Research efforts at Asian Healthcare Foundation focus on the etiopathology as well as molecular and genetic basis of gastrointestinal diseases employing cutting edge technologies including studies involving cellular (histopathological, immunohistochemical studies and Fluorescent Activated Cell Sorting, use of stem cell biology) and molecular (cytokine profiling, next generation sequencing,  microarray, Crispr etc.,) approaches. All our studies are conducted either with experimental animals or samples obtained from humans. These are conducted strictly in accordance with permission obtained from regulatory bodies such as Institutional Ethics Committee and Institutional Committee for Stem Cell Research. The studies are periodically reviewed by Research Advisory Committee and Institutional Review Board.

Research Areas:

INTESTINAL DISEASES

Functional disorders of the GI tract are those in which the bowel looks normal but doesn't work properly. They are the most common problems affecting the colon and rectum, and include constipation, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), IBD (both ulcerative colitis (UC) and Crohn's disease (CD), were once thought to be uncommon, but are now widely prevalent in India. Research findings made in our labs has resulted in the following findings:

Rapid and ultra-rapid metabolizers with CYP2C19*17 polymorphism do not respond to standard therapy with proton pump inhibitors.(Meta Gene. 2016 Jun 18;9:159-64)

Beneficial influence of probiotic administration on the fecal microbiota in diarrhea-predominant irritable bowel syndrome was demonstrated (Ind.JGastroenterol. 2015 May;34(3):275-6)

Differential expression of CD73 cells around granulomas of Intestinal Tuberculosis is involved in the evasion of Mycobacterium tuberculosis to host immunity (Dig Dis Sci. 2013 Aug;58(8):2301-7).

Variants in the NOD2 gene and the protective variant R381Q in IL23R are not associated with IBD in Indians (J GastroenterolHepatol. 2011 Apr;26(4):694-9).

Even though IL23 R polymorphisms are reported to enhance patient susceptibility to CD, we did not find any correlations between them (Journal of Gastroenterology and Hepatology, 2010; 26:694-699).

DISEASES OF THE LIVER AND BILIARY SYSTEM

Several viral and non-viral tropical infections such as malaria, typhoid, dengue fever, and leptospirosis may affect the hepatobiliary system as a part of multi-organ involvement. Hepatobiliary infections prevalent in tropical countries have a special predilection and distinct pattern. In view of the increased prevalence of diseases affecting the liver and biliary system, our researchers have conducted focused studies that resulted in the following findings:

Upon examining the incidence and risk of Gallstone disease (GS) in patients with Gilbert’s Syndrome experiencing intermittent episodes of jaundice, it was concluded that early recognition of GS by genetic analysis is required before they run the risk of unnecessary operations on their bile ducts from the mistaken assumption of ascribing the jaundice to a stone which has been left behind.(J ClinExpHepatol. – In press 2018)

Hereditary persistence of alpha fetoprotein was noted to be associated with the -119G>A polymorphism in AFP gene. ACG Case Reports Journal. 4: e33.

Regional differences in genetic susceptibility to NAFLD in two distinct Indian ethnicities (ancestral South Indians and North-East Indians) was examined considering the association of variants in PNPLA3 (rs2281135) and TM6SF2 (rs58542926) genes with ultrasound detected non-alcoholic fatty liver disease (NAFLD).World J. Hepatol. 2017;9(26): 1101–1107

The genetics of non-alcoholic fatty liver disease: from susceptibility and nutrient interactions to management was considered in detail focusing on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.World J Hepatol 2016; 8(20): 827-837

Genetic studies revealed that polymorphisms in UGT1A1 gene predispose South Indians to pigmentous gallstones.J.Clin. ExptlHepatol, 2016;6;3:216–223

The Riddle of Non Alcoholic Fatty Liver Disease involving the progression from NAFLD to NASH was reviewed integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome (J. Clin. Exptl Hepatol.2015;33(5)452)

Circulating visfatin and proinflammatory cytokine levels in non alcoholic fatty liver disease were measured. It was noted that increased levels of proinflammatory cytokines TNF-α, IL-6, IL-8 and decreased levels of Visfatin are independently associated with NAFLD (Int. J.Curr. Res, 2014;.6 (8), 8159-8162.

The enhanced expression of autophagy related gene Atg5 in Hepatitis B Virus Infection was ascribed to HBV mediated modulation of host's autophagy machinery to establishchronic infection.  (J. Microbiol Res Rev. 2014:Vol 2 (2). 68-73.

The possible mode of viral persistence in inactive carriers of Hepatitis B virus Infection was traced to the down regulation of Human Toll-like Receptor 2 and 4 Genes (J GastroenterolHepatol Res. 2014;3(4):1030-1034.

PN Rao, P.Balkumar Reddy, RM Mukherjee, R.Gupta, D.N.Reddy. Demonstrated the Spectrum of Incidentally Detected Hepatitis C Virus Infection in Southern India, Global Journal of Gastroenterology & Hepatology, 2, 69-73, 2014.

Demonstrated the reduced Expression of DNA Damage Repair Genes (High Mobility Group Box1 and Poly (ADP-ribose) Polymerase1) in Inactive Carriers of Hepatitis B Virus Infection underlying the Possible Stage of Viral Integration. (J. Clin Exptl Hepatol; 2013; 3:89-95).

HCV modulates host immunity by inducing IRF-2 gene (encoding oncogenic proteins) to counteract IRF-1-mediated IFN-α gene expression. (J. Clin. Exptl, Hepatol; 2012. 2:27–34).

Human RNA Methylating enzyme DNMT2 gene Expression is down regulated in Chronic Hepatitis B Virus infection. Considering DNMT2 as a major component of primitive antiviral defense mechanism, the influence of higher viral load in suppressing DNMT2 gene expression might contribute to persistence of HBV in chronic infection.(Exptl. Clin. Hepatol. 2012; 8 (1 – 2):53-59).

Characterized the reduced Expression of Human Chemokine Genes RANTES and IP-10 in Hepatitis B Virus Mediated Cirrhosis of Liver. Such a reduced expression of both the chemokines might be associated with lesser infiltration of immunocompetent cells to liver to avert further damage in cirrhosisJ. Biol Life Sci, 2012; 3 (1): ISSN 2157-60762012

Detection of diagnosis escape variants of Hepatitis B virus by in house polymerase chain reaction assay. The persistent heterogeneity of HBV in single infected individual could be attributed to the escape variant that cannot be detected by routine methods of detection using commercial assay, (J. Gen. Mol Virol.  February, 2011; 3:43-48)

A significant decline in visceral adipose tissue visfatin level was found to be associated with degree of steatosis in NAFLD patients. Annals of Hepatology, 2010; 9 (3):266-270.

Elucidated the relationship between serum HBsAg level, HBV DNA level, and peripheral immune cells in patients with chronic hepatitis B virus infection. (Hepatic Medicine: Evidence and Research: 2010; 2:157–162.

Polymorphisms in SNP D19H, but not in SNP T400K, within the hepatic cholesterol transporter (ABCG8) gene was noted to be significantly associated with gall stone disease Indian population.J.GastroenterolHepatol. 2010; 25: 1093–1098

PANCREATIC DISEASES

The exocrine and endocrine functions of pancreas are largely unruffled in healthy individuals since the organ is protected from environmental insults by virtue of its retroperitoneal location, sphincter-protected duct system and filtered blood supply. In recent years, diseases of the pancreas (acute and chronic types of pancreatitis, pancreatic cancer, cystic fibrosis) have emerged as a major challenge for the clinicians and basic scientists not only because of their increased incidence but also because relatively much less is known about the cellular and molecular mechanisms involved therein. Research conducted in this regard in our institution has resulted in the following significant findings:

Evaluated the early interactions of human pancreatic acinar injury with the resulting cytokine response in human acute pancreatitis (AP). Earliest immune response in AP was noted to originate within the acinar cell itself, which subsequently activates circulating PBMCs leading to systemic inflammatory response syndrome.   Sci Rep. 2017. 10;7(1):15276

Demonstrated the association of Systemic Inflammatory and Anti-Inflammatory responses with adverse outcomes in acute Pancreatitis: Dig Dis Sci. 2017 Dec;62(12):3468-3478

Demonstrated that T cell–mediated inflammation is associated with β-cell dysfunction during progression of CP.Pancreas. 2016 Mar;45(3):434-42

Explored intra-acinar events downstream of trypsin activation that lead to acinar cell death and noted that release of cathepsin B in cytosol causes cell death in Acute Pancreatitis. (Gastroenterology. 2016; 151(4):747-758).

The role of NF-kB, a molecule linking initial acinar injury to systemic inflammation leading to perpetuate inflammation, has been examined and the possible use of NF-kB inhibitors was suggested in pancreatitis (Pancreatology. 2016;16(4):477-88)

Islets from patients with chronic calcific pancreatitis of tropical region were characterized and found to be suitable for autologous islet transplantation. Advances in Bioscience and Biotechnology, 2016, 7,1-10

The enigma of Type 3c Diabetes in chronic pancreatitis was addressed in relation to its occurrence and the relative unawareness of the disease in India. Pancreas Open J. 2016;1(2): 19-21.

Demonstrated the ameliorating effect of antioxidants and pregabalin combination in pain recurrence after ductal clearance in chronic pancreatitis. J Gastroenterol. Hepatol 2016: 31: 1654-1662

Evaluated the association of claudin2 and PRSS1-PRSS2 polymorphisms with idiopathic recurrent acute pancreatitis (IRAP) and chronic pancreatitis (CP). Our research has demonstrated the association of claudin2 (rs7057398) polymorphism with IRAP and progression of IRAP to CP, as well as polymorphism in PRSS1 (rs10273639) with IRAP and ICP. J GastroenterolHepatol. 2015 Dec;30(12):1796-801

Demonstrated that interferon γ decreases nuclear localization of Pdx-1 and triggers β-cell dysfunction in chronic pancreatitis.J Interferon Cytokine Res. 2015 Jul;35(7):523-9

The association of claudin2 and PRSS1-PRSS2 polymorphisms with idiopathic recurrent acute and chronic pancreatitis could be demonstrated in Indian populations. J GastroenterolHepatol. 2015 Dec;30(12):1796-801

Identified that polymorphisms in cationic trypsinogen (PRSS1), SPINK1, cystic fibrosis trans-membrane conductance regulator (CFTR), Chymotrypsinogen C (CTRC), Cathepsin B (CTSB) and calcium sensing receptor (CASR) genes impart genetic susceptibility of an individual to pancreatitis.  World J GastrointestPathophysiol. 2014 Nov 15;5(4):427-37

Reviewed molecular events that are relevant to the development of targeted preventive and therapeutic modalities to prevent β-cell dysfunction in chronic pancreatitis. Digestive Disease Sciences, (2012) 57:1764–1772.

The role of interferon γ in maintaining glycemic status in diabetes associated with chronic pancreatitis was elucidated. Pancreatology 12 (2012) 65-70.

Determined that reduced expression of pdx-1 is associated with decreased β-Cell functions in chronic pancreatitis. Pancreas, 2010;39 (6):856-862.

Established that gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes.B M C Medical Genetics: 2008; 9:80.

GASTROINTESTINAL CANCER

GI cancers (including gastric cancer, colorectal cancer, hepatocellular carcinoma, esophageal cancer, and pancreatic cancer), causing considerable morbidity and mortality than cancers affecting other organs, pose serious challenges to the clinician as well as the basic scientist.  Our research efforts in this area have resulted in the following findings.

Involvement of pancreatic stellate cells in the cross talk between pancreatic cancer cells and cancer stroma in relation to tumor progression and metastasis was examined.   World J Gastroenterol. 2017; 23 (3): 382-405

In comparison to measurement of serum CA19-9 alone, its measurement in combination with plasma microRNA192 was noted to be an appropriate, non-invasive prognostic biomarker in periampullary carcinoma. Tumour Biol. 2017 Mar;39(3): 1010428317695018.

Upon studying the relevance of microsatellite instability and promoter methylation of genes involved in DNA mismatch repair., it was noted that significantly higher proportion of tumors with microsatellite instabilityhad promoter hypermethylationin Indian patients with colorectal cancer. Tumour Biol. 2014 May;35(5):4347-55

Studied the association of vascular endothelial growth factor (VEGF) gene polymorphism with increased serum VEGF concentration in pancreatic adenocarcinoma.Pancreatology 13 (2013) 267 – 272.

Differentially expressed common miRNA signatures identified in subgroups of periampullary carcinoma may have a role in disease pathogenesis. The expression patterns of miR-375, miR-31 and miR-196a would help in differentiate PAC subtypes. Pancreatology 2013; 14: 36-47

STEM CELLS AND ISLET TRANSPLANTATION

Stem cells are special types of cells capable of diving indefinitely and have the potential to give rise to specialized cells-any cell of the body. In adults, stem cells and its progenitor cells act as repair systems of the body. The therapeutic potentials of stem cells have already been explored and evaluated for the pre-clinical and clinical settings. Problems associated with transplantation, such as donor shortage, immunological rejection, surgical complications and high costs, an effort was developed for alternative strategies as cellular therapy like Mesenchymal stem cell (MSC) transplantation. As MSCs have multiple functions in cellular therapy especially anti-fibrosis and anti-inflammatory effects they are focused in treatment of various clinical conditions such as chronic liver failure, refractory Irritable bowel disease (IBDs) and Chronic Pancreatitis (CP).

Presently we are conducting approved clinical studies for autologous bone marrow (BM) derived MSC cell transplantation for the treatment of Chronic liver disease (CLD) and Chronic pancreatitis (CP). Currently bone marrow derived hematopoietic stem cells, Autologous BM derived MSCs and combination of both cell type is being investigated in Chronic liver disease patients.

Sasikala M, Surya P, Radhika G, Pavan Kumar P, R.M. Mukherjee, Rao P.N. Rao, Nageshwar  Reddy D. Identification of circulating CD90+ CD73 +cells in cirrhosis of liver. World Journal of stem cells, 2011,3 (7):63-69

Successful evaluation of long-term functions of encapsulated islets grafted in nonhuman primates and maintained without immunosuppression, paving way for islet transplantation studies. Transplantation. 2013; 15; 96(7):624-632.

Successfully demonstrated the beneficial effect of autologous infusion of mobilized peripheral blood CD 34+ cells in patients with non-viral decompensated cirrhosis. World J Gastroenterol 2015; 21 (23): 7264-7271.

P. Pavan Kumar, M. Sasikala, K. Mamatha, G. V. Rao, R. Pradeep, R.Talukdar, D. Nageshwar Reddy. Characterization of Islets from Chronic Calcific Pancreatitis Patients of Tropical Region with Distinct Phenotype. Advances in Bioscience and Biotechnology, 2016, 7,1-10

Demonstrated the enhanced capability of pancreatic ductal epithelial cells (PDEC) to proliferate and differentiate into endocrine mass, suggesting that PDECs form a source of progenitors for cell based therapy in chronic pancreatitis. Open J Endocrine and Metabolic Diseases 2015; 5: 177-183

M. Sasikala*, G. V. Rao, Manu Tandan, D. Nageshwar Reddy: Gastrointestinal Stem Cells. In Regenerative Medicine, Ed Prof Gustav Steinhoff & Dr. Hoang Tu-Rapp. 365-412. DOI 10.1007/978-94-007-5690-8_14  (Springer)

An economic method for the production of human hepatocytes from induced pluripotent stem cells was evolved (Indian Patent Application No: 3598/CHE/2011).

GUT MICROBIOTA

Observations on the altered intestinal microbiota implicate them to diabetes and metabolic absnormalities. Scientific Reports 2017; 7: 43640

The gut bacterial profile of the Indian population was noted to be similar to that of Mongolian population. Scientific Reports 2015; 5: 18563

The role of normal gut microbiota in humans was examined in relation to their immuno-modulatory effects and metabolic functions. World J Gastroenterol. 2015; 21 (29): 8787-8803