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

Down Regulated in Adenoma (DRA), the major chloride transporter in the mammalian intestine has recently emerged as a critical gene contributing to the pathogenesis of Ulcerative Colitis (UC). We have previously shown that DRA knockout (KO) mice display several features of UC including compromised barrier function and dysbiosis. Further, DRA KO mice show increased susceptibility to intestinal inflammation. To elucidate the mechanisms by which loss of DRA could impact gut inflammation, gene expression between DRA KO and wild type littermate controls (WT) by RNAseq was compared. The data showed that out of 1100 genes differentially expressed in DRA KO colon, majority were related to immune responses. Upon conducting more specific immune based analysis using nanoString nCounter® Immunology Panel, we observed a significant upregulation of genes promoting effector T cell expansion, specifically Th2. Interleukin‐33 (IL‐33), an alarmin cytokine is known to be significantly upregulated in colons of UC patients and is a key driver of type 2 immune cell expansion. Since alterations in epithelial‐immune cell crosstalk can trigger inflammatory responses, we hypothesized that DRA KO mice may have aberrant epithelial‐immune cell crosstalk which could trigger changes in Lamina Propria Lymphocytes (LPLs). Following isolation of colonic LPLs and staining for various innate and adaptive immune cells, we detected a significant increase (> 2‐fold) in type 2 innate lymphoid cells (ILC2) and in Th2 cells(~8‐fold) in DRA KO mice which were both GATA3+. These observations were specific to the colon and not seen in the ileal LP or mesenteric lymph nodes. We also observed a significant induction of type 2 effector protein amphiregulin, demonstrating an increased type‐2 immune tone in DRA KO colons. Since IL‐33 is important for immune cell activation following tissue injury at mucosal surfaces we analyzed IL‐33 protein levels in the colon. IL‐33 was markedly elevated in DRA KO colons and appeared to be independent of microbiome changes as this increase in IL‐33 still persisted even after cohousing with WT mice for over 4 weeks (allowing exchange of the microbiome). Confocal imaging of colonic tissues and colonoids further confirmed the increase in epithelial IL‐33 and its dissemination from the nucleus to the cytoplasm in DRA KO colonocytes. Since IL‐33 is known to specifically expand a subset of T regs which are also GATA3+; we gated LPLs double positive for FOXP3 and GATA3 using FACS. Interestingly, total T regs and GATA3+ T regs were both markedly elevated in DRA KO colonic LP compared to WT, confirming the functional relevance of increased IL‐33. These results were further validated in human colonoid derived monolayers where DRA was significantly reduced parallel to upregulation of IL‐33 protein in UC, mirroring the results from DRA KO mice. In conclusion, loss of DRA from colonocytes triggers the release of the IL‐33 to drive a type 2 immune response. These observations emphasize the critical importance of loss of DRA and its implications in the pathogenesis of UC.

Loss of Chloride Transporter DRA Triggers Interleukin‐33 Secretion from Colonocytes to drive Type 2 Lamina Propria Lymphocyte Expansion

Several adverse effects are related to medications that treat moderate to severe inflammatory bowel diseases (IBDs). Targeted drug administration is necessary to treat inflammatory bowel disease to maximize efficacy and minimize toxicity. This study investigated the prodrug approach for antibacterials that target the colon. We chose sulfonamide (Sulfamethoxazole) as an antibiotic to target the colon. The prodrug approach is one of the most effective treatments for inflammatory bowel disease (IBD), and this mutual azo prodrug might serve the same function. This investigation aims to synthesize mutual azo prodrugs (S1-S5) and evaluate the colon-targeted release (in-vitro and in-vivo release studies). The objective of synthesizing mutual azo prodrugs (S1- S5) is that due to the high molecular weight of synthesized prodrugs (>500), they will enter the colon intact and not be absorbed in the upper GIT (Lipinski rule of 5). A coupling reaction between the sulfamethoxazole diazonium salt and salicylic acid derivatives allowed for synthesizing of mutual azo prodrugs (S1-S5). By monitoring the chemical reactions, the purity of the synthesized prodrugs was assessed, and by using FTIR, NMR (1H and 13C), Mass Spectrometry (MS), and Elemental Analysis, the structures of newly synthesized mutual azo prodrugs (S1-S5) were analyzed. Studies on the in-vitro stability of synthesized prodrugs showed less release after 6 hours in HCl buffer (pH 1.2), and only 10% release after 6 hours in phosphate buffer (pH 7.4) was observed. The sensitivity of the synthesized azo prodrug to the bacterial enzyme azoreductase was shown by incubating the azo prodrugs with the cecal contents of a rat; the release results showed that the release of free drugs from the azo prodrugs was more than 80%. Using trinitrobenzene sulfonic acid (TNBS)-induced colitis rats model, the in-vivo study was evaluated, and results revealed that mutually synthesized azo prodrugs are effective as 5-aminosalicylic acid in ulcerative colitis. Based on the release studies results, it is concluded that the azo prodrugs are a potential therapeutic target for ulcerative colitis. 

Synthesis and Evaluation of Mutual Azo Prodrugs of Sulfamethoxazole and Salicylic Acid Derivatives for Colon Targeted Release

1004: safety of bedside percutaneous tracheostomy: comparing medical intensivists to surgeons

1 Division of Molecular Genetics & Biochemistry; Institute of Cytology & Preventive Oncology (ICMR), I-7, Sector-39, Noida, India 2 Utter Pradesh Technical University, Lucknow, U.P. India 3 Research Department , 4 Surgical Gynae Uro-Oncology, 5 Medical Oncology, Rajiv Gandhi Cancer Institute & Research Centre, Rohini, New Delhi, India 6 R.G. Stone Urology & Laparoscopy Hospital, New Delhi, India *Corresponding author

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Is a Retrovirus (XMRV) Risk Factor for Prostate Cancer in Indian Population

We test the hedge property of non-fungible token (NFT) coins against equity market fluctuations and compare it with the hedge property of Bitcoin. We employ daily the returns of Bitcoin;three NFT coins, namely Theta, Enjin Coin and Decentraland, and three equity market indices: S&P 500, NASDAQ and CAC 40, ranging from 18 January 2018 to 12 January 2021. We estimate the hedge effectiveness of the three NFT coins and Bitcoin against stock market fluctuations. Our results suggest that NFT coins are a better hedge against equity market fluctuations than Bitcoin.

Anoop Kumar

Papers

Loss of Chloride Transporter DRA Triggers Interleukin‐33 Secretion from Colonocytes to drive Type 2 Lamina Propria Lymphocyte Expansion

Synthesis and Evaluation of Mutual Azo Prodrugs of Sulfamethoxazole and Salicylic Acid Derivatives for Colon Targeted Release

1004: safety of bedside percutaneous tracheostomy: comparing medical intensivists to surgeons

Is a Retrovirus (XMRV) Risk Factor for Prostate Cancer in Indian Population

Are non‐fungible token coins a good hedge against the stock market volatility?