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Dietary Green Tea Extract and Antioxidants Improve Insulin secretory Functions of Pancreatic β-Cells in Mild and severe Experimental Rodent Model of Chronic Pancreatitis

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Open Journal of Endocrine and Metabolic Diseases 2024年第2期14卷 53-72页

作者： Galande sheethal Ranjeet K. Tokala Pavan Pondugala Krishna Vemula Vijayalakshmi Venkatesan Pothani suresh surya satyanarayana singh Guduru Venkat Rao Duvvur Nageshwar Reddy mitnala s.s.kala Basic science and Translational Research Division Asian Healthcare Foundation AIG Hospitals Hyderabad India Division of Cell and Molecular Biology National institute of Nutrition Hyderabad India National Animal Resource Facility for Biomedical Research Hyderabad India Department of Biochemistry Osmania University Hyderabad India Department of surgical Gastroenterology Asian Institute of Gastroenterology Hyderabad India Department of Gastroenterology Asian Institute of Gastroenterology Hyderabad India

Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. It is predominantly idiopathic (with an unknown cause) in India and mostly due to alcohol in the West. Diabetes that occur secondary to chronic pancreatitis (T3c Diabetes) is often brittle, and is difficult to attain normoglycemia with conventional treatment requiring multiple doses of insulin. Mild and severe model of CP was induced in mice by repeated intraperitoneal injections of cerulein and L-arginine respectively with an intent to study islet dysfunction and develop therapeutic strategy in animal models of CP. Dietary intervention of epigallocatechin-3-gallate (EGCG) was tested in both the models of CP for its beneficial effects on insulin secretory functions. Pancreata collected upon euthanasia were used to study alterations in the morphology of pancreatic parenchyma and inflammation by staining with H&E and fibrotic changes by Masson’s trichrome and picrosirius staining. Insulin secretory functions of islets were evaluated to test the efficacy of the dietary intervention on β-cell functions. Intraperitoneal glucose tolerance test was performed to monitor the glucose homeostasis before and after the dietary intervention. Both the models resulted in CP with dispersed acini, inflammation and fibrosis. The loss of acini and extent of fibrosis was more in L-arginine model. 2-fold improvement in glucose-stimulated insulin secretory functions of islets was observed with 0.5% EGCG dietary intervention in cerulein model of CP and 1.6-fold in L-arginine model of CP. A further improvement in insulin secretion by 3.2-fold was observed with additional dietary supplements like N-acetyl cysteine, curcumin in combination with EGCG. Our results thus demonstrate and highlight the therapeutic potential of dietary green tea (EGCG) supplementation in reversing islet dysfunction and improving glucose homeostasis in experimental chronic pancreatitis in mice.

关键词： Dietary Intervention C57BL6/J Mice Epigallocatechin-3-Gallate N-Acetyl Cysteine Curcumin Chronic Pancreatitis Islets Glucose stimulated Insulin secretion

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Pancreatic stellate cell: Pandora's box for pancreatic disease biology

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World Journal of Gastroenterology 2017年第3期23卷 382-405页

作者： Ratnakar R Bynigeri Aparna Jakkampudi Ramaiah Jangala Chivukula subramanyam mitnala s.s.kala G Venkat Rao D Nageshwar Reddy Rupjyoti Talukdar Institute of Basic sciences Asian Healthcare FoundationHyderabad 500082India Department of Medical Gastroenterology Asian Institute of GastroenterologyHyderabad 500082India Department of surgical Gastroenterology Asian Institute of GastroenterologyHyderabad 500082India

Pancreatic stellate cells(PsCs) were identified in the early 1980 s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PsCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PsCs are characterized by the presence of vitamin A laden lipid droplets. Upon PsC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PsCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis(CP) and pancreatic ductal adenocarcinoma(PDAC). several pathways(e.g., JAK-sTAT, smad, Wnt signaling, Hedgehog etc.), transcription factors and mi RNAs have been implicated in the inflammatory and profibrogenic function of PsCs. The role of PsCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PsCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PsCs and the cancer stroma.

关键词： Pancreatic stellate cells Pancreatic fibrosis Pancreatic cancer stroma Physiological functions Pancreatic stellate cells-cancer-stromal interactions Therapeutic targets

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Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

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World Journal of Hepatology 2016年第20期8卷 827-837页

作者： Vishnubhotla Venkata Ravi Kanth mitnala s.s.kala Mithun sharma Padaki Nagaraja Rao Duvvuru Nageshwar Reddy Asian Healthcare Foundation a Research Wing of Asian Institute of Gastroenterology Asian Institute of Gastroenterology

Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day(diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease(NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.

关键词： Transmembrane 6 superfamily member 2 gene Patatin-like phospholipase domain containing 3 gene Genotyping Nutrient interactions Non-alcoholic fatty liver disease Genetic susceptibility

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Pooled genetic analysis in ultrasound measured non-alcoholic fatty liver disease in Indian subjects:A pilot study

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World Journal of Hepatology 2014年第6期6卷 435-442页

作者： Vishnubhotla Venkata Ravi Kanth mitnala s.s.kala Padaki Nagaraja Rao Urmila steffie Avanthi kalashikam Rajender Rao Duvvuru Nageshwar Reddy Asian Healthcare Foundation Hyderabad 500082India Asian Institute of Gastroenterology Hyderabad 500082India Division of Endocrinology and Metabolism National Institute of NutritionTarnakaHyderabad 500082India

AIM: To investigate genetic susceptibility in Indian subjects with non-alcoholic fatty liver disease(NAFLD) by performing a pooled genetic ***: study subjects(n = 306) were recruited and categorized into NAFLD and control groups based on ultrasound findings of fatty infiltration. Of the 306 individuals, 156 individuals had fatty infiltration and thus comprised the NAFLD group. One hundred and fifty(n = 150) individuals were normal, without fatty infiltration of the liver, comprising the control group. Blood samples, demographic and anthropometric data from the individuals were collected after obtaining informed consent. Anthropometric data, blood glucose, lipids and liver function tests were estimated using standard methods. Genome wide association stud-ies done to date on NAFLD were identified, 19 single nucleotide polymorphisms(sNPs) were selected from these studies that were reported to be significantly associated with NAFLD and genotyping was performed on the sequenom platform. student's t test for continuous variables and χ2 test was applied to variant carriers from both groups. Required corrections were applied as multiple testing was *** The mean age of the control group was 39.78 ± 10.83 and the NAFLD group was 36.63 ± 8.20 years. The waist circumference of males and females in the control and NAFLD groups were 80.13 ± 10.35; 81.77 ± 13.65 and 94.09 ± 10.53; 92.53 ± 8.27 respectively. The mean triglyceride and alanine transaminase(ALT) levels in the control and NAFLD groups were 135.18 ± 7.77; 25.39 ± 14.73 and 184.40 ± 84.31; 110.20 ± 67.05 respectively. When χ2 test was applied to the number of individuals carrying the variant risk alleles between the control and NAFLD group, a significant association was seen between rs738409 of the patatin-like phospholipase domain containing 3(PNPLA3) gene(P = 0.001), rs2073080 of the PARVB gene(P = 0.02), rs2143571 of sAMM50 gene(P = 0.05) and rs6487679 of the pregnancy zone protein(PZP) gene(P = 0.0

关键词： Non-alcoholic fatty liver disease Genome wide association studies Genetic association Hepatic steatosis Genotyping single nucleotide polymorphisms susceptibility

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role of the normal gut microbiota

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World Journal of Gastroenterology 2015年第29期21卷 8787-8803页

作者： sai Manasa Jandhyala Rupjyoti Talukdar Chivkula subramanyam Harish Vuyyuru mitnala s.s.kala D Nageshwar Reddy Department of Gastroenterology Asian Institute of Gastroenterology Asian Healthcare Foundation Asian Institute of Gastroenterology

Relation between the gut microbiota and human health is being increasingly recognised. It is now well established that a healthy gut flora is largely responsible for overall health of the host. The normal human gut microbiota comprises of two major phyla, namely Bacteroidetes and Firmicutes. Though the gut microbiota in an infant appears haphazard, it starts resembling the adult flora by the age of 3 years. Nevertheless, there exist temporal and spatial variations in the microbial distribution from esophagus to the rectum all along the individual's life span. Developments in genome sequencing technologies and bioinformatics have now enabled scientists to study these microorganisms and their function and microbehost interactions in an elaborate manner both in health and disease. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. several factors play a role in shaping the normal gut microbiota. They include(1) the mode of delivery(vaginal or caesarean);(2) diet during infancy(breast milk or formula feeds) and adulthood(vegan based or meat based); and(3) use of antibiotics or antibiotic like molecules that are derived from the environment or the gut commensal community. A major concern of antibiotic use is the long-term alteration of the normal healthy gut microbiota and horizontal transfer of resistance genes that could result in reservoir of organisms with a multidrug resistant gene pool.

关键词： Normal gut microbiota Bioinformatics Health Immunomodulation Metabolic function

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