High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats

Abstract Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulat...

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Autores principales:	Mary Priyanka Udumula, Sureshbabu Mangali, Jaspreet Kalra, Deepika Dasari, Srashti Goyal, Vandana Krishna, Srivarsha Reddy Bollareddy, Dharamrajan Sriram, Arti Dhar, Audesh Bhat
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f83b2667215845768e01dc6f6103234c
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spelling	oai:doaj.org-article:f83b2667215845768e01dc6f6103234c2021-12-02T18:02:43ZHigh fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats10.1038/s41598-021-92345-22045-2322https://doaj.org/article/f83b2667215845768e01dc6f6103234c2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92345-2https://doaj.org/toc/2045-2322Abstract Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats. Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35 mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson’s trichrome staining and apoptosis by TUNEL assay. HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.Mary Priyanka UdumulaSureshbabu MangaliJaspreet KalraDeepika DasariSrashti GoyalVandana KrishnaSrivarsha Reddy BollareddyDharamrajan SriramArti DharAudesh BhatNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mary Priyanka Udumula Sureshbabu Mangali Jaspreet Kalra Deepika Dasari Srashti Goyal Vandana Krishna Srivarsha Reddy Bollareddy Dharamrajan Sriram Arti Dhar Audesh Bhat High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats
description	Abstract Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats. Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35 mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson’s trichrome staining and apoptosis by TUNEL assay. HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.
format	article
author	Mary Priyanka Udumula Sureshbabu Mangali Jaspreet Kalra Deepika Dasari Srashti Goyal Vandana Krishna Srivarsha Reddy Bollareddy Dharamrajan Sriram Arti Dhar Audesh Bhat
author_facet	Mary Priyanka Udumula Sureshbabu Mangali Jaspreet Kalra Deepika Dasari Srashti Goyal Vandana Krishna Srivarsha Reddy Bollareddy Dharamrajan Sriram Arti Dhar Audesh Bhat
author_sort	Mary Priyanka Udumula
title	High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats
title_short	High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats
title_full	High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats
title_fullStr	High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats
title_full_unstemmed	High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats
title_sort	high fructose and streptozotocin induced diabetic impairments are mitigated by indirubin-3-hydrazone via downregulation of pkr pathway in wistar rats
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f83b2667215845768e01dc6f6103234c
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High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats

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