTc, positron emission tomography radiolabeled with 64Cu, and near-infrared fluorescent enabled the researchers to visualize the retention and/or distribution of the theranostic liposomes within the tumors.Shihong et al. designed and developed a drug delivery system of theranostic liposomes with multifunctional capacity . By incoe tumors . Followiin vitro. However, siRNA-CPPs/TSL-NGR exhibited superior antitumor efficacy (three-fold) and in silencing c-myc (two-fold) in vivo in xenograft mouse model as compared with free CPP-siRNA under conditions of hyperthermia [Yang et al. reported another study that focused on the practical application of multifunctional liposomes . The resrthermia .2000-PEI) conjugate was modified on the surface of the liposomes and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) conjugate was incorporated onto drugs-loaded liposomes that were used as a targeting molecule for transporting drugs across the BBB and a functional molecule for targeting all glioma cells via receptor-mediated endocytosis, respectively. Besides, tetrandrine was incorporated into the lipid bilayer for inhibiting the multidrug resistance via blocking the expression of P-gp protein that was overexpressed on BBB and glioma stem cells. Vinorelbine was then entrapped into the liposomal vesicles as an antitumor drug. This modification results in multifunctional targeting drugs-loaded liposomes that could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit all glioma cells and induce apoptosis via activating related apoptotic proteins. Moreover, the in vivo results showed that multifunctional liposomes could significantly accumulate into brain tumor location, specific to tumor sites, and robust overall antitumor efficacy.Several research groups developed multifunctional as a strategy to transport drugs across the blood-brain barrier (BBB) for treating brain glioma. In 2016, for instance, Xue-tao and co-workers designed, synthesized, and characterized multifunctional targeting vinorelbine plus tetrandrine liposomes that were modified with polyethylenimine (PEI) and vapreotide (VAP) for transporting drugs across the BBB and targeting all glioma cells . In thisAnother group reported the use of cyclic RGD (c(RGDyK)) and p-hydroxybenzoic acid (pHA) for multifunctional glioma-targeted drug delivery . The menSimilarly, Zing et al. conjugated the cyclic derivative (cA7R) on the surface of DOX-loaded PEGylated liposomes . The sysIn addition, Fu and fellow workers prepared a functionalized liposome with TAT and cleavable PEG via a redox-responsive disulfide linker for the delivery of Paclitaxel (PTX-C-TAT-LP). These in vitro and in vivo results confirmed a superior delivery efficiency of PTX-C-TAT-LP for enhancing tumor distribution .From the above discussion, liposomal surfaces have been modified while using a variety of approaches to generate PEGylated, ligand targeted, and multifunctional liposomes. Based on the recent advances in liposomal surface modifications, it is worth acknowledging the various liposome-based carrier systems that have been used or hold the promise of being used in the future to deliver therapeutic substances to different organs and tissues in the body.Liposomes are part of the most reputed carriers of various molecular species, ranging from small and simple to large and complex molecules. As Nkanga et al. mention, the spherical sacs of phospholipid molecules are artificial lipid-based bilayered vesicles that have been subject to extensive evolution . NotablyIt is notable that surface modification of liposomes is determined by the specific application of the liposomes . TherefoThe application of liposomes in drug delivery is divided into two main sections: cancer therapy and applications in other fields, such as vaccinology and gene therapy ,132,133.A major challenge that is often encountered in cancer treatment is the side effects of anticancer agents and low drug accumulation at the tumor site ,137,138.The effectiveness of PEGylated liposomes for drug delivery in tumors was evaluated while using doxorubicin. Human models confirmed that the anticancer drug exhibited longer circulation times when it was entrapped in stealth liposomes compared to conventional liposomes  Stealth The need for selective targeting of tumor cells has led to the development of liposomes with functionalized surfaces. For example, targeting ligands  are coupled to the liposome surface to enhance the selective attachment of the liposomes on cells bearing certain receptors on their surfaces . In cancAs can be seen in In addition to developing targeted liposomes, as outlined above, researchers have explored the potential of multifunctional liposomes in cancer therapy. Such liposomes carry more than one ligand in order to improve their drug delivery and targeting efficacy. In a study that tested the usefulness of multifunctional liposomes, Zhang et al. prepared liposomes by attaching peptide DA7R (to target VEGFR2) and peptide T7 (to target TfR) to the surfaces of the liposomes and incorporating two anticancer agents (vincristine and doxorubicin) . The duaNeurodegenerative diseases are a major health burden, especially in the developed world, where they are among the four leading causes of death . AlzheimSome studies show that liposomes whose surfaces have been modified with appropriate ligands are able to cross the BBB and release their drug content or genetic material into the affected brain without damaging the brain. The ligand on the liposomes binds to the specific receptor on the BBB see . This isMost ligands that are used to modify the surfaces of liposomes for the delivery of neurotherapeutics target lipoprotein and transferrin receptors. For example, targeted liposomes carrying an antibody called OX26 specifically binds to transferrin receptor and can be used to cross the BBB to deliver important drugs, hormones, or growth factors . In one Liposomes have been studied in terms of their potential applications in the delivery of important vaccines for the prevention of various diseases, including TB, malaria, and hepatitis. Their application in this field is based on the modification of their cargo as well as lipid composition. For example, liposomes for vaccinology applications can be modified by incorporating antigens in the form of peptides, lipids, or nucleic acids . AlternaLipids are very important molecules during the production of liposome vaccines, as they function as second messengers during the regulation of molecular pathways that control the maturation of phagosomes and the subsequent antimicrobial responses . The abiApart from lipids, other liposome function modifiers, such as pathogen-associated molecular patterns (PAMPs), can be used to enhance the adjuvant properties of the liposomes. PAMPs added to the liposome structure facilitate the development of liposomes that play a central role in the activation and modulation of antigen-presenting cells (APCs) . The modOver the past one or two decades, research into the use of liposomes as efficient drug delivery vehicles has generated encouraging outcomes in the management and treatment of different diseases. Following the discovery of liposomes, the research fraternity has focused on designing and applying different surface engineering techniques. The application of the surface modification strategies has given rise to advanced liposomal formulations that are able to overcome the limitations of conventional liposomes. It is notable that a good number of credible studies on the surface modification of liposomes have been successful. However, there is evidence of a gap between the discovery of liposome surface modification and their application in human models. Future studies should aim at demonstrating the success story through clinical trials that are aimed at resolving various public health challenges while using liposome-based drug delivery systems. Soy lecithin-derived liposomal delivery systems are particularly promising as a lot has been accomplished in terms of their application in major illnesses, such as TB and malaria. However, it is also evident that the transition from mice models to human clinical trials has been slow. Going forward, researchers should conduct more clinical trials using soy lecithin-derived liposomal delivery systems.


In a deinstitutionalised mental health care system, those with mental illness require complex, multidisciplinary and intersectoral care at the primary or community service setting. This paper describes an Evidence Map of different strategies to strengthen the provision of mental health care at the primary health care (PHC) setting, the quality of the evidence, and knowledge gaps. Electronic and reference searching yielded 2666 articles of which 306 qualified for data extraction. A systematic review methodology identified nine different strategies that strengthen the provision of mental healthcare and these strategies are mapped in line with the outcomes they affect. The top three strategies that were reported the most, included strategies to empower families, carers and patients; integration of care or collaborative interventions; and e-health interventions. The least reported strategy was task shifting. The Evidence Map further shows the amount and quality of evidence supporting each of the listed strategies, and this helps to inform policy design and research priorities around mental health. This is the first systematic Evidence Map to show the different strategies that strengthen the provision of mental healthcare at PHC setting and the impact these strategies have on patient, hospital and societal level indicators. Mental illness is a major contributor to disability, morbidity and mortality globally . The WorDespite such a high global disease burden, there is a disproportionately weak response to mental illness, characterised by a lack of prioritisation of resources and policies . There iCommunity-based services, which include PHC, are considered the most effective approach to addressing mental illness and providing mental health care . The WHODespite evidence supporting investment in community services, mental health services are underfunded and under-prioritised in most low- and middle-income countries, with the bulk of the scarce resources targeting specialised mental healthcare hospitals and neglecting community services . ReasonsIn 2015, in the Gauteng Province, South Africa, over 1400 people with severe mental illness were abruptly transferred from institutional care at Life Esidimeni hospitals to alternative care facilities, most of which were community-based, and reliant on district health services to provide health care. Within a year of being transferred, 8.3% (119 people) died, despite the urgent rehospitalisation of many patients . The LifThe Constitution of the Republic of South Africa assures people with mental illness of their basic human rights, including the right to health care. The Mental Health Care Act No.17 of 2002 (‘the Act') enshrines the right of mental health care users to receive care, treatment and rehabilitation (CTR) close to their homes and in the least restrictive environment . The CTRThe poor resourcing of mental health care, inequity between provinces, lack of routinely collected data, and ongoing reliance on stand-alone mental hospitals, led to the publication of the National Mental Health Policy Framework and Strategic Plan 2013–2020 . This plEvidence maps are an evidence synthesis methodology that systematically selects, identifies and organise a body of knowledge, to provide a high-level picture of the size and nature of the available evidence to inform decision making and practice . The bodThe EM followed a comprehensive and systematic search process that facilitated the identification of the strategies that might improve the provision of mental health services at the PHC setting. The search strategy and screening followed the systematic review methodology.We conducted an initial scoping of the literature to clarify our question, develop a strategy for the EM and to confirm that there was relevant literature available. As part of the scoping, we conducted targeted searches, using limited words, in PubMed and PsycINFO, and out of 141-screened abstracts, only one review that looked at care for patients with serious mental illness treated in primary care setting was relevant for the review question. This review was conducted by the Norwegian Knowledge Centre for the Health Services in 2007  and focuFor the main search, we expanded our initial scoping strategy search in four ways. Firstly, we decided to copy the Norwegian study's  search sBased on the objectives, we included articles that met the following parameters:Population: Reviews that synthesise the evidence of the effect for mental health interventions for adult clients (18 years and older) with a mental illness.Intervention: Any strategy to strengthen the provision of mental health care at the PHC setting. The strategies could be concerned with general primary care, specialist psychiatric care or any psychiatric treatment offered to those with a mental illness.Comparator: We presumed each review would have decided on what comparators are acceptable in the studies to be included in their review. Therefore, the comparator was not part of our inclusion criteria.Outcome: Given that our topic covered a broad range of severe mental illnesses, the type of outcomes ranged from service level indicators , the process of care indicators , to the patient or family-level outcomes. Patient or family level outcomes included measures of function, quality of life, improvement in symptoms, as well as patients' acceptability of the intervention.Setting: Interventions implemented within PHC across high, middle or low-income country settings.Study type: Systematic reviewsWe excluded systematic reviews focusing on children and adolescents and where the intervention or strategy was not at the PHC setting, or where the focus of the review was the efficacy of a specific treatment (e.g. a drug or a therapy), see Our main search was guided by a protocol registered on PROSPERO (CRD42018093161) and reported according to the PRISMA guidelines . Two indAll records from the main search were collated into EndNote software. Duplicates were removed in EndNote and the remaining records were exported to Covidence software, where further duplicates and the screening of titles, abstracts and full-text were performed. The screening was guided by the inclusion criteria described earlier.All the records were screened in duplicate in Covidence software . Eight rIdentifying a critical appraisal tool that assesses the quality of both effectiveness and qualitative reviews and offers consistent assessment across both reviews, was a challenge. After reviewing existing critical appraisal tools such as the AMSTAR-2 and Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews and Research Syntheses, and consultations with evidence synthesis experts and methodologists, the team opted to amend the AMSTAR-2  tool to Identifying and categorising the strategies happened through an iterative process as reviewers screened titles, abstracts and full-texts. Groups of reviews were created in EndNote according to the identified strategies. Through discussions, the team resolved differences and issues arising from categorising the strategies. After a series of team meetings, the following nine PHC strategies were identified .A data extraction tool  was codeThereafter, all six reviewers  extracted data independently on the articles allocated to them via Eppi Reviewer 4. The following data categories were extracted from each article see .The designing and development of the evidence map did not report on the direction of impact of the outcomes but it describes the amount and quality of evidence linking each strategy with outcomes as well as indicates the areas with knowledge gaps. To understand what each strategy entails, a narrative synthesis is provided below.The extracted data was compiled into a JSON file in EPPI Reviewer 4 and exported into an evidence map wizard, which created the EM with linkages between each strategy and outcome types. Each strategy (rows) were mapped on to different outcomes (columns) see . Since sA PRISMA flow chart  shows thOf the 306 included systematic reviews, 9 were published before 2000, 29 between 2000 and 2005 and the remaining 268 articles were published after 2005. Most of the included articles were effectiveness reviews with a meta-analysis and of high quality. The included articles span a range of World Bank regions and income groups. Most of the reviews covered the following areas; North America, Europe and Central Asia, East Asia and Pacific, with relatively few articles from sub-Saharan Africa, Middle East and North Africa, and Latin America and Caribbean. High-income countries including United States of America (US), United Kingdom (UK) and Australia, accounted for most of the included articles . The resAlmost a third (n = 100) of the articles described strategies that empower families, carers and patients, as a way of strengthening the provision of mental healthcare. Enlisting families, carers and patients are reported as a way that may improve outcomes, and relieve PHC staff. Some of the reported strategies that empower families, carers and patients are community residential or day centres, self-help interventions, support groups, vocational interventions, healthy lifestyle interventions, counselling and addressing caregiver burden, psychoeducation, and financial incentives.Integration of care or collaborative interventions, such as care models, case management, consultation-liaison, inter-professional collaboration and shared patient-doctor decision-making, where the second (n = 58) most described strategy. Integration of care or collaborative interventions are models of care where different cadres of healthcare workers collaborate, or where physical and mental healthcare are provided in an integrated were. The third (n = 49) most described strategy is eHealth interventions, which are various healthcare practices that are supported by electronic processes and social media communication technologies. The rationale behind eHealth is that such technologies will relieve some of the workloads of PHC staff and some of these technologies are telemedicine, web-based therapy and mHealth.The balance between psychosocial and pharmacotherapy has implications for human resources and costs at the PHC level as well as patient outcomes. Psychotherapy and psychosocial interventions in combination with pharmacotherapy, were the fourth (n = 36) most reported strategy that might strengthen the provision of mental healthcare. Early detection and preventative strategies were the fifth (n = 31) most described strategy. Early detection, prevention and screening strategies all have implications for patient outcomes as well as cost implications, and these strategies involve identifying high-risk individuals, screening tools for early detection and interventions for prevention.Specialised community-based services and systemic strategies that may change provider behaviour and strengthen the quality of care are both the sixth (n = 21) most described strategies. Specialised community-based services are interventions run by specialists but located in the community, such as community mental health teams or Assertiveness Community Teams (ACT), and day hospitals or clinics. Systemic strategies (n = 21) that may change provider behaviour and strengthen the quality of care, can be monitoring frameworks for process or patient outcomes, improved data collection on mental illness at PHC, interventions to strengthen adherence to clinical guidelines or financial incentive frameworks for healthcare providers.Lastly, task shifting or sharing approaches (n = 13) and group therapy versus individual therapy (n = 11) are the least reported strategies. Task-shifting or sharing approaches are where less skilled or trained cadre take on tasks normally carried out by more highly trained staff, such as task shifting for mental health needs or physical needs of the mentally ill patients. Group therapy allows one healthcare worker to support several patients at once and this could potentially relieve the workload of PHC staff. Group therapy can be cognitive behavioural, vocational activities or occupational therapy.The 306 identified reviews report on several different outcomes impacted by the strategies mentioned above. Outcomes were grouped into 10 categories as follows: hospital admissions; adherence in care and treatment or retention in care; staff knowledge or skills; psychiatric or clinical symptoms; functional or quality of life; cost-effective; family or societal; feasibility, acceptability, safety and usability; and others. An additional outcome, no studies met the inclusion criteria, was created to cater to reviews that did not find studies to include.About 80% (n = 245) of the reviews assessing all of the nine strategies that might strengthen the provision of mental healthcare services at PHC level, reported the following outcomes: improve the psychiatric or clinical symptoms of patients, reduce hospital admissions, improve adherence in care and treatment or retention in care, improve functional or quality of life of patients, cost-effective, and patients, carers and healthcare workers find them feasible, acceptable, safe and useable.A total of 34 reviews assessing integration of care or collaborative interventions, strategies that empower families, carers and patients, psychotherapy and psychosocial interventions in combination with pharmacotherapy, early detection and preventative strategies and systemic strategies that may change provider behaviour and strengthen the quality of care, all indicated impact on family and societal views and perceptions towards mental health. In addition, four reviews evaluating specialised community-based services, integration of care or collaborative interventions and early detection and preventative strategies, reported that these three strategies reduce hospital or clinic waiting times and shorten the scheduling of appointments process.Twenty-two reviews on strategies that empower families, carers and patients, early detection and preventative interventions, task-shifting approaches and integration of care, show a varying impact on improving healthcare staff knowledge or skills on mental health. Fourteen reviews evaluating E-health, specialised community-based services, integration of care interventions and early detection and preventative interventions, reported mixed impact on other outcomes, such as returning to formal employment, improving budgeting, community reintegration and access to social services such as housing. Lastly, seven reviews did not report on any outcomes because they did not identify studies that met their inclusion criteria.The evidence map of the identified strategies to strengthen the provision of mental healthcare at the PHC setting is represented in There is much evidence on strategies that empower families, carers and patients: integration of care/collaborative interventions, and e-health interventions. These strategies have been shown to have some kind of impact on almost all the reported outcomes. Evidence on specialised community-based services, task-shifting/sharing approaches and group therapy versus individual therapy is not much.In as much as hospital-based mental health care have been justified for years , the effThe iterative process employed in the screening, identifying of included systematic reviews, quality assessment and identifying of the nine strategies that have been reported in the evidence map, was robust as each activity involved three or more reviewers. However, it should be noted that the identified strategies are based on how the reviewers understood and agreed to the group and name them. For example, understanding the integration of care/collaborative approaches might differ with context and content of how the implementation was conducted and reported. In addition, the reported outcomes as indicated in the EM were grouped in some instances according to the understanding of the reviewers based on how they defined and explained in the reviews.Although our evidence points to some positive impact of various strategies in strengthening provision of PHC mental health care, this evidence map does not explicitly show the magnitude of impact towards reviewed outcome categories. Therefore, the implementation of any of the identified strategies needs to be treated with an understanding that this evidence map is just showing the amount and quality of evidence supporting each strategy. For a full understanding of the magnitude of the impact of each of the identified nine strategies towards the reported outcomes, the team will also conduct a specific overview of reviews. In conducting the specific overview of reviews, additional specific searches of literature on each of the nine strategies will be done because there is a likelihood that additional systematic reviews and studies not yet included in systematic reviews will be identified.As there is a drive to adopt and implement strong PHC health systems for mental health in low- and middle-income countries , our EM This paper presents a map of evidence on the strategies that can strengthen the provision of mental health care at PHC level. Using systematic review methodology and critical appraisal of the included reviews, this paper provides a comprehensive overview of strategies that can be implemented in PHC to strengthen mental health management. In addition, the map also portrays the amount, quality and region of where the evidence came from.There are various levels of evidence on the nine different strategies, which have shown a potentially positive impact on several outcomes ranging from psychiatric/clinical symptoms of patients, hospital admissions, functional/quality of life, and health worker knowledge and skills. We believe that our EM is an important contribution to the ongoing discussions of what, why and how PHC mental health care can be strengthened as part of a comprehensive health systems drive in light of the 2030 SDGs.To facilitate wider knowledge translation and stimulate discussions around strengthening mental health care at PHC level, the evidence map is already being used to engage with clinicians, researchers, policy/decision-makers and mental health stakeholders from different provinces of South Africa and sub-Saharan African countries. These engagements are facilitating a broader understanding of how to take forward this evidence map in a way that is useful and meaningful to clinicians, decision-makers, mental health stakeholders, advocacy groups and the public at large. Through these interactions, requests for specific evidence (overview of reviews) on some of the nine strategies have been made as the drive to strengthen the provision of mental health care at PHC level gains momentum.S1 File(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.


Cereal-derived bioactive peptides with antimicrobial activity have been poorly explored compared to those from dicotyledonous plants. Furthermore, there are a few reports addressing the structural differences between antimicrobial peptides (AMPs) from cultivated and wild cereals, which may shed light on significant varieties in the range and level of their antimicrobial activity. We performed a primary structure analysis of some antimicrobial peptides from wild and cultivated cereals to find out the features that are associated with the much higher antimicrobial resistance characteristic of wild plants. In this review, we identified and analyzed the main parameters determining significant antifungal activity. They relate to a high variability level in the sequences of C-terminal fragments and a high content of hydrophobic amino acid residues in the biologically active defensins in wild cereals, in contrast to AMPs from cultivated forms that usually exhibit weak, if any, activity. We analyzed the similarity of various physicochemical parameters between thionins and defensins. The presence of a high divergence on a fixed part of any polypeptide that is close to defensins could be a determining factor. For all of the currently known hevein-like peptides of cereals, we can say that the determining factor in this regard is the structure of the chitin-binding domain, and in particular, amino acid residues that are not directly involved in intermolecular interaction with chitin. The analysis of amino acid sequences of alpha-hairpinins (hairpin-like peptides) demonstrated much higher antifungal activity and more specificity of the peptides from wild cereals compared with those from wheat and corn, which may be associated with the presence of a mini cluster of positively charged amino acid residues. In addition, at least one hydrophobic residue may be responsible for binding to the components of fungal cell membranes. Defense peptides, including antimicrobial peptides, are essential components of plant innate immunity and occur in all of the described species from the botanical families of flowering plants. Numerous research papers devoted to antimicrobial proteins and peptides from gymnosperm plants have demonstrated the so-called evolutionary succession and antiquity of these defense molecules in the plant kingdom. The overwhelming majority of wild flowering species (dicotyledonous and monocotyledonous) grow in unfavorable conditions . At the molecular level, this usually results in allelopathic interactions between plants cohabitants ,2. For eLeymus arenarius) is an endemic species that is widespread in the northern parts of Russia, and lives in acidic soils along the coastlines of the White and Barents seas, including littoral areas with low mean air temperatures . It. ItTritiA comparative analysis of amino acid sequences isolated from the main species of wild cereals did not achieve positive results. For example, we could not predict any structure–function relationship between members of this family in cultivated cereals or wild plants. However, if we consider the similarity of some estimated physicochemical parameters  between thionins  and defeHevea brasiliensis .These AMPs are highly homologous, but a single amino acid substitution in the chitin-binding domain is critical for the level of antifungal activity, which does not correlate with fungalysin inhibition ,83. HighL. arenarius). Additionally, the presence of the last arginine residue in the WAMP sequence compensates for a positive charge in the C-terminal fragment of the molecule and increases the binding to chitin. Accordingly, it is not possible to draw conclusions about the differences in the level of activity between the peptides of cultivated and wild cereals based on the example of peptides from this family .As we noted earlier, the only amino acid variable replacement in the structure of the WAMP family peptides has a significant effect on their functionality, which is also confirmed by comparison with the amino acid sequence of the antimicrobial peptide LAMP-1a from wild-grown plant lyme grass (Fusarium verticillioides in infection) and reduce the inactivation of the catalytic domain of corn chitinase IV type [Poaceae family (wild and cultivated) may broaden their ability to be activated under the action of signal molecules and heavy metals in plants [The members of both subfamilies typically have a long chitin-binding domain that functions at the initial stage of interaction with chitin from fungal cell walls. For example, one of these mechanisms is most likely responsible for the ability of WAMP peptides to inhibit the hydrolytic activity of the zinc metalloproteinase fungalysin , buckwheat (Fagopyrum esculentum), winterweed (Veronica hederifolia), pumpkin (Cucurbita maxima), loofah (Luffa aegyptiaca), and chickweed (S. media) [V. herdefolia) and BWI-2c from buckwheat (F. esculentum)) [E. crusgalli) [T. kiharae) [Hairpin-like peptides  are a family of defense molecules of plant immunity, which were found and described relatively recently. They include short alpha-helical peptides with four cysteine residues that form two disulfide bridges, generating a beta-hairpin between alpha helices. The four-cysteine maize basic peptide (MBP-1) isolated from bacteria . Peptide. media) ,91,92,93usgalli) ,95,96, akiharae) . Studyinkiharae) ,98. The The data presented demonstrates that isolated AMPs influence different fungus species in a broad range of active concentrations. It is characteristic that according to the results of comparative testing of biological activity in vitro, in general, certain experimentally found quantitative levels of antifungal effect of alpha-harpinins isolated from grain crops are less expressed than the level of their homologues from wild species, including dicots.These results may be explained by some fungi being able to cause diseases in many plant species, including cereals, whereas some other filamentous fungus are represented as having a too-narrow specificity toward cereals.The multiple alignment of amino acid sequences of alpha-hairpinins isolated from plant organs, including cultivated and wild cereal species, reveals a stable low percentage of homology between them. The only exception is a pair of MBP-1 and EcAMP1 from corn and barnyard grass, which are highly homologous. Our experiments and the literature data allowed us to identify a fragment of the polypeptide chain of plant alpha-hairpinins that is critical for their biological activity. This is a secondary structure element, a beta-hairpin, that connects two alpha-helices and is about 10–13 amino acid residues in length .Based on the detailed analysis of amino acid sequences of hairpin fragments in alpha-hairpinins, we may draw conclusions about the higher antifungal activity and greater specificity of peptides from wild cereals compared to peptides from wheat and corn. These parameters may result from the presence of a mini cluster of positively charged amino acid residues  . ConcernFurthermore, at least one hydrophobic residue  is responsible for binding to components of fungal cell membranes  ,35.This review for the first time provides a comparative analysis of the primary structures of AMPs from the most represented families of cultural and wild cereals’ seeds. These peptides were analyzed to identify differences in their amino acid sequences. Due those differences, significant variations in the level of antimicrobial activity in relation to both the pathogens of specific fungal diseases of cereals, and pathogens with a wide range of host plants, are observed. For this analysis, we selected AMPs that belong to both the most studied families , and the poorly studied families . As a result of the analysis, a large rate of variability of C-terminal fragments for peptides from the defensin family was detected. It should be noted that for representatives of wild forms of cereals, the presence of hydrophobic amino acid residues in those fragments is more intrinsic. We analyzed the similarity of various physicochemical parameters between thionins and defensins. The presence of highly pronounced divergence on a fixed part of any polypeptide that is close to defensins could be a determining factor. For all of the currently known hevein-like peptides of cereals, we can say that the determining factor in this regard is the structure of the chitin-binding domain, and in particular, amino acid residues that are not directly involved in intermolecular interaction with the polymer. The analysis of amino acid sequences of alpha-hairpinins revealed that the more significant quantitative antifungal activity and wide specificity of the peptides from wild cereals compared to those in the peptides from wheat and corn may be associated with parameters such as the presence of a mini cluster of positively charged amino acid residues and at least one hydrophobic residue that is responsible for binding to the components of fungal cell membranes. The conclusion indicates the possibility of using highly active AMPs of wild species of cereals as a basis for the creation of transgenic cultivated plants  that express genes, coding AMPs. In addition, the application of genome-editing techniques for the promoters of target genes, coding potentially active AMPs in cultural cereals, may significantly increase their expression, which can also lead to a decrease in susceptibility to diseases.