The symptoms most commonly reported by patients affected by coronavirus disease 2019 (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g. high blood pressure, thrombosis, pulmonary embolism) seem to suggest that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ of COVID-19.

On March 11, 2020, the World Health Organization declared the coronavirus outbreak a pandemic. Since December 2019, the world has experienced an outbreak of coronavirus disease 2019 (COVID-19). Epidemiology, risk factors, and clinical characteristics of patients with COVID-19 have been reported but the factors affecting the immune system against COVID-19 have not been well described. In this article, we provide a novel hypothesis to describe how an increase in cellular adenosine triphosphate (c-ATP) can potentially improve the efficiency of innate and adaptive immune systems to either prevent and fight off COVID-19.

Background: Gut-Brain-Axis provides bidirectional communicational route; imbalance of which can have pathophysiological consequences. It is a frontier in autism research, affects 85% of autistic children (NIH report). Their microbiome has few overall microbes and smaller number of health promising microbes than their neurotypical peers. We hypothesize autism gut might play a role in manifestation of autism behaviours and on treatment, can revert back to normal behaviour considerably. The aim is to better understand to what degree gut microbiota of autism subjects differs from controls and identify bacterial species present exclusively in autism. Materials and Methods: 16s-rRNA-sequence of autism-subjects were retrieved from the American Gut Project Archive. Taxonomic assignment was inferred by similarity based methods using Quantitative Insights Into Microbial Ecology (QIIME). Species abundance was characterized and co-occurrence network was built to infer species interaction using measures of diversity. Statistical parameters were considered to validate the findings. Result: A total of 206 (1.8%) of American Gut Project datasets onstituted of autistic samples. Various bacteria such as Akkermansia sp., and Prevotella sp., were harboured in higher abundance in autistic children with statistical significance than in controls. Conclusion: These findings indicate connecting-link between gut-microbiome-brain-axis and autistic behaviour which can result in improved management

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS. New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure. Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion. The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance - capillary ischemia-reperfusion - which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems. Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

Gut bacteria play an important role in several metabolic processes and human diseases, such as obesity and its co-morbidities, like fatty liver disease, insulin resistance/diabetes and cardiovascular events. Among several factors, dietary patterns, probiotics, prebiotics, synbiotics, antimicrobials and non-dietary factors, such as stress, age, exercise and climatic conditions, can dramatically impact the human gut microbiota diversity and equilibrium. However, the effect of minor food constituents, including food additives and trace contaminants, on human gut microbiota has received less attention. Consequently, the present review aimed to provide an objective perspective of the current knowledge regarding the impacts of minor food constituents on human gut microbiota and consequently, on human health.

New research points to a possible link between Autism Spectrum Disorder and the gut microbiota as many autistic children have co-occurring gastrointestinal problems. This review focuses on specific alterations of gut microbiota mostly observed in autistic patients. Particularly, the mechanisms through which such alterations may trigger the production of the bacterial metabolites or leaky gut in autistic people are described. Various altered metabolite levels were observed in autistic children, many of those were of bacterial origin such as short chain fatty acids (SCFAs), indoles and lipopolysaccharides. A less integrative gut-blood-barrier is abundant in autistic individuals. This explains the leakage of bacterial metabolites into the patients triggering new body responses or altered metabolism. Some other co-occurring symptoms such as mitochondrial dysfunction, oxidative stress in the cells, altered tight junctions in the blood brain barrier and structural changes in cortex, hippocampus, amygdala and cerebellum were detected. Moreover, this paper suggests that autism is associated with an unbalanced gut microbiota (dysbiosis). Although the cause-effect relationship between autism and gut microbiota is not yet well established, consumption of specific probiotics may represent a powerful tool to re-establish gut homeostasis and promote gut health. Diagnostic and therapeutic value of new biomarkers leading to the perturbation in the phenylalanine metabolism will be discussed.

Background: Exposure to chronic low levels of aflatoxin B1 (AFB1) contamination can lead to immune suppression and nutritional consequences that might greatly contributed in the increase of hepatocellular carcinoma (HCC). The toxicity of AFB1 is greatly vary between different population, affected by age, gender, and environmental factors. Material and subjects: Aflatoxin B1 (AFB1) was measured in 50 blood samples collected from non B, C hepatitis viruses and non CMV-Ab liver disease patients from different general hospitals and polyclinic in KSA during period 01-2013 to 06-2014. All Patients demonstrate elevation of ALT and AST with unknown etiology. Serum samples were obtained and kept at −20 °C for AFB1detection. Results: Out of the 50 blood samples, 38 demonstrate a detectable serum level of AFB1 while the remaining 12 patients were AFB1 negative and used as control participants. While AST was non-significantly different in AFB1 exposed patients, ALT was significantly higher in AFB1 positive samples compared to control AFB1-negative. AFB1 was positively correlated with AST and ALT as liver function enzymes and with age as a risk factor of long duration of AFB1 chronic exposure. Multiple linear regression analysis ascertained the association between AFB1 chronic exposure and ALT increase in liver dysfunction Saudi patients. Conclusion: Measurement of elevated ALT as marker of liver injury in AFB1 chronically exposed Saudi patients can help to avoid the future development of HCC. Moreover, early detection of AFB1 exposure, together with early vaccination against HBV and HCV can remove the synergistic effects of these two etiological factors and thus decrease the risk of developing liver cancer.

Toll-like receptor 5 ligand, flagellin, and Vascular Adhesion Protein-1 (VAP-1) are involved in non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected to C57BL/6J WT and C57BL/6-Aoc3^-/- (VAP-1 KO) mice on high-fat diet twice a week every two weeks for 10-weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration and lipolysis in visceral adipose tissue. Consequently, increased release of glycerol led to hepatic steatosis in WT but not KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

The rapid increase in metabolic diseases occurred in the last three decades in both industrialized and developing countries has been related to the rise in sugar-added foods and sweetened beverages consumption. An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation Endproducts (AGEs). AGEs can be ingested with high temperature processed foods, but also endogenously formed as consequence of a high dietary sugars intake. Animal models of high sugars consumption, in particular fructose, have reported AGEs accumulation in different tissues in association with peripheral insulin resistance and lipid metabolism alterations. The in vitro observation that fructose is one of the most rapid and effective glycating agent when compared to other sugars has prompted the investigation of the in vivo fructose-induced glycation. In particular, the widespread employment of fructose as sweetener has been ascribed by many experimental and observational studies for the enhancement of lipogenesis and intracellular lipid deposition. Indeed, diet-derived AGEs have been demonstrated to interfere with many cell functions such as lipid synthesis, inflammation, antioxidant defences, and mitochondrial metabolism. Moreover, emerging evidences also in humans suggest that this impact of dietary AGEs on different signalling pathways can contribute to the onset of organ damage in liver, skeletal and cardiac muscle, and brain, affecting not only metabolic control, but global health. Indeed, the here reviewed most recent reports on the effects of high sugars consumption and diet-derived AGEs on human health suggest the need to limit the dietary sources of AGEs, including added sugars, to prevent the development of metabolic diseases and related comorbidities.

Perturbation in the microbial population/colony index has harmful consequences on human health. Both biological and social factors influence the composition of the gut microbiota and promote gastric diseases. Changes in the gut microbiota manifest in disease progression owing to epigenetic modification in host which influences differentiation and function of immune cells adversely. Uncontrolled use of antibiotics; chemotherapeutic drugs and change in the diet pattern usually contribute to the changes in the colony index of sensitive strains known to release microbial content in the tissue micromillieu. Ligands released from dying microbes induce TLR mimicry on interaction with TLR abnormally which skew hypoxia and sterile inflammation contributing to severity of disease like IBD autoimmunity and cancer. Various modalities/interventions practiced across the globe and future strategies for microbiota based therapeutic approaches with special emphasis on tumor and inflammatory diseases are reviewed here. Therefore the major aim and scope of this manuscript is to both discuss various modalities/interventions across the globe and to design future microbiota based therapeutic approaches for mitigating the burden with special emphasis on tumor and Inflammatory diseases.

Plants and plant-derived food products have been used for medicinal purposes since the ancient. Medicinal Plant-based functional foods or plant-based dietary compounds are a re-emerged interest for their therapeutic benefits and nutritive supports which has implicated in healthcare systems across the world. Neurological disorders are one of the greatest threats to public health and according to the World Health Organization, about 100 million people are affected globally by several neurological and mental ailments. In a traditional medication system, medicinal plants have been applied as both neuro-therapeutic purposes and micro-macro nutrients provider for the wellbeing of psychological states e.g. anti-depressant, anti-anxiety, anti-convulsions, anti-dementia, anti-psychotic, etc. Herein, it is a topic of great interest to present a conceptual aspect by reviewing relevant scientific literature about the plant-based functional foods or bioactive phytochemicals for the prevention and treatment of mental and neurological disorders. From the literature assessment, we have found that nutritional neuroscience is becoming an advanced research discipline and there has been a growing pile of evidence concerning the therapeutic use of plant-based functional foods and/or plant-derived food compounds for the management of neurologic health, evolving with promising impact over the time.

HIV-1 is a complicated and perplexing virus. It infects T cells, reverse transcribes its RNA into DNA, utilizes its host DNA machinery to replicate its HIV-DNA, translates the HIV-DNA into proteins, assembles itself for a budding escape from the T cell, and rapidly mutates its conformation. Partially, due to its complexity, there remains no cure for HIV or AIDs. However, recently with the discovery of TALENs, the use of zinc fingers, and most of all the applications of CRISPR-Cas9 technology, has given researchers new hope in finding alternative gene therapies and treatments for diseases. With more focus on CRISPR-Cas9, this new and novel technology uses a guiding RNA, sgRNA, to lead a Cas9 nuclease to its target for deletion or to change that DNA site. CRISPR-Cas9 can delete point mutations and multiple DNA sites. Because CRISPR can alter DNA sequences, several scientists have conducted research into CRISPR, possibly treating more diseases such as cancer, diabetes, and even HIV. HIV-1 drew the focus of a researcher named Dr. Ebina in 2013 when he was the first to design and apply CRISPR-Cas9 to genes found in the binding sites of HIV-1, inhibiting HIV-1 gene expression. Since 2013, several other researchers have blocked HIV replication and infection through CRISPR-Cas9 targeting the receptors of T cells called the CC chemokine receptor 5 or CCR5. HIV-1 binds to the CD4 receptor of T cells, which consists of co-receptors CCR5 and CXCR4. If CCR5 expression can be removed, the HIV virus cannot bind to T-cells, blocking the initial attachment stage, and discontinuing the infection. However, there remain obstacles and issues for the CRISPR deletion of CCR5 for treating HIV-1. The issues include: 1) finding new and safe methods of CRISPR-Cas9 delivery, 2) clearing the latent HIV reservoirs, 3) improving the sgRNA design to avoid off-target mutations or deletions, and 4) effectively analyze the viral escape of HIV from CRISPR-Cas9 modifications. Therefore, the purpose of this review is to discuss possible techniques for removing the obstacles that can lessen the potential of CRISPR to delete CCR5, repressing HIV-1 into long-term remission or a functional cure.

Biological nitrogen (N) provisioning is a seminal function of the gut microbes in several terrestrial insects, given the unbalanced carbon (C) and N ratios of their diets. Although freshwater insects face comparable dietary N limitations like terrestrial insects, little is known about this function by their gut microbiomes. In this study, we investigated microbial nitrate reduction to ammonium pathways as possible routes of biological N provisioning in two freshwater insects; filter-feeding Hydropsychidae and grazers/collectors Baetidae. After incubation in filtered (microbe-free) artificial stream water (ASW) containing dissolved ¹⁵N-labeled nitrate (treatment) or standard nitrate (control), bulk δ¹⁵N values of treatment samples (Baetidae = 100.62 ± 10.23, mean ± S.E.; Hydropsychidae = 76.82 ± 7.20) were significantly higher than controls (Baetidae = 10.14 ± 0.12 ; Hydropsychidae = 9.03 ± 0.20) in both functional feeding groups (F _{(3, 13)} = 296, P < 0.0001). The treatment δ¹⁵N values are cautiously interpreted as reflecting uptake and incorporation of microbe-derived ¹⁵N-metabolites (¹⁵NH₄ or ¹⁵N-amino acids) into host tissues following nitrate reduction to ammonium pathways in the gut lumen. Microbial nitrate reduction to ammonium activities was assessed via the quantification of dissimilatory (nrfA) and assimilatory (nasA) nitrate reduction to ammonium gene transcripts. There were no significant differences between control and treatment groups within each insect groups. Overall, this study provides a demonstration of the feasibility of applying ¹⁵N-stable isotope analysis for investigating, potential symbiotic functions of freshwater insect gut microbiomes, despite the preliminary nature of the results.

Background: Diets based on meat products are not recommended in the case of ulcerative colitis (UC). However, some foods, as those containing high oleic acid and a low omega-6/omega-3 ratio show anti-inflammatory properties. The objective here is to test if some traditional cured meat products, as acorn-fed ham (high levels of oleic acid), may be useful for controlling inflammatory diseases as UC in animal models. Methods: 3 rat cohorts have been used: vegetable rat feed, control ham and acorn-fed ham (a traditional ham where high oleic acid concentration from acorns is storage in the muscle fat). UC was induced with DSS in drinking water ad libitum for one week. Short-chain fatty acids (SCFAs) and 16S rRNA from bacterial populations were analyzed in cecum samples. Colon samples were analyzed for histological parameters (inflammatory cell density, mucosa damages, myeloperoxidase). Results: In the acorn-fed ham cohort, a protective effect was observed with respect to UC disease activity index, inflammatory cells density, colon mucosa alterations, myeloperoxidase levels, blood total antioxidant capacity and lower levels of pro-inflammatory cytokines, in comparison with feed cohort. Both ham diets caused a reduction in Firmicutes and an increase in Actinobacteria, Bacteroidetes and Proteobacteria in comparison with rat feed diet. Also, acorn-fed ham diet induced changes in gut microbiota composition, with pronounced enrichments in anti-inflammatory bacterial genera such as Alistipes, Bacteroides, Blautia, Butyricimonas and Parabacteroides. Conclusions: In the acorn-fed ham cohort, as a result of the dietary intake of oleic acid and low intake of omega-6 fatty acids, a strong preventive effect against UC symptoms was observed, indicating a valuable effect of this traditional Mediterranean cured meat product.

Inflammatory bowel diseases (IBD) represent a growing public health concern due to increasing incidence worldwide. The current notion on the pathogenesis of IBD is that genetically susceptible individuals develop intolerance to dysregulated gut microflora (dysbiosis) and chronic inflammation develops as a result of environmental triggers. Among the environmental factors associated to IBD, diet plays an important role in modulating the gut microbiome, influencing epigenetic changes and, therefore, could be applied as a therapeutic tool to improve the disease course. Nevertheless, the current dietary recommendations for disease prevention and management are scarce and of weak evidence. This review summarizes the current knowledge on the complex interactions among diet, microbiome and epigenetics in IBD. Whereas over-abundance of calories and some macronutrients increases gut inflammation, several micronutrients have the potential to modulate it. Immunonutrition has emerged as a new concept putting forward the importance of vitamins such as vitamins A, C, E, D, folic acid and beta-carotene and trace elements such as zinc, selenium, manganese and iron. However, when assessed in clinical trials, specific micronutrients exerted a limited benefit. Beyond nutrients, anti-inflammatory dietary patterns as a complex intervention approach have become popular over the recent years. Hence, exclusive enteral nutrition in pediatric Crohn’s disease is the only nutritional intervention currently recommended as a first-line therapy. Other nutritional interventions or specific diets including the Specific Carbohydrate Diet, the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyol diet and most recently the Mediterranean diet have shown strong anti-inflammatory properties and provide a promise for improving disease symptoms. Definitely, more work is required to evaluate the role of individual food compounds and complex nutritional interventions with potential to decrease inflammation as means for prevention and management of IBD.

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology considerably advanced in the last few years. A wealth of data show that the 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows to rescue long term potentiation (LTP) and long term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, possibly playing a role in the gut-brain axis, and modulates the function of immune cells. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gut and immune system.

Identifying appropriate animal models is critical in developing translatable in vitro and in vivo systems for therapeutic development and investigating disease pathophysiology. These animal models should have direct biological and translational relevance to the underlying disease they are supposed to mimic. Aging dogs naturally develop a cognitive decline in many aspects including learning and memory, but also exhibit human-like individual variability in the aging process. Neurodegenerative processes that can be observed in both human and canine brains include the progressive accumulation of β-amyloid (Aβ) found as diffuse plaques in the prefrontal cortex, including the gyrus proreus, the hippocampus, and in the cerebral vasculature. A growing body of epidemiological data shows that human patients with neurodegenerative diseases have concurrent intestinal lesions, and histopathological changes in the gastrointestinal (GI) tract occurs decades that evolve before neurodegenerative changes. Gut microbiome alterations also have been observed in many neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases, and inflammatory CNS diseases. Interestingly, only recently has the dog gut microbiome been recognized to more closely resemble in composition and in functional overlap with the human gut microbiome as compared to rodent models. This article aims to review the physiology of the gut-brain axis (GBA), and its involvement with neurodegenerative diseases in dogs and humans. Additionally, we outline the advantages and disadvantages of traditional in vitro and in vivo models and discuss future research directions investigating major human neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases using dogs.

Recently scientific research began to shift their focus on looking at both the gut and the skin microbiota as having a reciprocal and integral relationship with one another, rather than assessing them as separate and unrelated fields. In the past five years, the field of microbial endocrinology emerged, which examines how our gut microbiota influences and modulates hormones. We’ve known for decades that hormones greatly affect the condition of the skin, and many skin conditions are often treated with oral hormonal therapy as means to internally treat skin conditions visible on the dermis. Now, a growing body research and discourse examining this triad of biological spheres – gut microbiota, skin microbiota, and the endocrine system – as interconnected rather than binary and unrelated. While there is ample research established and being conducted examining the gut-skin axis, the gut-brain axis, and the gut-hormone axis, through this paper I will review and synthesize some of the significant advancements in this emerging and inclusive field of science to suggest that the fields need to expand the axis and their modality for researching these fields as a connected whole in order to better understand the role of the microbiota in disease prevention as a whole.

Cardiac dynamics are traditionally linked to a left ventricle, right ventricle and septum morphology, a topography that differs from the heart’s 5-century-old anatomic description of containing a helix and circumferential wrap architectural configuration. Torrent Guasp’s helical ventricular myocardial band (HVMB) defines this anatomy and its structure, explains why the heart’s 6 dynamic actions of narrowing, shortening, lengthening, widening, twisting and uncoiling happen. This database raises questions about deductions behind “accepted cardiac mechanics”, and its functional aspects will challenge and overturn them. These suppositions include the LV, RV, and septum description, timing of mitral valve opening, isovolumic relaxation period, reasons for torsion/twisting, untwisting, reasons for longitudinal and circumferential strain, echocardiographic sub segmentation, resynchronization, RV function dynamics, and diastolic dysfunction’s cause and unrecognized septum impairment. Torrent Guasp’s revolutionary contributions may alter future understanding of the diagnosis and treatment of cardiac disease.

Gut microbiota play critical roles in development of obese-related metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, and insulin resistance, which highlighted the potential of gut microbiota-targeted therapies on these diseases. There are various ways that can manipulate gut microbiota including probiotics, prebiotics, synbiotics, antibiotics and some active components from herbal medicines. In this review, we first reviewed the main roles of gut microbiota in mediating the development of NAFLD, and the advances in gut microbiota-targeted therapies on NAFLD in both the experimental and clinical studies, as well as the conclusions on the prospect of gut microbiota-targeted therapies in the future.

As the name implies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus and a member of the corona virus family, primarily affecting the upper respiratory system and the lungs. Like many other respiratory viruses, SARS-CoV-2 can spread to other organ systems. Apart from causing diarrhea, another most common but debilitating complication caused by the SARS-CoV-2 is neurological symptoms and cognitive difficulties, which occur in up to two thirds of hospitalized covid patients and ranging from shortness of concentration, overall declined cognitive speed to executive or memory function impairment. Neuro-cognitive dysfunction and “brain fog” are frequently present in COVID-19 cases, which can last several months after the infection, leading to disruption of daily life. Cumulative evidence suggests that SARS-CoV-2 affects vasculature in the extra pulmonary systems directly or indirectly, leading to impairment of endothelial function and even multi-organ damage. The post COVID-19 long-lasting neurocognitive impairments have not been studied fully; and the underlying mechanism remains elusive. In this review, we summarize the current understanding of the effects of COVID-19 on vascular dysfunction and how vascular dysfunction leads to cognitive impairment in patients.

The human gastrointestinal tract is inhabited by trillions of commensal bacteria collectively known as the gut microbiota. Our recognition of the significance of the complex interaction between the microbiota, and its host has grown dramatically over the past years. A balanced microbial community is a key regulator of the immune response, and metabolism of dietary components, which in turn, modulates several brain processes impacting mood and behavior. Consequently, it is likely that disruptions within the composition of the microbiota would remotely affect the mental state of the host. Here, we discuss how intestinal bacteria and their metabolites can orchestrate gut-associated neuroimmune mechanisms that influence mood and behavior leading to depression. In particular, we focus on microbiota-triggered gut inflammation and its implications in shifting the tryptophan metabolism towards kynurenine biosynthesis while disrupting the serotonergic signaling. We further investigate the gaps to be bridged in this exciting field of research in order to clarify our understanding of the multifaceted crosstalk in the microbiota-gut-brain interphase, bringing about a novel microbiota-targeted therapeutics for mental illnesses.

The modification the gut microbiota in metabolic syndrome and associated chronic diseases is among leading tasks of microbiome research and needs for clinical use of probiotics. Evidence lack for the implications for microbiome modification to improve metabolic health in particular when applied impersonalized. Probiotics have tremendous potential in personalized nutrition and medicine to develop healthy diets. The aim was to to conduct comprehensive overview of recent updates of role of microbiota on human health and development of metabolic syndrome and efficacy of microbiota modulation considering specific properties of probiotic strain and particular aspects of metabolic syndrome and patient`s phenotype to fill the gap between probiotic product and individual to facilitate development of individualized / personalized probiotic and prebiotic treatments. We discuss the relevance of using host phenotype-associated biomarkers, those based on imaging and molecular and patrient`s history, reliable and accessible to facilitate person-specific appication of probiotics and prebiotic substances. Microbiome phenotypes can be parameters of predictive medicine to recognize patient`s predispositions and evaluate treatment responses; the number of phenotype markers can be effectively involved to monitor microbiome modulation. The studied strain-dependent properties of probiotic strains are potentially relevant for individualized treatment for gut and distant sites microbiome modulation. The evidence regarding probiotic strains properties can be taken to account via pathophysiology-based approach for most effective individualized treatment via gut, oral and vaginal and other sites microbiome modulation according to phenotype of the patient providing individualized and personalized medical approaches. Preventive potential of probiotics is strong and well-documented. Recommendations for individualized clinical use of probiotics, and for probiotic studies design have been suggested.

Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rapidly increasing worldwide. A choline-deficient L-amino acid-defined high fat diet (CDHFD) has been used to create a mouse model of nonalcoholic steatohepatitis (NASH). There are some reports about the effects on mice of being fed CDAHFD for a long time, 1 to 3 months. However, the effect of this diet over a short period has been unknown. Therefore, we examined the effect of one week of feeding CDAHFD on the mouse liver. Feeding this diet for only one week induced lipid droplet deposition in the liver with increasing activity of liver-derived enzymes in the plasma. On the other hand, it did not induce fibrosis and cirrhosis. Additionally, it was demonstrated that mitochondrial respiration is significantly impaired with severe oxidative stress in the liver by CDAHFD, associated with a decreasing mitochondrial DNA copy number and complexes-proteins. In the gene expression analysis of the liver, inflammatory and oxidative stress markers were significantly increased by CDAHFD. These results demonstrated that one week of feeding CDAHFD to mice induces steatohepatitis with mitochondrial dysfunction and severe oxidative stress, without fibrosis, which can partially mimic the early stage of the NASH in humans.

Background: Patients with mild cognitive impairment end up progressing to Alzheimer’s disease (AD) leading to straining burden on public health. R. officinalis long been known as the herb of remembrance and can be a potential cognition enhancer for AD. The aims of the review were to summarize the qualitative and quantitative aspects of R.O and its active constituents in enhancing the cognition. MATERIALS AND METHOD Google scholar and PubMed structured search to find relevant studies that assessed the effect of R.O extract or any of its active constituents on cognitive performance in animals. Data extraction: Following information from each included study was extracted: (1) article information (2) characteristics of study animals (3) type of intervention; type, dose, duration, and frequency of administration of R.O (4) type of outcome measure. Data synthesis: Data were analyzed using Review Manager (RevMan 5.3, 2014] and meta-analysis was performed for the outcome measures on all relevant tasks within the included papers by computing the standardized mean difference ps. RESULTS. 23 studies for qualitative and fifteen for meta-analysis were selected. From fifteen included papers, 22 studies with 35 comparisons were meta-analyzed. Effect sizes for intact animals and impaired animals respectively was (mean g and 95% CI 1.19 [0.74, 1.64; 0.57 [0.19,0.96]. The R. officinalis had positive effect on both groups of animals. The subgroup analyses exhibited substantial unexplained heterogeneity between studies. Mechanisms of R.O was anticholinesterase, procholinergic, antioxidant, anti-amyloid, neuroprotective and anti-inflammatory agent CONCLUSIONS: R.O improves cognitive function. Limitations: Considerable heterogeneity between studies.

There is robust evidence that major depression (MDD) is accompanied by a low-grade activation of the immune-inflammatory response system, which is involved in the pathophysiology of this disorder. It is also becoming apparent that glia cells are in reciprocal communication with neurons and orchestrate various neuromodulatory, homeostatic, metabolic, and immune mechanisms and have a crucial role in neuroinflammatory mechanisms in MDD. Those cells mediate the central nervous system (CNS) response to systemic inflammation and psychological stress, but at the same time, they may be an origin of the inflammatory response in the CNS. The sources of activation of the inflammatory response in MDD are immense, however, in recent years, it is becoming increasingly evident that the gastrointestinal tract with gut-associated lymphoid tissue (GALT) and increased intestinal permeability to bacterial LPS and food-derived antigens contribute to activation of low-grade inflammatory response with subsequent psychiatric manifestations. Furthermore, an excessive permeability to gut-derived antigenic material may lead to subsequent autoimmunities which are also known to be comorbid with MDD. In this chapter, we discuss fascinating interactions between the gastrointestinal tract, increased intestinal permeability, intestinal microbiota, and glia-neuron crosstalk, and their roles in the pathogenesis of the inflammatory hypothesis of MDD. To emphasize those crucial intercommunications for the brain functions, we propose the term of microbiota-gut-immune-glia (MGIG) axis.

Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g. ill/critically ill, post-trauma, sepsis, exhausted athletes) it is currently difficult to determine whether glutamine parenteral or enteral supplementation should be recommended based on the amino acid plasma concentration (glutaminemia). Although the beneficial immune based effects of glutamine supplementation is already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review on how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism, action and important issues related to the effects of glutamine supplementation in catabolic situations.

Recent research has revealed surprisingly important connections between animals’ microbiome and social behaviour. Social interactions can affect the composition and function of the microbiome; conversely, the microbiome affects social communication by influencing the hosts’ central nervous system and peripheral chemical communication. These discoveries set the stage for novel research venues focusing on the evolution and physiology of animal social behaviour in relation to microbial transmission strategies. Here, we discuss the emerging roles of teleost fish model candidates and their key potential for advancing research fields linked to sociality and microbial regulation. We argue that fish models, such as the zebrafish, sticklebacks, guppies and cleaner-client dyads, will provide valuable insights into the roles of microbiome in shaping social behaviour and vice versa, while also being of direct relevance to the food and ornamental fish trades.

Increasing numbers of researchers are interested in the importance of dietary fiber for the gut microbiota, microbiotal metabolite SCFA, energy metabolism and gut health of the host. However, studies have demonstrated that long-term and longitudinal observation may be needed to evaluate the effect of dietary fiber better, and few such works have been made in chickens. Therefore, we successively fed low-fiber, high--fiber and low-fiber diets to two breeds of chickens during different growth periods (1—8, 9—20 and 21—50 weeks), aiming to longitudinally observe the long-term effect of altered dietary fiber on the gut microbiota, SCFA and development of cecum of chickens with age. The results showed that the composition and function of the gut microbiota, SCFA and the development of the cecum were different during different periods, which was largly affected by dietary fiber. However, the causes of some effects were different during the different periods. For example, compared with that in low-fiber chickens at 8 weeks, dominant fiber-degradation bacteria such as Bacteroidetes, Alloprevotella and SCFA-producing bacteria such as Faecalibacterium increased due to a high-fiber diet at 20 weeks, while due to a high feed intake in 50 weeks. Moreover, the concentration of SCFA in 20 weeks was significantly higher than in 8 weeks and 50 weeks, but the causes of this difference were also distinct. It was proposed that a long-term observation was needed to evaluate the effect of dietary fiber better on chickens. The metabolite pathways of ATP-binding cassette (ABC) transporters encoded by Firmicutes were enriched in 8 weeks, while a two-component system and β–glucosidase encoded by Bacteroidetes were enriched in 20 and 50 weeks. The trend was the same in two breeds of chickens except for Alloprevotella. In addition, the total content of SCFA in the contents of cecum was also affected by the size of the cecum. Surprisingly, the length of the cecum shortened from 20—50 weeks, maybe due to reduced dietary fiber.

In the last years evidence has emerged that neurodegenerative diseases (NDs) are strongly associated with the microbiome composition in the gut. Parkinson’s disease (PD) is the most intensively studied neurodegenerative disease in this context. In this review, we performed a systematic evaluation of published literature comparing changes in colonic microbiome in PD to the ones observed in other NDs including Alzheimer’s Disease (AD), Multiple system atrophy (MSA), Multiple sclerosis (MS), Neuromyelitis optica (NMO) and Amyotrophic lateral sclerosis (ALS). To warrant comparability of different studies, only human case-control studies were included. Several studies showed an increase of Lactobacillus, Bifidobacterium, Verrucomicrobiaceae and Akkermansia in PD. A decrease in PD was observed of Faecalibacterium spp., Coprococcus spp., Blautia spp., Prevotella spp. and Prevotellaceae. On low taxonomic resolution, like phylum level, the changes are not disease specific and inconsistent. However, on higher taxonomic resolution like genus or species level, a minor overlap was observed between PD and MSA, both alpha synucleinopathies. We show that a methodical standardization of sample collection and analysis is necessary for ensuring the reproducibility and comparability of data. We also provide the evidence, that assessing the microbiota composition at high taxonomic resolution, reveals changes in relative abundance, that may be specific or characteristic for one disease, or a disease-group and might evolve discriminative power. The interactions between bacterial species and strains and moreover the co-abundances must be more deeply investigated before assumptions of the effects of specific bacteria on the host can be made with certainty.

Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is sufficient experimental evidence to confirm that SARS-CoV-2 infection produces states of ciliary and flagellar dysfunction. However, these studies are unable to explain the observed effects molecularly, because they lack a sufficient understanding of the interaction between human proteins and virus proteins. Using the physical-chemical study of the human interactome in interaction with the SARS-CoV-2 proteome, we found evidence of interactions to explain the experimental effects from a molecular perspective. We found that ten viral proteins interact with key components in the maintenance of the molecular structure of axoneme. Additionally, we evaluated the pulmonary and extrapulmonary pathogenesis of COVID-19 from the point of view of ciliary dysfunction, and warned about other possible complications such as episodes of transient infertility that, due to the limitations of our work, would need verification.

Relationship between the results of penile duplex doppler ultrasound (PDDU) and response to vardenafil was investigated in patients diagnosed with erectile dysfunction (ED). Data of 148 patients with ED were analysed retrospectively. Patients who did not respond to therapy were classified as Group I (n = 32), those responded partially were classified as Group II (n = 40) and complete responders were classified as Group III (n = 76). Age, comorbid diseases, vascular and penile pathology were compared among the three groups. While diabetes mellitus (DM) and dyslipedimia positivity adversely affect the response to treatment, the presence of hypertension (HT), peyronie's disease and priapism increase the therapeutic response to the treatment (p < 0.05). Arterial insufficiency was present in 20(30.3%), 25(37,9%) and 21(31.8%) of the patients in Group I, Group II and Group III, respectively (p = 0.001). Venous insufficiency was observed in 3(14.3%) patients in Group I and in 8(85.7%) patients in Group III (p = 0.001). Arterial/venous insufficiency was seen in 9(30%), 14(46.7%) and 7(23.3%) of the patients in Group I, Group II and Group III, respectively (p = 0.001). Response rate to treatment was highest in normal patients according to PDDU, followed by patients with venous insuffiency. Besides, it was found that DM decreased the response to treatment, whereas response was increased in cases with HT, priapism and Peyronie’s disease.

Three different fields intersect in search of an understanding of the point-of-origin of modern-age diseases: 1) D-amino acids and their role under stress conditions; 2) evolutionary origin of the mitochondrion organelle in the eukaryotic cell; and 3) gut microbiota and human healthHere it is first suggested that D-amino acids function as universal signaling agents, after having evolved as prokaryotic communication, part of an organic communication process that governs the basic activities of all the cells and coordinates cell action.Mitochondria (symbiotic prokaryotic organelles), are creative source of D-amino acids as signaling agents in the central nervous system and in the neuroendocrine systems.Amino acids racemases catalyzes the conversion between the L-enantiomers ( protein building blocks) into D-enantiomers (signaling agents).It is suggested that hectic modern life may affect human health by causing stress to the gut microbiota. These affected, gut microbiota then secrete D-amino acids that enter the blood stream, as signaling agents, causing communication errors in the central nervous system, and in the neuroendocrine systems due to excessive quantity of D-amino acids.Treating gut microbiota with inhibitors of amino acids racemases or finding D-amino acid scavengers may be used in developing novel therapeutic strategies for diseases related to the central nervous system and neuroendocrine systems caused by stressed gut microbiota.

The combination of freeze-dried aronia, red ginseng, ultraviolet-irradiated shiitake mushroom and natokinase (AGM; 3.4: 4.1: 2.4: 0.1) was examined to evaluate its effects on insulin resistance, insulin secretion and gut microbiome in a non-obese type 2 diabetic animal model. Pancreatectomized (Px) rats were provided high fat diets supplemented with either of 1) 0.5 g AGM (AGM-L), 2) 1 g AGM (AGM-H), 3) 1 g dextrin (control), or 4) 1g dextrin with 120 mg metformin (positive-control) per kg body weight for 12 weeks. AGM (1 g) contained 6.22 mg cyanidin-3-galactose, 2.5 mg ginsenoside Rg3 and 0.6 mg β-glucan. Px rats had decreased bone mineral density in the lumbar spine and femur and lean body mass in the hip and leg compared to the normal-control and AGM-L and AGM-H prevented the decrease. Visceral fat mass was lower in the control group than the normal-control group and its decrease was smaller by AGM-L and AGM-H. HOMA-IR was lower in descending order of the control, positive-control, AGM-L, AGM-H and normal-control groups. Glucose tolerance was deteriorated in the control group and it was improved by AGM-L and AGM-H more than in the positive-control group. Glucose tolerance is associated with insulin resistance and insulin secretion. Insulin tolerance indicated insulin resistance was highly impaired in diabetic rats, but it was improved in the ascending order of the positive-control, AGM-L and AGM-H. Insulin secretion capacity, measured by hyperglycemic clamp, was much lower in the control group than the normal-control group and it was improved in the ascending order of the positive-control, AGM-L and AGM-H. Diabetes modulated the composition of gut microbiome and AMG prevented the modulation of gut microbiome. In conclusion, AGM improved glucose metabolism by potentiating insulin secretion and reducing insulin resistance in insulin deficient type 2 diabetic rats. The improvement of diabetic status alleviated body composition changes and prevented changes of gut microbiome composition.

Deficit schizophrenia is characterized by leaky tight and adherens junctions and bacterial translocation. Here we examine whether (deficit) schizophrenia is accompanied by leaky paracellular, transcellular and vascular barriers in the gut and blood brain barriers. We measured IgA responses to occludin, claudin-5, E-cadherin and β-catenin (paracellular pathway, PARA), talin, actin, vinculin and epithelial intermediate filament (transcellular pathway, TRANS) and plasmalemma vesicle-associated protein (PLVAP, vascular pathway) in 78 schizophrenia patients and 40 controls. IgA responses to claudin-5, E-cadherin and β-catenin, the sum of the four PARA proteins and the ratio PARA/TRANS were significantly higher in deficit schizophrenia than in non-deficit schizophrenia and controls. A large part of the variance in PHEMN (psychosis, hostility, excitation, mannerism and negative) symptoms, psychomotor retardation, formal thought disorders, verbal fluency, word list memory, word list recall and executive functions was explained by the PARA/TRANS ratio coupled with plasma IgA responses to Gram-negative bacteria, IgM to malondialdehyde, CCL-11 (eotaxin), IgA levels of the ratio of noxious to more protective tryptophan catabolites (NOX/PRO TRYCATs) and a plasma immune activation index. Moreover, IgA levels to Gram-negative bacteria were significantly associated with IgA to E-cadherin, β-catenin and PLVAP, while IgA levels to claudin-5 were significantly predicted by IgA to E-cadherin, NOX/PRO TRYCAT ratio, Gram-negative bacteria and CCL11. The phenomenology of the deficit syndrome is to a large extent explained by the cumulative effects of lowered natural IgM, breakdown of the paracellular and vascular pathways, increased bacterial translocation, peripheral immune-inflammatory responses and indices of BBB breakdown.

The mammalian gut ecosystem plays critical roles in multiple functions related to health and homeostasis. In many cases, disturbances in the gut ecosystem are associated with a large number of metabolic and chronic diseases and disorders such as diabetes, cancer, and obesity. A diverse community of microorganisms ranging from viruses to bacteria comprise the gut microbiota, which is often considered as an organ in itself. Recent studies have profiled the influence of lifestyles and dietary behavior by comparing the gut microbiome of populations with different cultural underpinnings. In this review, we provide an overview of the studies which report the influence on the gut microbial composition of dietary and lifestyle patterns in different contexts such as western industrialized countries and indigenous cultures (corresponding to different lifestyle gradients such as hunter-gatherers and pastoralists) and how this association may influence health and disease.

Abstract: Role of gut microbiome in human health is becoming apparent. The major functional impact of gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment or get absorbed in the circulation to impact distant cells/organs. Short chain fatty acids (SCFAs) are the major microbial metabolites that are produced in the gut through fermentation of non-digestible fibers. SCFAs are known to function through various mechanism, however, their signaling through free-fatty acid receptor 2 and 3 (FFAR2/3; type of G-coupled protein receptors) is new therapeutic approach. FFAR2/3 are widely expression in diverse cell types in human and mice, and functions as sensors of SCFAs to change several physiological and cellular functions. FFAR2/3 modulates neurological signaling, energy metabolism, intestinal cellular homeostasis, immune response and hormone synthesis. FFAR2/3 functions through Gi and/or Gq signaling, that is mediated through specific structural features of SCFAs-FFAR2/3 bindings and modulating specific signaling pathway. In this review, we discussed the wide-spread expression and structural homologies between human and mice FFAR2/3, and their role in different human health conditions. This information can unlock opportunities to weigh the potential of FFAR2/3 as drug target to prevent human diseases.

The latest research cumulates staggering information about the correlation between the microbiota-gut-brain axis and neurodevelopmental disorders. This review aims to shed light on the potential influence of the microbiome on the development of the most prevalent neurodevelopmental disease, attention-deficit-hyperactive disorder (ADHD). As the etiology and pathophysiology of ADHD are still unclear, finding viable biomarkers and effective treatment still represent a challenge. Therefore, we focused on factors that have been associated with a higher risk of developing ADHD while simultaneously influencing the microbial composition. We reviewed the effect of a differing microbial composition on neurotransmitter concentrations important in the pathophysiology of ADHD. Additionally, we deduced factors that correlate with a high prevalence of ADHD while simultaneously affecting the gut microbiome such as emergency c-sections, and premature birth as the former leads to a decrease of the gut microbial diversity and the latter causes neuroprotective Lactobacillus levels to be reduced. Also, we assessed nutritional influences such as breastfeeding, ingestion of short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs) on the host’s microbiome and development of ADHD. Finally, we discussed the potential significance of Bifidobacterium as a biomarker for ADHD, the importance of preventing premature birth as prophylaxis and nutrition as a prospective therapeutic measurement against ADHD.

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown cause characterized by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and more recently post-COVID-19 condition (Long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. Accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and Long COVID. To address this issue, this article aimed to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

The article describes the rational for inhibition of the angiotensin-converting enzyme 2 (ACE2) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent the establishment of positive feedback loops triggered by COVID-19 in some predisposed subjects. Making use of a large quantity of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, it is hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of the zinc metalloprotease ACE2 and its downstream pathway for SARS-CoV-2 patients. Of even more interest, metal (zinc) chelators and renin inhibitors (both FDA approved drugs) may also work alone or in combination in inhibiting the positive feedback loops, initially triggered by COVID-19 and subsequently sustained by hypoxia independently on viral trigger, when both arms of renin-angiotensin system (ACE2 and ACE) are upregulated, leading to critical, advanced and untreatable stages of the disease.

This research was to investigate beneficial impact and molecular mechanism of B. coagulans on piglets intestine. Twenty-four 21 days old weaned piglets were allotted to three treatments: control group (basal diet), B6 group (basal diet + 2×10⁶ CFU/g B. coagulans), B7 group (basal diet + 2×10⁷ CFU/g B. coagulans). The results showed that compared with control group, B6 and B7 group significantly decreased diarrhea rate and the concent of CHOL, GGT and DAO in plasma; decreased villus height and increase crypt depth in jejunum and ileum; increased the activities of SOD and CAT and decreased the concent of MDA and H₂O₂ in intestine. These data suggested that supplementing B. coagulans had beneficial impacts on promoting nutrients metabolism, maintaining intestinal integrity and alleviating oxidative stress and diarrhea. Futher research of molecular mechanisms showed that, these beneficial impacts were regulated by changing expression levels of related proteins (including HSP70, Caspase-3, Bax, Villin and Occludin), and genes (including RPL4, IFN-α, IFN-β, IFN-γ, MX1, MX2, OAS1, IL-1β, IL-4, CXCL-9, CCL-2, AQP3, SGLT-1, LPL, INSR and b^0,+AT), and altering community composition of gut microbiota (particularly family Clostridiaceae, Enterobacteriaceae, and Veillonellaceae and genus Prevotella, Turicibacter, and Lactobacillus).

The pleiotropic biochemical and antioxidant functions of Vitamin C (Vit C) have recently sparked interest in its application in intensive care. Vit C protects important organ systems such as the cardiovascular, neurologic and renal system during inflammation and oxidative stress. Vit C also influences the systems of coagulation and inflammation and its application might prevent the development of organ damage. The current evidence of Vit C’s effect on the pathophysiological reactions during various acute stress events, such as sepsis, shock, trauma, burn and ischemia-reperfusion injury imposes the question, if the application of Vit C might be especially beneficial for cardiac surgery patients, who are routinely exposed to ischemia/reperfusion and subsequent inflammation, systematically affecting different organ systems. This review covers current knowledge about the role of Vit C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between Vit C and clinical health outcomes are reviewed with special emphasis on its application in cardiac surgery. Additionally, this review pragmatically discusses evidence regarding the administration of Vitamin C in every day clinical practice, tackling the issues of safety, monitoring, dosage and most the appropriate application strategy.

This review describes the positive effects of growth hormone on the cardiovascular system. We analyze why the vascular endothelium is a real internal secretion gland, whose inflammation is the first step for developing atherosclerosis, as well as the mechanisms by which GH acts on the vascular endothelium improving its dysfunction. We also report how GH acts on coronary arterial disease and heart failure, and on peripheral arterial disease inducing the generation of new collateral vessels able to bypass a major artery occlusion. We include some preliminary data from a trial in which GH or placebo is given to elder people suffering from critical limb ischemia, showing the effects of the hormone on plasma markers of inflammation, and stating that the administration of GH in short periods of time is safe and effective even in diabetic patients. We also analyze how Klotho may have strong relationships with GH, inducing, after being released from the damaged vascular endothelium, the pituitary secretion of GH to repair the damaged tissue. Lastly, we show how GH induces wound healing by increasing the blood flow to the ischemic tissue. In summary, we postulate that short-time GH administration is useful for treating cardiovascular diseases.

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases, characterized by memory dysfunction and the presence of hyperphosphorylated tau and amyloid β (Aβ) aggregate in multiple brain regions, including the hippocampus and cortex. The exact etiology of AD has not yet been confirmed. However, epidemiological reports suggest that populations who were exposed to environmental hazards are more likely to develop AD than those who were not. Arsenic (As) is a naturally occurring environmental risk factor abundant in the Earth’s crust and human exposure to As predominantly occurs through drinking water. Convincing evidence suggests that As causes neurotoxicity and impairs memory and cognition although the hypothesis and molecular mechanism of As-associated pathobiology in AD are not clear yet. However, exposure to As and its metabolites leads to various pathogenic events such as oxidative stress, inflammation, mitochondrial dysfunctions, ER stress, apoptosis, impaired protein homeostasis, and abnormal calcium signaling. Evidence has indicated that As exposure induces alterations that coincide with most of the biochemical, pathological, and clinical developments of AD. Here, we overview existing literature to gain insights into the plausible mechanisms that underlie As-induced neurotoxicity and the subsequent neurological deficits in AD. Prospective strategies for the prevention and management of arsenic exposure and neurotoxicity have also been discussed.

The gut microbiota has recently been associated with susceptibility/resistance to malaria in animal models and humans, yet the impact of the gut microbiota on the risk of a malaria attack remains to be assessed. This study aims at assessing the influence of the gut microbiota on malaria attacks and Plasmodium parasitæmia in children living in a malaria-endemic area in Mali. Three hundred healthy children were included in a 16-months cohort study in Bandiagara. Their gut bacteria and fungi community structures were characterised via 16S and ITS metabarcoding from stool samples collected at inclusion. Clinician team monitored the occurrence of malaria attacks. Asymptomatic carriage of Plasmodium was assessed by qPCR. Over the 16-month period, 107 (36%) children experienced at least one occurrence of malaria attacks, and 82 (27%) at least one asymptomatic Plasmodium parasitæmia episode. A higher gut bacteria richness was independently associated with susceptibility to asymptomatic parasitæmia episodes and malaria attacks; while the Shannon H diversity and Chao-1 richness index of gut fungi community structure was relatively homogeneous in children who were and were not infected with P. falciparum. Using a linear discriminant effect size analysis of operational taxonomic units assigned to the species level, 17 bacteria, including Clostridiaceae, Eubacteriaceae, Senegalimassilia sp., Atopobiaceae and Lachnosipraceae, and seven fungi, including Dioszegia fristigensis, Ogataea polymorpha and Cutaneotrichosporon cyanovorans, were associated with susceptibility; whereas eight bacteria, including, Bifidobacterium spp., Weissela confusa and Peptostreptococcacea, and 3 fungi, Malassezia sp., Niesslia exosporoides, and Didymocrea leucaenae, were associated with resistance to malaria. Moreover, 15 bacteria, including Coproccus eutactus, Terrisporobacter petrolearius, Klebsiella pneumoniae and Ruminococcaceae, and 13 fungi, including Wallemia mellicola, were associated with susceptibility, whereas 19 bacteria, including Bifidobacterium spp., Bacteroides fragilis, Peptostreptococcacea, and Lactobacillus ruminis, and three fungi, including Cryptococcus neoformans, were associated with resistance to asymptomatic Plasmodium parasitæmia episodes. Further studies are needed to confirm these findings that point the way towards strategies aiming to reduce the risk of malaria by modulating gut microbiota components in at-risk populations.

In 2001, the first author of this paper reported that schizophrenia is associated with an increased frequency of the haptoglobin (Hp)-2 gene. The precursor of Hp-2 is zonulin, a molecule that affects intercellular tight junction integrity. Recently, we reported increased plasma IgA/IgM responses to Gram-negative bacteria in deficit schizophrenia indicating leaky gut and gut dysbiosis. The current study was performed to examine the integrity of the paracellular (tight and adherens junctions) and transcellular (cytoskeletal proteins) pathways in deficit versus non-deficit schizophrenia. We measured IgM responses to zonulin, occludin, E-cadherin, talin, actin and vinculin in association with IgA responses to Gram-negative bacteria, CCL-11, IgA responses to tryptophan catabolites (TRYCATs), immune activation and IgM to malondialdehyde (MDA) and NO-cysteinyl in 78 schizophrenia patients and 40 controls. We found that the ratio of IgM to zonulin + occudin / talin + actin + viculin (PARA/TRANS) was significantly greater in deficit than in non-deficit schizophrenia and higher in schizophrenia than controls and was significantly associated with increased IgA responses to Gram-negative bacteria. IgM responses to zonulin were positively associated with schizophrenia (versus controls), while IgM to occludin was significantly associated with deficit schizophrenia (versus non-deficit schizophrenia and controls). A large part of the variance (90.8%) in negative and PHEM (psychosis, hostility, excitation and mannerism) symptoms was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, IgM to E-cadherin and malondialdehyde (MDA) and memory dysfunctions, while 53.3% of the variance in the latter was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, CCL-11, TRYCATs and immune activation. The results show an upregulated paracellular pathway with breakdown of the tight and ahherens junctions and increased bacterial translocation in deficit schizophrenia. These dysfunctions in the intestinal paracellular route together with lowered natural IgM, immune activation and production of CCL-11 and TRYCATs contribute to the phenomenology of deficit schizophrenia.

Citrullinemia is the earliest identifiable biochemical abnormality in neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn screening panels using tandem mass spectrometry. However, only one neonate was positive among 600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by tandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. Using their initial NBS data, we examined citrulline concentrations and ratios of citrulline to total amino acids. Although their citrulline values exceeded the mean of the normal neonates and 80 % of them surpassed +3SD, all were below the cutoff of 40 nmol/mL. The ratios of citrulline to total amino acids significantly elevated in patients with NICCD compared to the control. By evaluating two indicators simultaneously, we could select about 80% of patients with missed NICCD. Introducing an estimated index comprising citrulline values and citrulline to total amino acid ratios could assure NICCD detection by NBS.

In the last three decades, the robust scientific data emerged, demonstrating that the immune-inflammatory response is a fundamental component of the pathophysiology of major depressive disorder (MDD). Psychological stress and various inflammatory comorbidities contribute to such immune activation. Still, this is not uncommon that patients with depression do not have defined inflammatory comorbidities, and alternative mechanisms of immune activation need to take place. The gastrointestinal (GI) tract, along with gut-associated lymphoid tissue (GALT), constitutes the largest lymphatic organ in the human body and forms the biggest surface of contact with the external environment. It is also the most significant source of bacterial and food-derived antigenic material. There is a broad range of reciprocal interactions between the GI tract, intestinal microbiota, increased intestinal permeability, activation of immune-inflammatory response, and the CNS that has crucial implications in brain function and mental health. This intercommunication takes place within the microbiota-gut-immune-glia (MGIG) axis, and glial cells are the main orchestrator of this communication. A broad range of factors, including psychological stress, inflammation, dysbiosis and other, may compromise the permeability of this barrier. This leads to excessive bacterial translocation and the excessive influx of food-derived antigenic material that contributes to activation of the immune-inflammatory response and depressive psychopathology. This chapter summarizes the role of increased intestinal permeability in MDD and mechanisms of how the "leaky gut" may contribute to immune-inflammatory response in this disorder.

One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways, however, the role of endothelial dysfunction and thrombosis have not been truly explored. This review aims to highlight the pathogenic mechanisms of these inflammatory triggers leading to thrombogenic complications. There are direct and indirect pathogenic pathways of the infection that are examined in detail. We also describe the case of carotid artery thrombosis in a patient following the SARS-CoV-2 infection, while reviewing the literature on the role of ACE2, the endothelium, and the different mechanisms by which SARS-CoV-2 may manifest both acutely and chronically. We also highlight differences from the other coronaviruses that have made this infection pandemic with similarities to the influenza virus.

Background: Obesity and diabetes are two metabolic disorders linked by an inflammatory process named insulin resistance (IR). Various research on the role of gut microbiota in developing obesity and its associated disorders has led to the growing interest in probiotic supplementation. Considering the life-threatening complications of diabesity this mini-review explored the effects of probiotic supplementation on IR in obesity-associated diabetes. Method: This review is based on recent articles from 2005-2020, studying the role of probiotic supplementation on glucose and insulin parameters in healthy and diabetic mouse models. Result: Probiotic supplementation altered the gut microbiota composition, increased short-chain fatty acid production, and decreased pro-inflammatory cytokines. Additionally, they decreased intestinal permeability, circulating lipopolysaccharide, and metabolic endotoxemia hence improved insulin sensitivity and reduced obesity. Although multi-strain probiotic supplementation showed greater benefits than single strain interventions, variations in the concentration of probiotics used and the duration of treatment also influenced the results. Conclusion: Probiotic supplementation could manipulate the gut microbiota by reducing intestinal permeability, inflammation and ameliorate IR and obesity-associated diabetes in animal models which requires further long-term clinical studies in humans.

We set up this preliminary study to evaluate one main question: could strengthening the microbiome have potential benefits for patients suffering with adverse effects after stopping long term topical steroid use? We aim to turn it into a much larger study if the results show promise. After commonly being prescribed for eczema, cessation of topical steroid use, especially after long periods of inappropriate use, can leave lasting adverse effects on the body and skin, known by some as topical steroid withdrawal (TSW). Furthermore, the subsequent withdrawal the body experiences when coming off the drug can leave lasting adverse effects on the body and skin, known by some as topical steroid withdrawal (TSW). This preliminary study involved seven human participants suffering with skin problems associated with TSW who approached Dr. Anja Gijsberts-Veens of their own volition because they were interested in more natural recovery methods. Five completed the study in full. Progress in skin condition was tracked by self-assessed symptom severity questionnaires filled out at the beginning and end of the study. The skin microbiome was addressed by using a 100% natural product shown in previous work to significantly increase skin microbiome biodiversity. Three participants implemented dietary changes and supplementation in response to guidance after fecal sample analysis to improve their gut health and biodiversity. The average improvement in skin symptoms for all participants was 40% and average symptom improvement ranged from 14% for Patient 5 to 92% for Patient 1. On average, the participants saw an improvement in 85% of their symptoms and a stagnation or regression in 11% and 4% respectively. We believe these results show enough promise to warrant expansion of this research to use a larger sample size, preferably 50+ participants, in future work. We also aim to swab the skin of participants to assess the effect on the skin microbiome from skin and gut treatments, as well as including more in-depth analysis of skin and gut microbiomes.

The microbiome gut brain (MGB) axis involves bidirectional routes of communication and has emerged as a potential therapeutic target for multiple medical specialities including psychiatry. Significant numbers of preclinical trials have taken place with some transitioning to clinical studies in more recent years. Some positive results have been reported secondary to probiotic administration in both healthy populations and specific patient groups. This review aims to summarise the current understanding of the MGB axis and the preclinical and clinical findings relevant to psychiatry. The link between the gut microbiome and irritable bowel syndrome (IBS) is well established. Significant differences have been identified between the microbiome of patients with a diagnosis of depressive disorder and healthy controls. Similar findings have occurred in patients diagnosed with bipolar affective disorder. A probiotic containing Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum produced clinically measurable symptom improvement in patients with depressive disorder. To date some promising results have suggested that probiotics could play a role in the treatment of stress-related psychiatric disease. However, more well-controlled clinical trials are required to determine which clinical conditions are likely to benefit most significantly from this novel approach.

Mitochondrial dysfunctions remained a pivotal mechanism in manifold neurodegenerative diseases. Mitochondrial homeostasis within the cell is an essential aspect of cell biology. Mitochondria which is also known as the power-generating set of the cell, have a dominant role in several processes associated with the genomic integrity and cellular equilibrium maintenance. They are involved in maintaining optimal cells functioning and guidance from possible DNA damage which could lead to mutations and onset of diseases. Conversely, system perturbations which could be due to environmental factors or senescence induce changes in the physiological balance and result in the mitochondrial functions impairment. The focal point of this review focuses on mitochondrial dysfunction as a significant condition in the onset of neuronal disintegration. We explain the pathways associated with the dysfunction of the mitochondria which are common amongst the most recurring neurodegenerative diseases including Alzheimers and Parkinsons disease. Do mitochondrial dysfunctions represent an early event in causing a shift towards neuropathological processes?

Because of lower solubility and considerable metabolism, vardenafil (VRD) bioavailability is 15 %. To get over this obstacle, this study aimed to increase the solubility, hasten the onset of action, and mask the unpleasant taste of VRD utilizing β-cyclodextrin (β-CD) and formulation of the inclusion complex as oral disintegrating tablets (ODTs). The solubility of the obtained complexes in various ratios has been studied. A Box-Behnken design (BBD) was utilized to investigate the influence of excipients on the quality of ODTs. The solubility of VRD was improved at 1:2 drug: β-CD ratio. The formulated VRD-ODTs exhibited satisfying results regarding the hardness and disintegration time. In addition, in vivo taste masking and disintegration time showed improved results, after placing the tablets in the oral cavity of the healthy volunteers. The pharmacokinetic parameters for the optimized VRD–ODTs exhibited a significant improvement with P < 0.05 in the maximum plasma concentration and reduction in the time needed to reach this concentration when compared with the marketed tablets. Finally, the optimized VRD-ODTs exhibited increased oral absorption of VRD and subsequent decreasing the time of onset of clinical effect and masking the unpleasant taste, which is favored for patients with erectile dysfunction.

Dietary factors play an important role in shaping the gut microbiome which, in turn, regulates the molecular events in colonic mucosa. The composition and resulting metabolism of the gut microbiome have been implicated in the development of colorectal cancer (CRC). Diets low in dietary fibers and phytomolecules as well as other lifestyle-related factors may predispose to CRC. Emerging evidence demonstrates that the predominance of microbes, such as Fusobacterium nucleatum, can predispose the colonic mucosa to malignant transformation. Dietary and lifestyle modifications have been demonstrated to restrict the growth of potentially harmful opportunistic organisms. In this study, we aim to present evidence regarding the relationship of dietary factors to the gut microbiome and development of CRC.

Muscle mass, strength and physical function are known to decline with age. This is associated with the development of geriatric syndromes including sarcopenia and frailty. These conditions are associated with disability, falls, longer hospital stay, higher readmission rates, institutionalisation, osteoporosis, and death. Moreover, they are associated with reduced quality of life, as well as substantial costs to health services around the world. Dietary protein is essential for skeletal muscle function. Older adults have shown evidence of anabolic resistance, where greater amounts of protein are required to stimulate muscle protein synthesis and therefore require higher daily amounts of dietary protein. Research shows that resistance exercise has the most beneficial effect on preserving skeletal muscle. A synergistic effect has been noted when this is combined with dietary protein, yet studies in this area lack consistency. This is due, in part, to the variation that exists within dietary protein, in terms of dose, quality, source, amino acid composition and timing. Research has targeted participants that are replete in dietary protein with negative results. Inconsistent measures of muscle mass, muscle function, physical activity and diet are used. This review attempts to summarise these issues, as well as introduce the possible role of the gut microbiome and its metabolome in this area.

Both lactic acid and short chain fatty acid (SCFA) play important roles in maintenance of intestinal epithelial structure and function. Trilactic glyceride (TLG) obtains both excellences of lactic acid and SCFA. This study was to investigate the effects of trilactic glyceride on growth performance, blood parameters, liver function, intestinal morphology and intestine function of piglets. Twelve weaned piglets (21±2 d) were randomly allocated to two treatment groups: 1) control group, piglets fed the basal diet; 2) TLG group, piglets fed the basal diet supplemented with 0.5 % TLG. On day 21 of the trial, D-xylose (0.1 g/kg·BW) was orally administrated to all piglets and blood samples were collected 1 h thereafter. Then, all the piglets were sacrificed to examine intestinal mucosal morphology and collect fatty tissue, liver and intestinal mucosa for further analysis. The results showed that: compared with the control group, TLG group decreased blood ALB and GGT on day 10 and 20, TLG group decreased blood TP and increased blood TG on day 20 of the trail (p < 0.05); TLG group decreased blood D-xylose and LDL, increased blood HDL (p < 0.05). These data suggested that supplementing trilactic glyceride had beneficial impacts on promoting nutrients’ metabolism, maintaining intestinal integrity, and alleviating oxidative stress and diarrhoea. Further research of molecular mechanisms showed changing expression levels of related proteins and genes, suggesting that these could be involved in the regulation of the impact. The community composition of the gut microbiota was also found to be altered in several operational taxonomic units within the genus, Prevotella (order Bacteroidales), and the order, Clostridiales.

Understanding the importance of gut microbiota (GM) in non-alcoholic fatty liver disease (NAFLD) has raised the hope for therapeutic microbes. We have shown that high hepatic fat associated with low abundance of Faecalibacterium prausnitzii in humans and further, administration of F. prausnitzii prevented NAFLD in mice. Here, we aimed to target F. prausnitzii by prebiotic xylo-oligosaccharides (XOS) to treat NAFLD. First, the effect of XOS on F. prausnitzii growth was assessed in vitro. Then, XOS was supplemented or not with high (HFD) or low (LFD) fat-diet for 12-weeks in Wistar rats (n=10/group). XOS increased F. prausnitzii growth having only minor impact on the GM composition. When supplemented with HFD, XOS prevented hepatic steatosis. The underlying mechanisms involved enhanced hepatic β-oxidation and mitochondrial respiration. 1H-NMR analysis of caecal metabolites showed that compared to HFD, LFD group had healthier caecal short-chain fatty acid profile and the combination of HFD and XOS was associated with reduced caecal isovalerate and tyrosine, metabolites previously linked to NAFLD. Caecal branched-chain fatty acids associated positively and butyrate negatively with hepatic triglycerides. In conclusion, our study identifies F. prausnitzii as a possible target to treat NAFLD with XOS. The underlying preventive mechanisms involved improved hepatic oxidative metabolism.

Proper nutrition is crucial for normal brain and neurocognitive development. Failure to optimize neurodevelopment early in life can have profound long-term implications for both mental health and quality of life. Although the first 1000 days of life represent the most critical period of neurodevelopment, the central and peripheral nervous systems continue to develop and change throughout life. All this time, development and functioning depend on many factors, including adequate nutrition. In this review, we outline the role of nutrients in cognitive, emotional, and neural development in infants and young children with special attention to the emerging roles of polar lipids and high quality (available) protein. Furthermore, we discuss the dynamic nature of the gut-brain axis and the importance of microbial diversity in relation to a variety of outcomes, including brain maturation/function and behavior are discussed. Finally, the promising therapeutic potential of psychobiotics to modify gut microbial ecology in order to improve mental well-being is presented. Here we show that the individual contribution of nutrients, their interaction with other micro-and macronutrients, and the way in which they are organized in the food matrix are of crucial importance for normal neurocognitive development.

Alzheimer's disease (AD) has been the subject of extensive investigation as to its biological underpinnings. However, this has produced little of therapeutic benefit or indeed provided any accepted biomarkers that could tailor treatment. This chapter reviews data on the main pathophysiologic processes that have been widely shown to be altered in AD, including circadian dysregulation, mitochondrial dysfunction, gut dysbiosis, and immune-glia-platelet activation. It is proposed that alterations in the gut microbiome, including gut dysbiosis and increased gut permeability drive changes in mitochondrial function that are intimately associated with significant variations in sirtuin expression. Both mitochondria-located and nucleus/cytoplasm located sirtuins can act on mitochondrial function in different cells and body systems to co-ordinate the ageing-associated changes that underpin AD. The sirtuins are therefore key aspect to a developmental model of AD that is more 'holistic' in perspective, thereby providing a framework for the detection of earlier biomarkers and more successful treatment for the heterogenous nature of AD pathoetiology.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Given the growing evidence of gut microbiota being involved in psychiatric (including neurodevelopmental) disorders, we aimed to identify differences in gut microbiota composition between participants with ADHD and controls and to investigate the role of the microbiota in inattention and hyperactivity/impulsivity. Fecal samples were collected from 107 participants (NADHD=42; Ncontrols=50; NsubthreholdADHD=15; range age: 13-29 years). The relative quantification of bacterial taxa was done using 16S ribosomal RNA gene amplicon sequencing. Beta-diversity revealed significant differences in bacterial composition between participants with ADHD and healthy controls, which was also significant for inattention, but showing a trend in case of hyperactivity/impulsivity only. Ten genera showed nominal differences (P < 0.05) between both groups, of which seven genera were tested for their association with ADHD symptom scores (adjusting for age, sex, body mass index, time delay between feces collection and symptoms assessment, medication use and family relatedness). Our results show that variation of a genus from the Ruminococcaceae family (Ruminococcaceae_UCG_004) is associated (after multiple testing correction) with inattention symptoms, and suggest a role of gut microbiota in ADHD pathophysiology.

Early detection, isolation, and management of COVID-19 patients are crucial to contain the current pandemic. The CDC in USA recently included "sudden loss of taste (dysgeusia/ageusia) and smell (anosmia/hyposmia)” as symptoms of COVID-19. If these symptoms are reliable forerunner symptoms of COVID-19, then it may facilitate early detection and containment of the disease. Hence, we systematically evaluated the contemporary evidence on dysgeusia and anosmia as trigger symptoms in COVID-19. Ovid MEDLINE, EBSCO host, and Web of Science databases were searched between December 25, 2019-May 30, 2020.Of the 13 identified records, eight (totaling 11,054 COVID-19 patients), were included, as per the selection criteria. The studies emanated mostly from the European community, as well as China, the USA, and Iran. In total, anosmia and dysgeusia symptoms were present in 74.9 % and 81.3% ambulatory as well as hospitalized, mild-to-severe cases of COVID-19 patients, respectively. The European, US, and Iran data indicate that olfactory, and gustatory symptoms appear prior to general COVID-19 symptoms in a majority of the patients. To our knowledge, this is the first systematic review analyzing the prevalence of chemosensory dysfunction in COVID-19. Further, studies are essential to evaluate their utility as harbingers of COVID-19 onset, and to establish clinical practice guidelines.

Spondyloarthritis comprises of a group of inflammatory diseases of the joints and spine with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.

The brain reciprocally communicates with the rest of the body via neural, endocrine, immune, and other systems. This is crucial for coordinating the complex behavioral and physiological responses needed to cope with the many challenges of life. The Anterior Cingulate Cortex (ACC) is a key brain structure involved in assessing rewards and threats, as well as activating appropriate responses. This is a dynamic process that depends on evolving needs and challenges. Important challenges include illness or injury. These typically involve inflammation and pain, which evoke neuroinflammatory processes in the brain to drive sickness behaviours. In the short term, sickness behaviours are considered adaptive, as they promote convalescence (e.g. low mood; lethargy, fatigue, social withdrawal), and enhanced threat appraisal (e.g. anxiety) to combat increased risk/vulnerability associated with sickness. Chronic inflammation, however, appears to remodel the system to inappropriately activate threat-coping responses, resulting in depressive and/or anxious phenotypes. These mood disorders are particularly pronounced in diseases and disorders associated with gut dysfunction, which feature chronic inflammation and altered ACC function. We propose that chronic inflammation remodels ACC physiology such that it errantly predicts heightened danger based on a mental model (a.k.a ‘schema’) of the world. This evokes chronic activation of threat-coping systems, including endocrine signaling (e.g. adrenaline), and anxiety. Inflammation can be driven by brain systems involving ACC, leading to a feedback-cycle that self-reinforces pathological states. This theory accounts for a wealth of clinical and preclinical data that implicate the ACC in disorders of mood and gastrointestinal function, and reveals a key player in the gut-brain axis that may represent a novel therapeutic target.

Introduction and objectives: a close association between metabolic syndrome among subjects with erectile dysfunction has been addressed, since mechanisms underlying metabolic syndrome compromise the blood flow to the penis in numerous ways. This study aims to analyze the relationship between erectile dysfunction and metabolic syndrome in a group of Mexican patients, to study the influence of other morbidity factors on erectile dysfunction, and to define the specific metabolic syndrome components most associated with erectile dysfunction severity. Methods: a descriptive and cross-sectional study was completed in a group of 86 adult Mexican patients with previous diagnosis of erectile dysfunction. Participants were classified as with or without metabolic syndrome. Erectile dysfunction severity, alcohol or tobacco consumption, and depressive behavior were identified through validated questionnaires and compared between both groups, as well as anthropometric, biochemical, and clinical parameters. Results: anthropometric measures, laboratory values, clinical characteristics and the Beck Depression Inventory score were significantly different among both groups. Additionally, more patients affected by severe and moderate erectile dysfunction were identified in the group with metabolic syndrome. Among the metabolic syndrome components, HbA1c >5.7% and fasting glucose >110 mg/dl were significantly associated to the development of erectile dysfunction (p = 0.004 and 0.04, respectively). Conclusions: metabolic syndrome components aggravate erectile dysfunction, particularly the lack of glycemic control manifested by Hb1Ac >5.7% and/or fasting glucose >110 mg/dL. The inclusion of fasting glucose and HbA1c as a complementary biochemical screening among patients with erectile dysfunction should be assessed.

Background: The gut microbiome plays a major role in chronic diseases, of which several are characterized by an altered composition and diversity of bacterial communities. Large-scale sequencing projects allowed characterizing the perturbations of these communities. However, translating these discoveries into clinical applications remains a challenges. To facilitate routine implementation of microbiome profiling in clinical settings, portable, real-time, and low-cost sequencing technologies are needed. Results: Here, we propose a computational and experimental protocol for whole genome quantitative metagenomics studies of human gut microbiome with Oxford Nanopore sequencing technology (ONT) that could be applied to other microbial ecosystems. We developed a bioinformatic protocol to analyse ONT sequences taxonomically and functionally and optimized pre-analytic protocols including stool collection and DNA extraction methods to maximize read length. This is a critical parameter for the sequence alignment and classification. Our protocol was evaluated using simulations of metagenomic communities which reflect naturally occuring compositional variations. Next, we validated both protocols using stool samples from a bariatric surgery cohort, sequenced with ONT, Illumina and SOLiD technologies. Results revealed similar diversity and microbial composition profiles. Conclusion: This protocol can be implemented in the clinical or research setting, bringing rapid personalized whole genome profiling of target microbiome species.

Cardiopulmonary lesions, which manifest from various types of diseases such as pulmonary arterial hypertension, atherosclerosis, pulmonary arteriovenous malformations, lymphangioleiomyomatosis, and peripheral arterial disease, pose a public health problem. Vascular remodeling, which refers to alternations to the structure of the vessel is an important pathophysiological feature of these diseases. The Inhibitor of DNA-binding/Differentiation-3 (ID3), which is part of the ID family of transcriptional regulators, has been demonstrated to contribute to an essential role in the vasculature and therefore may influence the alterations of these lesions. This review will cover the existing understanding of how ID3 may contribute to cardiopulmonary lesion perturbations via involvement in vascular remodeling. Furthermore, based on the accumulative quantity of reports that indicate oxidative stress plays a essential function in the pathophysiology of vascular remodeling, we will also consider the impact of exposure to estrogenic endocrine disruptors (EEDs) such as polychlorinated biphenyls (PCBs) and bisphenol A (BPA) on ID3 & cardiopulmonary disease. Improved understanding of how ID3 pathways contributes to these molecular mechanisms in the lesion will prospectively deliver beneficial information in the mediation of vascular remodeling associated with ID3 & EED exposure, which may play an essential role in cardiopulmonary disease prevalence.

Objectives: To demonstrate the efficacy of Gemtuzumab ozogamicin in refractory AML patients with organ dysfunctions and poor performance status. Three refractory AML patients with are described. One of them was pretreated by intensive chemotherapy, two other patients progressed during Azacitidine treatment. WHO performance status III . Two patients had respiratory failure grade 2, the other one suffered from acute kidney insufficiency. Two patients were highly febrile with elevated CRP level. Gemtuzumab ozogamicin administration was performed in three patients followed by further switch to Gemtuzumab ozogamicin + Azacitidine or “7+3” treatment. Results: Gemtuzumab ozogamicin administration resulted in abrupt fever cessation in two febrile patients simultaneously with CRP level decrease and fast gradual resolution of respiratory failure. Recovery of kidney function was noticed in patient with renal insufficiency. WHO performance status have elevated in all three patients. No adverse effects grade II-III were noticed. Further treatment made two patients eligible for intensive chemotherapy, one patient was transplanted, patient with kidney failure obtained complete remission. Conclusions: Gemtuzumab ozogamicin therapy appeared to be safe and highly efficacious in relapsed/refractory AML patients with organ dysfunctions and poor performance status.

Since the discovery of the Coronavirus disease 2019 (COVID-19) outbreak, a vast majority of studies have been carried out that confirmed the worst outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with preexisting health conditions, including diabetes, obesity, hypertension, cancer, and cardiovascular diseases. Likewise, diabetes itself is one of the leading causes of global public health concerns that impose a heavy global burden on public health as well as socio-economic development. Both diabetes and SARS-CoV-2 infection have their independent ability to induce the pathogenesis and severity of multi-system organ dysfunction, while the co-existence of these two culprits can accelerate the pathophysiology and magnify the severity of the diseases. However, the exact pathophysiology of multi-system organ failure in diabetic patients after SARS-CoV-2 infection is still obscure. This review summarized the organ-specific possible molecular mechanisms of SARS-CoV-2 and diabetes-induced pathophysiology of several diseases of multiple organs, including the lungs, heart, kidney, brain, eyes, gastrointestinal system, and bones, and subsequent manifestation of multi-system organ failure.

Abstract: Supplementation of infant formula with ingredients potentially able to manage, in a way positive for the host, the gut microbiota of infants, is nowadays widely used by infant food producers. The impact of this class of compounds, named prebiotics, on gut microbiota composition, was initially measured on the enrichment of Bifidobacterium and Lactobacillus spp., but the use of culture-independent analytical techniques has allowed to establish that a larger number of intestinal microorganisms are affected by the ingestion of prebiotics. However, despite a relevant number of scientific publications, actually there is no consensus on the amount of prebiotics to be administered daily, the potentially different actions exerted by prebiotics which differ in biochemical structures, as well as the impact of different percentages of the same prebiotics when used in mixtures and/or combination. This paper is aimed to critically review the available data on the use of prebiotics in infant formula, with special attention paid to identify a link between, the dosage used, the mixture composition and the observed outcomes, keeping in mind the influences in nutrition quality and growth influence.

Erectile dysfunction (ED) due to diabetes mellitus remains difficult to treat despite advances in pharmacotherapeutic approaches in the field. Therefore, this study investigated the erectogenic effect of the methanolic extract of Maytenus procumbens roots on type 2 diabetes in rats. The fructose-streptozotocin model was used to induce type 2 diabetes-linked ED in male rats. The sexually active male Sprague Dawley rats were randomly divided into two major groups; normal group and high fructose fed group for 120 days. After 120 days, the high fructose fed group rats were given a single intraperitoneal injection of a freshly prepared streptozotocin solution (30 mg/kg). The diabetic ED rats were orally administered with the extract at 250 mg/kg, daily for 28 days. The serum, brain and penile tissues were removed for biochemical analysis and protein expression. Increased testosterone level, mounting frequency, reduced blood glucose level and serum fructosamine content was observed after 28 days of treatment in diabetic rats. Methanolic extract also exhibited an inhibitory effect on arginase, AChE, and ACE activities. The crude extract further downregulated proteins PDE-5, RhoA and increased expression of eNOS in the diabetic ED treated rats. The results obtained indicate that the methanolic extract of Maytenus procumbens roots ameliorates erectile dysfunction in type 2 diabetes-induced erectile dysfunction in rats.

Background: A Few preclinical studies have shown that Knee osteoarthritis (KOA) is linked to gut microbiome dysbiosis and chronic inflammation. This pilot study was designed to look at the gut microbiome composition in KOA patients and normal individuals with or without vitamin D deficiency (VDD, serum vitamin D <30 ng/ml). Methods: This pilot study was conducted prospectively in 24 participants. The faecal samples of all the participants were taken for DNA extraction. The V3-V4 region of 16s rRNA was amplified and the library was prepared and sequenced on the Illumina Miseq platform. Results: The mean (±SD) age was 45.5 (±10.2) years with no defined co-morbidities. Of 447 total Operational Taxonomic Units (OTUs), a differential abundance of 16 nominally significant OTUs between the groups were observed. Linear discriminate analysis (LEfSe) revealed a significant difference in bacteria among the study groups. Pseudobutyrivibrio and Odoribacter were specific for VDD while Parabacteroides, Butyricimonas, and Gordonibacter were abundant in the KOA_VDD group and Peptococcus, Intestimonas, Delftia, and Oribacterium were abundant in the KOA group. About 80% of bacterial species were common among different groups and hence labeled as core bacterial species. However, the core microbiome of KOA and VDD groups were not seen in the KOA_VDD group, suggesting that these bacterial groups were affected by the interaction of the KOA and VDD factors. Conclusion: Parabacteroides, Butyricimonas, Pseudobutyrivibrio, Odoribacter, and Gordonibacter are the predominant bacteria in vitamin D deficient patients with or without KOA. Together these results indicate an association between the gut microbiome, vitamin D, and knee osteoarthritis.

Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection triggers various events from molecular to tissue level, which in turn is given by the intrinsic characteristics of each patient. Given the molecular diversity characteristic of each cellular phenotype, the possible cytopathic, tissue and clinical effects are difficult to predict, which determines the heterogeneity of COVID-19 symptoms. The purpose of this article is to provide a comprehensive review of the cytopathic effects of SARS-CoV-2 on various cell types, focusing on the development of COVID-19, which in turn may lead, in some patients, to a persistence of symptoms after recovery from the disease, a condition known as long COVID. We describe the molecular mechanisms underlying virus-host interactions, including alterations in protein expression, intracellular signaling pathways, and immune responses. In particular, the article highlights the potential impact of these cytopathies on cellular function and clinical outcomes, such as immune dysregulation, neuropsychiatric disorders, and organ damage. The article concludes by discussing future directions for research and implications for the management and treatment of COVID-19 and Long-COVID.

Background and objectives: Smoking leads to autonomic dysfunction. However, the clinical methods for diagnosing this dysfunction are not sufficient. Since exogenous hypoxia leads to changes in the autonomic cardiac control, the aim of our study was to compare the activity of the autonomic nervous system via heart rate variability (HRV) in young “healthy” smokers and non-smokers before, during and after a short-term exogenous hypoxic exposure. Methods: Twenty-one healthy non-smoking males aged 28.0±7.4 (mean±SD) and fourteen healthy smoking males aged 28.1±4.3 with 9.2±5.6 pack-years were subjected to one-hour hypoxic exposure (FiО2=12.3±1.5%) via hypoxicator (AltiPro 8850 Summit+, Altitude Tech, Canada) with simultaneous recording of electrocardiography and pulse oximetry. HRV data was derived via specific software (Kubios HRV, Finland) by analyzing the pre-hypoxic, hypoxic and post-hypoxic periods. Results: Standard deviation of the intervals between normal beats (SDNN) was higher in non-smokers in the pre-hypoxic period (62.0±32.1 vs 40.3±16.2, p=0.013) but not in hypoxia (75.7±34.8 vs 57.9±18.3, p=0.167). When comparing intragroup HRV changes of shifting from hypoxic to post-hypoxic (normoxic) conditions we found that there is a significant increase in the root mean square of successive RR interval differences (RMSSD) (65.9±40.2 vs 75.1±45.9, p=0.011) and in the high frequency (lnHF) (6.8±1.4 vs 7.2±1.3, p=0.014) and a decrease in LF/HF (3.0±2.3 vs 1.9±1.5, p<0.001), but these changes were observed only in the group of non-smokers. Conclusions: Smoking likely impairs autonomic regulation in young healthy males and may lead to a decreased HRV even before subjective clinical signs and symptoms. Hypoxic exposure test could be applied in clinical practice for early detection of autonomic dysfunction in smokers, because their parasympathetic reactivation is blunted when shifting from hypoxic to normoxic ambient conditions measured by HRV.

Psoriasis is a chronic inflammatory disease characterized by skin lesions. Psoriasis development has been associated both with genetic and environmental factors. Though skin and gut microbiota has been implicated in number of pathologies including atopic dermatitis, inflammatory bowel disease, Crohn’s disease, allergy, obesity, its role has been poorly studied in psoriatic disease, which incorporates both psoriasis and psoriatic arthritis. This literature review summarizes the most recent and major findings on microbiota features in psoriatic disease as well as gives immune system role in the given condition. Despite conflicting findings, psoriasis patients were frequently found to have distinct microbial composition in both skin and guts especially in the major bacterial phyla, Firmicutes, Bacteroidetes, and Akkermansia. Furthermore, bacterial DNA has been found in psoriatic patients both locally and systemically, and altogether suggesting role of bacteria in the chronic disease and future studies in this field.

With the ever-increasing rate, obesity has become an epidemiological problem throughout the globe comprising about 39% of the world population as of now. Among several reasons, disruption of the gut microbial ecosystem might contribute to the pathogenesis of metabolic disorders, including obesity, metabolic syndrome, type 2 diabetes, and other associated comorbidities. Though the mechanisms related to dysbiosis are unclear, diet might play a modulating role where different dietary approaches manipulate microbial richness and abundance as well as stability. For instance, shifting of Firmicutes and Bacteroidetes ratio in the gut might have a role in association with the dietary approaches and ingestion duration. Along with altered gut microbial composition, microbial metabolites such as short-chain fatty acids (SCFA) after ingestion of non-digestible dietary starches may have an impact on host metabolism by regulating lipogenesis, gluconeogenesis, and inflammation with potential associations to health and obesity. The dietary approaches like carbohydrates, fibre, protein, and/or fat diet at various arrangements can make a shift in the composition of gut microbiota if introduced for a short period. However, the unique pattern of the gut microbes usually remains the same along with the longer period of habitual diet. Though the short-term dietary intervention or circadian rhythm influences a transient change in gut microbes, other than habitual diet, the understanding related to long-term dietary change-induced permanent alterations is minimum. Alternatively, the usage of prebiotics, probiotics as well as postbiotics could be beneficial to overcome dysbiosis. This review highlights the current knowledge and the interaction between the human intestinal microbiota and diet as a modifying factor, in obesity allowing the scientists to uncover novel targets and tools to use as customized therapy.

Introduction: Left atrial hypertension is one of the pathophysiologies of heart failure with preserved ejection fraction. We hypothesized that left atrial pressure response (LAPR) to incremental pacing is higher in patients with atrial fibrillation (AF) and can predict left ventricular diastolic dysfunction. Methods: Patients requiring left atrial access as a part of a therapeutic procedure for AF (n=204, AF group) or supraventricular tachycardia (n=34, control group) were analyzed (male n=183, 54±12 years old). LAPR was measured during incremental pacing. Results: Baseline left atrial pressure and LAPR at all pacing rates were not different between the AF and control groups. They were higher in patients with a high E/e’ (≥ 8) than in those with a low E/e’ (&lt; 8). LAPR at a pacing interval of 400ms and E/e' were positively correlated (r=0.373, p&lt;0.001). Body mass index and a high E/e' were independent predictors of pacing-induced left atrial hypertension. Conclusions: The LAPR to incremental pacing was constant regardless of AF. The non-invasive echocardiographic marker E/e' reflected pacing-induced left atrial hypertension.

Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence development of both ASD and PD with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.

Flavonoids comprise a large group of structurally diverse polyphenolic compounds of plant origin and are abundantly found in human diet such as fruits, vegetables, grains, tea, dairy products, red wine and so on. Major classes of flavonoids include flavonols, flavones, flavanones, flavanols, anthocyanidins, isoflavones, and chalcones. Owing to their potential health benefits and medicinal significance, flavonoids are now considered as an indispensable component in a variety of medicinal, pharmaceutical, nutraceutical, and cosmetic preparations. However, flavonoids play a significant role in preventing cardiovascular diseases (CVDs), which could be mainly due to their antioxidant, antiatherogenic, and antithrombotic effects. Epidemiological and in vitro/in vivo evidences of antioxidant effects support the cardioprotective function of dietary flavonoids. Further, the inhibition of LDL oxidation and platelet aggregation following regular consumption of food containing flavonoids and moderate consumption of red wine might protect against atherosclerosis and thrombosis. A study suggests that daily intake of 100 mg of flavonoids through diet may reduce the risk of developing morbidity and mortality due to coronary heart disease (CHD) by approximately 10%. This review summarizes dietary flavonoids with their sources and potential health implications in CVDs including various redox-active cardioprotective (molecular) mechanisms with antioxidant effects. Pharmacokinetic (oral bioavailability, drug metabolism), toxicological and therapeutic aspects of dietary flavonoids are also addressed herein with future directions for the discovery and development of useful drug candidates/ therapeutic molecules.

The central nervous system (CNS) and the human gastrointestinal (GI) tract communicate through the gut-brain axis (GBA). Such communication is bi-directional and involves neuronal, endocrine and immunological mechanisms. The scientific data are mounting that gut microbiota is a source of a number of neuroactive and immunocompetent substances, which shape the structure and function of brain regions involved in control of emotions, physical activity and cognition. Most of GI maladies are associated with altered transmission within the GBA and influenced both by genetic and environmental factors. Current treatment protocols widely advocated for the treatment of GI disorders may positively or adversely affect the composition of intestinal microbiota with diverse impact on therapeutic outcome. The alterations of gut microbiota have been associated with mood and depressive disorders. and mental health is frequently altered in the course of many GI and non-GI ailments. Deregulation of the GBA may constitute a grip point for the development of diagnostic tools and personalized microbiota-based therapy. For example next generation sequencing (NGS) offers detailed analysis of microbiome footprints in patients with mental and GI disorders. Psychobiotics are new class of beneficial bacteria, with documented efficacy in the treatment of gut-brain axis disorders.

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity.Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia (“OSOS”); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in the OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

Hazardous toxic metals, such as lead and cadmium, and to a lesser extent aluminum, are extensively recognized as detrimental for health following ingestion within food and water, or following inhalation. Gut and food-derived microbes, by interacting with heavy metals, may actively or passively modulate their bioavailability inside the gut, either by adsorption or by sequestration. Such a bioremediation within the gut implies the selection of safe microbes, based on their specific capacities to immobilize metals. We investigated the metal removal ability of 225 bacteria toward the potential harmful trace elements lead, cadmium and aluminum in vitro, using Inductively Coupled Plasma Mass Spectrometry analysis. Interspecies and intraspecies comparisons were addressed and discussed among bacteria from the phylum Firmicutes, which are mostly lactic acid bacteria, including Lactobacillus spp, with some Lactococcus, Pediococcus and Carnobacterium representatives, Actinobacteria as well as Proteobacteria. The effect on mixture of lead and cadmium was also investigated. Although the purpose of such a screening is so far not to elucidate each of the various strain specific- and metal dependent- mechanisms of heavy metal removal, we identified potential bacteria which are able to alleviate Pb(II) and Cd(II) concerns in order to propose performing candidate probiotics for metal xenobiotic bioremediation.

(1) Background: Nicotine is implicated in the SARS-COV-2 infection through activation of the α7-nAChR and over-expression of ACE2. Our objective is to clarify the role of nicotine in SARS-CoV-2 infection exploring its molecular and cellular activity. (2) Methods: HBEpC or si-mRNA-α7-HBEpC were treated for 1, 48 h or continuously with 10-7 M Nicotine, a concentration mimicking human exposure to a cigarette. Cell viability and proliferation were evaluated by trypan blue dye exclusion and cell counting, migration by cell migration assay, senescence by SA-beta-Gal activity, and anchorage-independent growth by cloning in soft agar. Expression of Ki67, p53/phospho-p53, VEGF, EGFR/pEGFR, phospho-p38, intracellular Ca+2, ATP and EMT were evaluated by ELISA and/or western blotting. (3) Results: Nicotine induced through α7-nAChR (i) increase in cell viability (ii) cell proliferation; (iii) Ki67 over-expression, (iv) phospho-p38 up-regulation (v) EGFR/pEGFR over-expression; (vi) increase in basal Ca+2 concentration, (vii) reduction of ATP production; (viii) decreased level of p53/phospho-p53, (ix) delayed senescence, (x) VEGF increase, (xi) EMT and consequent (xii) enhanced migration, and (xiii) ability to grow independently of the substrate. (4) Conclusions: Based on our results and on evidence showing that Nicotine potentiates viral infection it is likely that Nicotine is involved in SARS-CoV-2 infection and severity

‘Dysbiosis’ of the adult gut microbiota, in response to challenges such as infection, altered diet, stress, and antibiotics treatment has been recently linked to pathological alteration of brain func-tion and behavior. Moreover, gut microbiota composition constantly controls microglia matura-tion as revealed by morphological observations and gene expression analysis. However, it is un-clear whether gut microbiota influences microglia functional properties and crosstalk with neu-rons, known to shape and modulate synaptic development and function. Here, we investigated how antibiotic mediated alteration of the gut microbiota influences microglial and neuronal functions in adult mice hippocampus. Hippocampal microglia from adult mice treated with oral antibiotics exhibited increased microglia density, altered basal patrolling activity, and impaired process rearrangement in response to damage. Patch clamp recordings at CA3-CA1 synapses revealed that antibiotics treatment alters neuronal functions, reducing spontaneous postsynaptic glutamatergic currents and decreasing synaptic connectivity, without reducing dendritic spines density. The effect of dysbiosis on neuronal functions are mediated by microglia-neuron cross-talk through the CX3CL1-CX3CR1 axis, as antibiotics treatment of CX3CR1 deficient mice, mod-ulates microglia density and processes rearrangement leaving unaltered synaptic function. To-gether, our findings show that the antibiotics alteration of gut microbiota impairs synaptic effi-cacy, probably through CX3CL1-CX3CR1 signaling supporting microglia as a major player in in the gut-brain axis, and in particular in the gut microbiota-to-neuron communication pathway.

Nutrition is crucial for the management of patients affected by chronic kidney disease (CKD) to slow down disease progression and to correct symptoms. The mainstay of the nutritional approach to renal patients is protein restriction coupled with adequate energy supply to prevent malnutrition. However, other aspects of renal diets, including fiber content, can be beneficial. This paper summarizes the latest literature on the role of different types of dietary fiber in CKD, with special attention to intestinal microbiota and the potential protective role of renal diets. Fibers have been identified based on aqueous solubility, but other features, such as viscosity, fermentability, and bulking effect in the colon should be considered. A proper amount of fiber should be recommended not only in the general population but also in CKD patients, to achieve an adequate composition and metabolism of intestinal microbiota and to reduce the risks connected with obesity, diabetes, and dyslipidemia.

The oral cavity is the gateway for microorganisms into your body where they disseminate not only to the directly connected respiratory and digestive tracts, but also to the many remote organs. Oral microbiota, traveling to the end of the intestine and circulating our body through blood vessels, not only affect a gut microbiome profile, but also many systemic diseases. By gathering information accumulated from the era of focal infection theory to the age of revolution in microbiome research, we propose a pivotal role of “leaky gum”, as an analogy of “leaky gut”, to underscore the importance of the oral cavity in systemic health. The oral cavity has unique structures, the gingival sulcus (GS) and the junctional epithelium (JE) below the GS, which are rarely found anywhere else in our body. The JE is attached to the tooth enamel and cementum by hemidesmosome (HD), which is structurally weaker than desmosome and is thus vulnerable to microbial infiltration. In the GS, microbial biofilms can build up for life, unlike the biofilms on the skin and intestinal mucosa that fall off by natural process. Thus, we emphasize that the GS and the JE are the weakest leaky point for microbes to invade human body, making the leaky gum just as important as, or even more important than, the leaky gut.

Knowledge regarding the influence of the microbial community in cancer promotion or protection has expanded even more through the study of bacterial metabolic products and how they can modulate cancer risk, which represents an extremely challenging approach for the relationship between intestinal microbiota and colorectal cancer (CRC). This review discusses research pro-gresses in the effect of bacterial dysbiosis from a metabolic point of view, particularly on the bio-chemical mechanisms of butyrate, one of the main short chain fatty acids (SCFAs) with an-ti-inflammatory and anti-tumor properties in CRC. Increased daily intake of omega-3 polyun-saturated fatty acids (PUFAs) significantly increases the density of bacteria that are known to produce butyrate. Omega-3 PUFAs have been proposed as a treatment to prevent gut microbiota dysregulation and lower the risk or progression of CRC.

Diet plays a pivotal role in the overall health of an individual. Not only does it help carry out and regulate certain physiological functions, but it also can determine the composition of the gut microbiome. While the relative number of microorganisms that make up the gut microbiome vary between individuals and can be dependent on different environmental factors, there is evidence to suggest that composition of the microbiome can correlate with overall health or disease. When the GI microbiome is disturbed or suddenly changes it results in microbiome dysbiosis, a condition that correlates with the presence of certain diseases. Diseases linked to microbiome dysbiosis range from metabolic disorders, inflammatory bowel diseases to disorders of the brain. Many of these diseases are linked to the connection between the brain and the gut, known as the brain-gut axis. This bidirectional communication is important to maintain normal intestinal function, but is also responsible for the GI response to emotions as well as the emotional response to GI disturbances. By exploiting the interaction between microbiome health and nutrition, diet can be used to alleviate disease symptoms, protect against the development of certain conditions, and better maintain overall health. This review will examine the effects of nutrition on the microbiome, diseases linked to disruption of the normal microbiome, and the way that altering the diet can mitigate symptoms or prevent disease.

Prevention of obstetric trauma from damage to the pelvic floor is not always possible and sacral nerve stimulation (SNS) may be necessary later in life. Sacral nerve stimulation has been a promising innovation in the management of moderate to severe faecal incontinence and following sphincter repair failure. Although the indication spectrum for SNS is expanding, the success of neuromodulation for constipation is limited. Adverse events of SNS requiring re-intervention are not common but a long-term successful outcome may depend on interventions for maintenance of the device.

Background and objectives: Alzheimer's disease (AD) is a progressive neurodegenerative illness, responsible for 60-70% of all dementias, affecting over 50 million people worldwide, and nearly 11 million in European countries. Several putative factors are identified in the literature as causative agents or risk factors for the development of AD. The amyloid cascade hypothesis has been the main hypothesis about the pathophysiology of AD for decades. Recent studies raised the possible role of dysbiosis in the development of AD which prevents memory loss. The amyloid-β (Aβ) deposition might be considered as an inflammatory reaction to certain molecular products arising from the altered microbiome. Based on the above observations, it has been suspected, that antibiotic consumption patterns of different antibiotic classes might be associated with the prevalence of AD in European countries. Methods: Antibiotic consumption (ECDC) for 1997-2007, 2008-2018, and as the whole 1997-2018 period, have been compared to the AD prevalence for 2018 expressed in percentage of the population and statistically analyzed by Pearson calculation. Results: A significant positive correlation has been found between the AD prevalence (2018) and the average quinolone consumption for the year 1997-2007 (p: 0.044). A similar association was not observed for the entire 22 years (1997-2018) of the average quinolone consumption, and the years 2008-18, indicating 10-20 years of time-lapse between the antibiotic exposure and the development of AD. The ratio of broad-spectrum and narrow-spectrum antibiotics (B/N) estimated in the ECDC database for the years of 2008-2018 showed a strong positive association with AD prevalence (2018) (p: 0.026) and a positive correlation tendency for the entire 22 years 1997-2018 (p: 0.063), but none for the years 1997-2007 (p: 0.241). Broad-spectrum, beta-lactamase sensitive penicillin (J01CA) consumption showed a positive (non-significant) correlation with the prevalence of AD for the years 2008-2018 (p:0.080).Discussion: Our study indicated the possible sequential role of certain classes of antibiotics in the development of dysbiosis leading to amyloid deposits of AD, which strengthen the possible role of different mediator molecules (short-chain fatty acids, lipopolysaccharides, etc.) produced by the altered microbiome in the development of AD.

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most of children diagnosed with isolated GHD presents with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature.

Hepatocellular carcinoma (HCC), one of the leading causes of death worldwide, has a causal nexus with liver injury, inflammation, and regeneration that accumulate over decades. Observations from recent studies have accounted for the involvement of the gut-liver axis in the pathophysiological mechanism responsible for HCC. The human intestine nurtures a diversified colony of microorganisms residing in the host ecosystem. The intestinal barrier is critical for conserving the normal physiology of the gut microbiome. Therefore, a rupture of this barrier or dysbiosis cause the intestinal microbiome to serve as the main source of portal-vein endotoxins such as lipopolysaccharide, in the progression of hepatic diseases. Indeed, increased bacterial translocation is a key sign of HCC. Considering the limited number of clinical studies on HCC with respect to the microbiome, we focus on the clinical as well as animal studies involving the gut microbiota with the current understandings of the mechanism by which the intestinal dysbiosis promotes hepatocarcinogenesis. Future research might offer mechanistic insights into the specific phyla targeting the leaky gut, as well as microbial dysbiosis, and their metabolites, as key pathways that drive HCC-promoting microbiome-mediated liver inflammation and fibrosis, thereby restoring the gut barrier function.

Type 2 Diabetes Mellitus is being increasingly associated with dysfunction of cognition. Dementia, including vascular dementia and Alzheimer’s disease, is being recognized as comorbidities of this metabolic disorder. The progressive hallmarks of this cognitive dysfunction include mild impairment of cognition and cognitive decline. Dementia and mild impairment of cognition appear in older patients primarily. Studies on risk factors, neuropathology, and brain imaging have provided important suggestions for mechanisms that lie behind the development of dementia. It is a significant challenge to understand the disease processes related to diabetes which affect the brain and lead to dementia development. The connection between Diabetes Mellitus and dysfunction of cognition has been observed in many human and animal studies that have noted mechanisms related to Diabetes Mellitus are possibly responsible for aggravating cognitive dysfunction. This article attempts to narrate the possible association between type 2 diabetes and Dementia, reviewing studies that have noted this association in vascular dementia and Alzheimer’s disease and helping to explain the potential mechanisms behind the disease process. The Google search for ‘Diabetes Mellitus and Dementia’ was carried out. Also, the search was done using ‘Diabetes Mellitus,’ ‘Vascular Dementia,’ ‘Alzheimer’s Disease.’ The literature search was done from Google Scholar, Pubmed, Embase, ScienceDirect, and MEDLINE. Keeping in mind the increasing rate of Diabetes Mellitus, it is important to establish the type 2 diabetes effect on the brain and diseases of neurodegeneration. This narrative review aims to build awareness regarding different types of dementia and their relationship with diabetes.

The main neurovascular unit of the Blood Brain Barrier (BBB) consists of a cellular component, which includes endothelial cells, astrocytes, pericytes, microglia, neurons and oligodendrocytes, as well as a non-cellular component resulting from the extracellular matrix. The endothelial cells are the major vital component of the BBB able to preserve the brain homeostasis; these cells are situated along the demarcation line between the bloodstream and the brain. Therefore, an alteration or the progressive disruption of the endothelial layer may clearly impair the brain homeostasis. The proper functioning of the brain endothelial cells is generally ensured by two elements: 1) the presence of junction proteins; 2) the preservation of a specific polarity involving an apical-luminal and a basolateral-abluminal membrane. In view of the above, this review intends to identify the molecular mechanisms underlying BBB function and their changes occurring in early stages of neurodegenerative processes in order to develop novel therapeutic strategies aimed to counteract neurodegenerative disorders.

We demonstrated the role of natural probiotics 3L, 3 Lactobacilli, in the establishment of a strong and sustainable beneficial healthy gut flora, after chemotherapy through experimental results through in vivo model. Using rat CTX model (immunosuppression induced by cyclophosphamide), we suggested some new adjuvant to chemotherapy as drugs + lactobacillus treament. Further, we proposed a new probiotic formulation (L. acidophilus + L. casei + L. plantarum) to be explored in the prevention of health condition loss by alteration of the general immune system, in numerous studies that reported the use of probiotics involving Lactobacillus in the post-chemo or post-surgical procedures. Here, in our study, Illumina MiSeq sequencing was used to generate sequencing data from microbial genomic DNA libraries, which is appreciable to check for the effects of 3L on bacteria. Microbiome analysis, phylogenetic and classification reports, community data have supported the experiments and the results where 3L had strong beneficial effects on the microbiome. Further, the influence on specific metabolic pathways are assisted in deriving the conclusion of the study (use of 3L for cancer therapy) to the mode of action, mechanistically by correcting microbiota composition and enhancing specific gut metabolic functions.

Background: We aimed to assess the risk of chemotherapy- and radiotherapy-related cognitive impairment in colorectal cancer patients. Methods: We randomly selected 40% of colorectal cancer patients from Korean National Health Insurance Database (NHID), 2004-2018 (N=148,848). Patients with one or more ICD-10 diagnostic codes for dementia or mild cognitive impairment was defined as cognitive impairment cases. Patients who were aged 18 or younger, diagnosed with cognitive impairment before colorectal cancer (N=8,225) and did not receive primary resection (N=45,320) were excluded. The effects of each chemotherapy agent on cognitive impairment were estimated. We additionally estimated the effect of radiotherapy in rectal cancer patients. Time-dependent competing risk Cox regression was conducted to estimate overall and age-specific hazard ratios (HR) separately for colon and rectal cancer. Results: In colon cancer, capecitabine and irinotecan was associated with higher cognitive im-pairment, while 5-fluorouracil was not. In rectal cancer, no chemotherapy agents increased the risk of cognitive impairment, nor did radiotherapy. Hazardous association of irinotecan was estimated larger in elderly patients compared with younger counterparts. Conclusion: Heterogeneous associations between various chemotherapy agents and cognitive impairment were observed. Elderly patients were more vulnerable to possible adverse cognitive effects. Radiotherapy did not increase the risk of cognitive impairment.

We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms behind these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12-weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.

Introduction: Despite the introduction of increasingly multifaceted diagnostic techniques and the general progress of emergency abdominal and vascular surgery, the outcome of treatment of patients with acute impaired intestinal circulation remains unsatisfactory. The non-invasive and high-resolution technique of optical coherence tomography (OCT) can be used intraoperatively to assess intestine viability and associated conditions that frequently emerge under conditions of impaired blood circulation. This study aims to demonstrate the effectiveness of multimodal (MM) OCT for intraoperative diagnostics of both the microstructure (cross-polarization OCT mode) and microcirculation (OCT angiography mode) of the small intestine wall in patients with acute mesenteric ischemia (AMI). Methods and Participants: A total of 18 patients were enrolled in the study. Nine of them suffered from AMI in segments II-III of the superior mesenteric artery (AMI group), where the ischemic segments of the intestine were examined. Nine others were operated for adenocarcinoma of the colon (control group), thus allowing areas of their normal small intestine to be examined for comparison. Data on the microstructure and microcirculation in the walls of the small intestine were obtained intraoperatively from the side of the serous membrane using the MM OCT system (IAP RAS, Russia) before bowel resection. The MM OCT data were compared with the results of histological examination. Results: The study finds that MM OCT visualized the damage to serosa, muscularis externa, and blood vessels localized in these layers in 100% of AMI cases. It also visualized the submucosa in 33.3% of AMI cases. The MM OCT image of non-ischemic (control group), viable ischemic and necrotic small intestines (AMI group) differed significantly across stratification of the distinguishable layers, the severity of intermuscular fluid accumulations and the type and density of the vasculature. Conclusion: The MM OCT diagnostic procedure optimally meets the requirements of emergency surgery. Data on the microstructure and microcirculation of the intestinal wall can be obtained simultaneously in real time without requiring contrast agent injections. The depth of visualization of the intestinal wall from the side of the serous membrane is sufficient to assess the volume of the affected tissues. However, the methodology for obtaining MM OCT data needs to be improved to minimize the motion artefacts generated in actual clinical conditions.