Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as Inflammatory Bowel Diseases (IBD), are caused by a complex interplay between genetic, immunologic, microbial and environmental factors. Dysbiosis of the gut microbiome is increasingly considered to be causatively related to IBD and is strongly affected by components of a Western life style. Bacteria that ferment fibers and produce short chain fatty acids (SCFAs) are typically reduced in mucosa and feces of patients with IBD, as compared to healthy individuals. SCFAs, such as acetate, propionate and butyrate, are important metabolites in maintaining intestinal homeostasis. Several studies have indeed shown that fecal SCFAs levels are reduced in active IBD. SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function. Recent findings, however, show that SCFAs, and in particular butyrate, also have important immunomodulatory functions. Absorption of SCFAs is facilitated by substrate transporters like MCT1 and SMCT1 to promote cellular metabolism. Moreover, SCFAs may signal through cell surface G-protein coupled receptors (GPCRs), like GPR41, GPR43, and GPR109A, to activate signaling cascades that control immune functions. Transgenic mouse models support the key role of these GPCRs in controlling intestinal inflammation. Here, we present an overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for IBD. Moreover, we discuss the therapeutic potential of SCFAs for IBD, either applied directly or by stimulating SCFAs-producing bacteria through pre- or probiotic approaches.

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Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases.

There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.

The role of short-chain fatty acids in health and disease.

Structure–function relationships of immunostimulatory polysaccharides: A review

Butyrate: A Double-Edged Sword for Health?

Introduction Japanese encephalitis (JE) is among the most important viral encephalitides in Asia, especially in rural and suburban areas where rice culture and pig farming coexist. (1-3) It has also occurred rarely and sporadically in northern Australia and parts of the Western Pacific. (4-6) JE is due to infection with the JE virus (JEV), a mosquito-borne flavivirus. The main JEV transmission cycle involves Culex tritaeniorhynchus mosquitoes and similar species that lay eggs in rice paddies and other open water sources, with pigs and aquatic birds as principal vertebrate amplifying hosts. (1,2,7) Humans are generally thought to be dead-end JEV hosts, i.e. they seldom develop enough viremia to infect feeding mosquitoes. Fewer than 1% of human JEV infections result in JE. Approximately 20-30% of JE cases are fatal and 30-50% of survivors have significant neurologic sequelae. (8) JE is primarily a disease of children and most adults in endemic countries have natural immunity after childhood infection, but all age groups are affected. In most temperate areas of Asia, JEV is transmitted mainly during the warm season, when large epidemics can occur. In the tropics and subtropics, transmission can occur year-round but often intensifes during the rainy season. (1-3) The global incidence of JE is unknown because the intensity and quality of JE surveillance and the availability of diagnostic laboratory testing vary throughout the world. Countries that have implemented high-quality childhood JE vaccination programmes have seen a dramatic decline in JE incidence. Although JE is reportable to the World Health Organization (WHO) by its Member States, reporting is highly variable and incomplete. In the late 1980s, Burke and Leake estimated that 50 000 new cases of JE occurred annually among the 2.4 billion people living in the 16 Asian countries considered endemic at the time (approximate overall annual incidence: 2 per 100 000). (2) In the intervening two decades, despite major population growth, urbanization, changes in agricultural practices and increased use of the JE vaccine in many countries, this figure has been widely quoted, including very recently. (9-13) In 2000, assuming an annual, age-group-specific incidence of 25 cases per 100 000, Tsai estimated that in the absence of vaccination 175 000 cases of JE would occur annually among Asian children aged 0-14 years living in rural areas. (14) The current study used more recent, published, local or national incidence estimates and current population data to produce an updated estimate of the annual global incidence of JE. Methods We approximated the JE-affected territory of each of the 24 countries endemic for JE using a recent update (15) of an earlier approximation by Tsai (16) with some modifications (Table 1, available at: http://www.who.int/bulletin/ volumes/89/10/10-085233). Based on these same approximations, (15,16) we then stratified the JE-affected territory of some countries (e.g. China excluding Taiwan, India and Nepal) into two or more incidence strata. Because suitable studies of JE incidence were not available for every endemic country or incidence stratum, we sorted JE-endemic countries and incidence strata into 10 incidence groups (A, B, C1, C2 and D through I) based primarily on geographic proximity, ecologic similarity, vaccine programme similarity. Table 1 briefly describes the status of each endemic country's JE vaccination programme as of 2009, according to recent publications and unpublished sources. (8,17-20) Incidence data We identified studies that contained potentially useful data on the incidence of JE in Asia in a manner similar to the one used in a recent study of global typhoid fever incidence. (21) Whenever possible, this review followed the relevant guidelines for Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). (22) The review process is described as follows and no protocol is available. …

Estimated Global Incidence of Japanese Encephalitis: A Systematic review/Estimation De L'incidence Mondiale De L'encephalite Japonaise: Une Evaluation Systematique/ Incidencia Global Estimada De la Encefalitis Japonesa: Una Revision Sistematica

In the current investigation, we have compared the potential of statin drugs (Simvastatin, Rosuvastatin and Fluvastatin) as potential anti-bacterial agent by conducting in silico, in vitro and ex vivo studies. In silico study was conducted to check the interaction of statin drugs towards various targets of bacteria. The percentage growth retardation, bacterial growth kinetics, MIC determination, post antibiotic effect and biofilm formation assay were conducted to check the anti-bacterial effect of statin drugs under in vitro conditions. Finally, MTT assay was used to check the percentage of immune cell viability after Simvastatin treatment. Docking studies have revealed good interaction of Simvastatin, Rosuvastatin and Fluvastatin towards various targets of bacterial strains as that of the internal ligand. Simvastatin has shown good antibacterial activity against S. aureus, B. pumilus, P. aeruginosa and S. enterica as compared to Rosuvastatin and Fluvastatin. In vitro results have shown concentration and time dependent inhibition of bacterial growth by Simvastatin in concentration range of 64–256 μg/ml. Finally, MTT assay have shown non-cytotoxic effect of Simvastatin against adaptive immune system. In conclusion, Simvastatin could be a potential candidate as an anti-bacterial agent against a wide range of bacterial infections. However, further studies are required to check its complete role before starting phase I clinical trial.

Comparative potential of Simvastatin, Rosuvastatin and Fluvastatin against bacterial infection: an in silico and in vitro study

Background The incidence of fungal infections has increased significantly. Specifically the cases of candida albicans infection are increasing day by day and their resistance to clinically approved drugs is a major concern for humans. Various classes of antifungal drugs are available in the market for the treatment of these infections but unfortunately, none of them is able to treat the infection. Objectives Thus, in the present investigation, we have repurposed the well-known drug (Fluvastatin) in the treatment of Candida albicans infections by using in silico, in vitro and ex vivo techniques. Material and methods Computational and in vitro techniques. Results Firstly, we developed and validated a simple model of CYP45014α-lanosterol demethylase of Candida albicans by using crystal structure of Mycobacterium tuberculosis (1EA1). Further, fluvastatin was docked with a validated model of CYP45014α-lanosterol demethylase and revealed good binding affinity as that of fluconazole. In vitro results (Percentage growth retardation, Fungal growth kinetics, Biofilm test and Post antifungal test) have shown good antifungal activity of fluvastatin. Finally, the results of MTT assay have shown non-cytotoxic effect of fluvastatin in murine splenocytes and thymocytes. Conclusion However, further in vivo studies are required to confirm the complete role of fluvastatin as an antifungal agent.

Repurposing of Fluvastatin Against Candida albicans CYP450 Lanosterol 14 α-demethylase, a Target Enzyme for Antifungal Therapy: An In silico and In vitro Study.

Deltamethrin (DLM) is a well-known pyrethroid insecticide which is widely used in the agriculture and home pest control due to restriction on the sale of organophosphate. DLM induced apoptosis is well known but its mechanism is still unclear. This study has been designed to find out its mechanism of apoptosis with the help of computational methods along with in vivo methods. The QikProp and ProTox results have shown that DLM has good oral absorption. The docking results reveal that DLM has a strong binding affinity toward the CD4, CD8, CD28 and CD45 receptors. Further, to understand the toxicity of DLM on lymphoid cells, a single dose of DLM (5 mg/kg, oral for seven days) has been administered to male Balb/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (caspase-3 activity, DNA fragmentation) have been assessed in thymic and splenic single cell suspensions. Lowering of body weight, cellularity and loss in cell viability ...

Mechanism of deltamethrin induced thymic and splenic toxicity in mice and its protection by piperine and curcumin: in vivo study.

Background Recently, Food and Drug Administration (FDA) has approved sodium/ glucose co-transporter 2 (SGLT2) inhibitors for the treatment of diabetes mellitus. However, regarding adverse drug reactions (ADRs) of SGLT2 inhibitors in large group of population, very less information is available. Thus, we have tried to find out the risk profile of SGLT2 inhibitors. Materials and methods A total of 1,042 studies have been published from Nov. 2012-Nov. 2017 regarding SGLT2 inhibitors. After inclusion and exclusion criteria, 27 studies have been selected for the analysis of risk. Results and discussion The emerging evidence indicates various adverse drug reactions such as foot and toe amputation, cancer, diabetic ketoacidosis, bone fracture risk and urinary as well as mycotic genital infection. The causality assessment has shown a correlation between SGLT2 inhibitors and diabetic ketoacidosis and urinary tract infection. Conclusion In conclusion, Marketing Authorization Holder (MAH) and Regulatory Authorities (RA) should monitor various adverse drug reactions such as diabetic ketoacidosis and urinary tract infection with the use of SGLT2 inhibitor.

Safety of SGLT2 Inhibitors in Patients with Diabetes Mellitus.

Japanese encephalitis virus (JEV) infection affects millions of population worldwide whose incidence is increasing year by year and currently, no specific drugs are available for its treatment. How...

Natural chemical entities from Arisaema genus might be a promising break-through against Japanese encephalitis virus infection: a molecular docking and dynamics approach

Anoop Kumar

Papers

Comparative potential of Simvastatin, Rosuvastatin and Fluvastatin against bacterial infection: an in silico and in vitro study

Repurposing of Fluvastatin Against Candida albicans CYP450 Lanosterol 14 α-demethylase, a Target Enzyme for Antifungal Therapy: An In silico and In vitro Study.

Mechanism of deltamethrin induced thymic and splenic toxicity in mice and its protection by piperine and curcumin: in vivo study.

Safety of SGLT2 Inhibitors in Patients with Diabetes Mellitus.

Natural chemical entities from Arisaema genus might be a promising break-through against Japanese encephalitis virus infection: a molecular docking and dynamics approach