Novel Indazole Propionic Acid Derivatives as AMPK Activators.

Research progress of Adenosine 5'-monophosphate-activated protein kinase in the regulation of glycolipid metabolism

Normal intestinal microflora (gut flora) resides in the gastrointestinal tract, demonstrating mutual symbiotic relationship with host. Intestinal flora contains pathogenic microorganisms, primarily in the large bowel; but most are benign, and some have advantageous effects. Dysbiosis, i.e., the alteration of diversity and composition of the microbiota, contributes to many autoimmune and inflammatory disorders. Studies have demonstrated the great potential of modulating them to treat and prevent diseases. In this chapter the reader will understand the benefits of probiotics in autoimmune, inflammatory, and gastrointestinal disorders like multiple sclerosis, rheumatoid arthritis, type-1 diabetes, ulcerative colitis, gastrointestinal discomfort, improving immune health, relieving constipation, or avoiding the common cold, asthma, alcohol-induced liver injury, etc. Probiotics have provided attractive niche of being administered by different formulations, which may ultimately lead to the widespread use of probiotics in autoimmune and inflammatory disorders, which shall be highlighted here in this chapter with its future prospects.

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Guilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune Disorders

Low IgG trough and lymphocyte subset counts are associated with hospitalization for COVID-19 in patients with primary antibody deficiency

The aim of this study was to explore the shared genetic architecture between inflammatory bowel disease and depression and other upper gastrointestinal dysfunctions and inflammatory diseases, and to identify shared risk loci, potential key tissues, and associated genetic mechanisms to study. Based on pooled data from a large-scale genome-wide association study (GWAS), we observed a genetic correlation between inflammatory bowel disease and depression and other upper gastrointestinal tract dysfunctions and inflammatory disorders and performed cross-trait pleiotropy analyses to detect shared pleiotropic loci and genes. In addition, we performed a series of functional annotation and tissue-specific analyses to determine the impact of pleiotropic genes. Genetic power enrichment analysis was used to detect key immune cells and tissues. Finally, immunological associations between these diseases were explored using an immunolocalization approach. Our study highlights the existence of shared genetic mechanisms between depression, IBS, GORD, chronic gastritis, and IBD. A total of 160 promising pleiotropic loci were identified at the genome-wide significance level (P: 5 × 10-8) and annotation identified 54 dominant risk SNP loci, 30 of which passed causal co-localization tests. Further gene level analyses identified 2 unique pleiotropic genes such as rs142762983 and rs7865719. Pathway analyses identified nikolsky breast cancer 17q11 q21 amplicon, kegg type idiabetes mellitus, and gg intestinal immune network for iga production. The key role of these signaling pathways in these disorders was demonstrated by SNP level and gene level tissue enrichment analyses, which showed that pleiotropic mechanisms were significantly enriched in WholB blood, Spleen, Colon Transverse, and Small Intestine Terminal Ileum. Final analysis of immune cells byphenotypic levelimmunolocalization results showed 49 pleiotropic loci that support an important role for five unique immune cells in IBD and depression and three other gastrointestinal disorders through shared causal variants. Our study demonstrates the existence of a genetic association between symptomatic bowel disease and depression and other upper gastrointestinal tract dysfunctions and inflammatory disorders and reveals underlying immunomodulatory mechanisms.

Alcoholic steatosis is the earliest and common response to heavy alcohol intake, and may precede severe forms of liver injury. As an effort to develop an efficacious pharmaceutical composition, this study evaluated the effects of metadoxine, garlic oil or their combination on alcoholic steatosis. Feeding rats an alcohol‐containing diet for 4 weeks increased hepatic triglyceride content with CYP2E1 induction. Concurrent administration of metadoxine and garlic oil (MG, 1:1 w/w ratio) to rats synergistically abrogated both fat accumulation and CYP2E1 induction compared to the individual treatment. Histopathology confirmed the ability of MG combination to inhibit lipid accumulation. Blood biochemistry verified improvement of liver function in MG‐treated rats. Alcohol administration resulted in decreases in the AMPKα and ΑCC phosphorylations, which was restored by MG treatments. Hepatic fatty acid synthase (FAS) expression was decreased after alcohol consumption, which correlated with a decrease in AMPK activity and a commensurate increase in lipid content. Combined MG treatments allowed FAS expression restored. These results demonstrate that a pharmaceutical composition comprising MG effectively treats alcoholic steatosis, which may be associated with CYP2E1 repression and recovery of AMPK activity, promising pharmaceutical therapy for alcoholic steatosis.Supported by a contract fund from the Seoul R&BD Program (2005–2010).

Provided herein are novel imidazotriazine derivatives used as IL-17 modulators, their pharmaceutical compositions, the use of such compounds in treating inflammatory and autoimmune disorders, and processes for preparing such compounds.

Provided herein are novel imidazotriazine derivatives as IL-17 modulators, pharmaceutical compositions, use of such compounds in treating inflammatory and autoimmune disorders, and processes for preparing such compounds.

The research was aimed at understanding the perception and raising awareness on colorectal cancer among the public and in particular among individuals with anorectal and gastrointestinal disorders, usually traditionally designated as “pile” in northern Nigeria. The fact that some gastrointestinal abnormalities with symptoms of inflammation and hemorrhages in individuals could be signs of early-stage polyposis justifies the need to raise awareness on colorectal cancers among this particular risk group and the general populace. Survey information like background knowledge on colorectal cancer, familial cancer history, usage of herbal remedies, and incidence of anal inflammation, bleeding, and hemorrhages was collected using a self-administered questionnaire. Criteria used for inclusion were that the respondents have symptoms of anorectal or gastrointestinal disorders or were asymptomatic but believed they are at risk and hence were taking herbal remedies for preventive purposes against such disorders. A total of 142 men patronizing herbalists selling pile remedies in rural Zaria were sampled for the study. All were adults, 25% were above fifty years, 31% were in their forties, and 26% were in their thirties while 18% were less than thirty years. From the survey, 82% of respondents believed they have symptoms of gastrointestinal or anorectal disorders (out of whom 77% are using herbal remedies) while 18% consume this herbal preparations because they believe they have preventive effects against gastrointestinal diseases. From the results, 95% are aware of the term “cancer,” but only 44% have an idea of what colorectal cancers are while only 12% have knowledge of the signs and symptoms of colorectal cancers. Majority of the respondents (79%) believed that cancers generally are better managed using traditional alternative medicine. The study further reveals that majority (86%) of the respondents do not know or believe that inflammatory bowel diseases and anal bleeding are potential risk factors in colorectal cancer; however, 47% of the respondents know or believe that early detection of cancers in general is important for treatment. In addition, only 17% of these respondents have attended clinics in respect to their gastrointestinal or anorectal disorders while none of these have undergone any clinical screening for colorectal cancer. The results from the study summarily indicate that there is generally poor knowledge of colorectal cancer and a general perception among the respondents that gastrointestinal disorders and cancers are better cured using alternative traditional medicines. The study recommends, among others, increased cancer education with particular attention to enlightenment on benefits of clinical treatments and importance of screening for early detection and possible intervention. Citation Format: Mubarak Labaran Liman, Mubarak L. Liman, Sunday E. Atawodi, Iliemene E. Dorathy, Iliemene E. Dorathy, Nafisat Aliyu. Knowledge and perceptions on colorectal cancer among male adults taking herbal remedies against anorectal or gastrointestinal disorders in rural Zaria, Nigeria [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C13.

Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms. In a population-based case-control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes. Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype. Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.

Recently, the increased prevalence of chronic civilization diseases triggered by environmental pollution has been observed. In this context, the role of air pollution in the pathogenesis of autoimmune and/or inflammatory disorders is poorly elucidated. Here, we asked whether seasonal changes in the air quality of the city of Cracow affect the polarization of T cell subsets in healthy donors (HD) and patients with rheumatoid arthritis (RA), multiple sclerosis (MS), and atherosclerosis (AS). Peripheral blood mononuclear cells (PBMCs) from HD and patients were exposed in vitro to particulate matter isolated from the air of Cracow (PM CRC). Blood samples were collected in two seasons (winter and summer), with differences in air concentration of particulate matter of 10 μm (PM10) (below or above a daily limit of 50 µg/m3). The obtained data showed a significantly elevated frequency of CD4+ lymphocytes specific for IFN-γ and IL-17A after the exposure of PBMCs to PM CRC. This was observed for all patients’ groups and HD. In the case of patients, this effect was dependent on the seasonal concentration of PM in the air, paradoxically being less pronounced in the season with a higher concentration of air pollution. These observations may suggest the role of air pollution on the course of inflammatory and autoimmune disorders.

In recent years, the exploration of regulatory T cell (Treg)-based cellular therapy has become an attractive strategy to ameliorate inflammation and autoimmunity in various clinical settings. The main obstacle to the clinical application of Treg in human is their low number circulating in peripheral blood. Therefore, ex vivo expansion is inevitable. Moreover, isolation of Treg bears the risk of concurrent isolation of unwanted effector cells, which may trigger or deteriorate inflammation upon adoptive Treg transfer. Here, we present a protocol for the GMP-compliant production, lot-release and validation of ex vivo expanded Tregs for treatment of patients with autoimmune and inflammatory disorders. In the presented production protocol, large numbers of Treg, previously enriched from a leukapheresis product by using the CliniMACS® system, are ex vivo expanded in the presence of anti-CD3/anti-CD28 expander beads, exogenous IL-2 and rapamycin during 21 days. The expanded Treg drug product passed predefined lot-release criteria. These criteria include (i) sterility testing, (ii) assessment of Treg phenotype, (iii) assessment of non-Treg cellular impurities, (iv) confirmation of successful anti-CD3/anti-CD28 expander bead removal after expansion, and (v) confirmation of the biological function of the Treg product. Furthermore, the Treg drug product was shown to retain its stability and suppressive function for at least 1 year after freezing and thawing. Also, dilution of the Treg drug product in 0.9% physiological saline did not affect Treg phenotype and Treg function for up to 90 min. These data indicate that these cells are ready to use in a clinical setting in which a cell infusion time of up to 90 min can be expected. The presented production process has recently undergone on site GMP-conform evaluation and received GMP certification from the Bavarian authorities in Germany. This protocol can now be used for Treg-based therapy of various inflammatory and autoimmune disorders.

New Role of Antiphospholipid Antibodies (APLA)? Correlations with Disease Activity in Non-Thrombotic and Thrombotic Autoimmune and Hematologic Disorders.

The activation of AMPK has emerged as a promising therapeutic approach for the treatment of metabolic diseases. AdipoRon, an agonist of the adiponectin receptor, has been identified as a compound capable of activating AMPK via the adiponectin receptor. To identify novel AdipoRon analogues with AMPK activation potential, a total of 17 analogues were designed, synthesized, and subjected to biological evaluation. Among these analogues, X-12 was discovered to exhibit potent activation of AMPK. In experimental studies, X-12 demonstrated dose-dependent improvements in glucose tolerance in normal mice. Furthermore, it significantly reduced fasting blood glucose levels and ameliorated insulin resistance in db/db diabetic mice. These findings highlight the therapeutic potential of X-12 as a novel class of AMPK activators for the treatment of metabolic diseases.