Publications by authors named "Uday Kumar Putcha"

32 Publications

Carrot Juice Consumption Reduces High Fructose-Induced Adiposity in Rats and Body Weight and BMI in Type 2 Diabetic Subjects.

Nutr Metab Insights 2021 15;14:11786388211014917. Epub 2021 Jul 15.

Division of Lipid Biochemistry, ICMR-National Institute of Nutrition, Hyderabad, Telangana, India.

Nutritional intervention is a key strategy in the control and management of non-communicable diseases. Here, initially, we evaluated the effects of carrot juice (CJ) on some of the physical and biochemical parameters in rats fed with high-fructose diet, then in type 2 diabetic subjects. For the animal study, weanling male Wistar rats were given control (n = 6) or high fructose (HFr; n = 24) diet for 8 weeks. Then, the HFr group rats were subdivided into 4 groups (n = 6 in each) and continued either on HFr diet or shifted to control diet, with or without CJ (0.3 mg β-carotene) ingestion orally for 8 weeks. At the end, the ingestion of CJ reversed the HFr-induced adiposity (23 ± 1.6 vs 18 ± 1.1,  = .038), hypertriglyceridemia (182 ± 18.2 vs 90 ± 10.5 mg/dL, <0.001), and hyperinsulinemia (81 ± 14.7 vs 40 ± 7.5 µU/mL,  = .014), while increased the retinol levels in liver (240 ± 38.4 vs 492 ± 61.2 µg/g,  = .002) and adipose tissue (1.8 ± 0.09 vs 2.5 ± 0.18 µg/g,  = .026). On the other hand, in the diabetic subjects (7 males and females each, n = 14) compared to their baseline, the daily consumption of 50 mL CJ (~2400 µg β-carotene) for 6 weeks significantly reduced the body weight (69.4 ± 4.13 vs 69.0 ± 4.09 kg,  = .014), BMI (27.4 ± 1.07 vs 27.2 ± 1.06 kg/m,  = .007), and fat% (33.4 ± 1.87 vs 31.9 ± 2.13,  = .029) with an increase in plasma β-carotene levels (0.21 ± 0.045 vs 0.45 ± 0.089 µmol/L,  = .044). Although CJ increased the glucose (145 ± 10.4 vs 165 ± 11.4 mg/dL,  = .039), insulin, and glycated hemoglobin levels remained unaltered. In conclusion, the consumption of carrot juice reversed the HFr-induced metabolic abnormalities in a rat model and decreased body weight and BMI of diabetic subjects.
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http://dx.doi.org/10.1177/11786388211014917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287410PMC
July 2021

Impact of maternal iron deficiency anaemia on the expression of the newly discovered multi-copper ferroxidase, Zyklopen, in term placentas.

J Obstet Gynaecol 2022 Jan 2;42(1):74-82. Epub 2021 May 2.

Division of Bio-statistics, National Institute of Nutrition, Hyderabad, India.

In the present study, we investigated the effect of maternal iron deficiency anaemia (IDA) on expression of the newly discovered iron transporter, Zyklopen in term placenta, in 200 pregnant women. Placental expression of Zyklopen was studied by mRNA analysis and immunohistochemistry for the protein. In addition neonatal anthropometric parameters were also analysed. 58.8% of 200 subjects were anaemic. Both Zyklopen mRNA as well as protein expression in the placenta showed a statistically significant increase with increasing severity of anaemia. Although all the neonatal anthropometric parameters were lower in newborns of anaemic mothers, none showed any statistical significance. Zp mRNA levels did not show any significant correlation with newborn and placental parameters (except newborn skinfold thickness and head circumference). Similar to mRNA expression, Zp IHC expression correlated positively, albiet non-significantly, with newborn length and Hb levels, the correlation was however negative with birth weight, head circumference, mid-arm circumference unlike the mRNA expression, where it positively correlated with the above parameters. Our study for the first time demonstrated a definite increase in expression of Zyklopen at both mRNA and protein levels in term placenta, in maternal IDA.IMPACT STATEMENT Iron deficiency anaemia (IDA) in a pregnant mother can lead to anaemia in the developing foetus; which is frequently observed to be of lesser severity than that in the mother. Recently a copper-containing oxidase called Zyklopen was discovered which was involved in iron efflux in BeWo cells. The gene encoding Zyklopen has been identified with a putative C-terminal membrane-spanning sequence and high sequence identitical to hephaestin (Heph) and ceruloplasmin (Cp), the other known vertebrate multicopper ferroxidase (MCF). Protein expression of this new MCF was observed in multiple diverse mouse tissues, including placenta and mammary gland. Zyklopen protein immunohistochemical expression showed a statistically significant increase with increasing severity of anaemia. Similarly, placental mRNA expression of the Zyklopen gene was observed to be higher in anaemic mothers when compared to non-anaemic mothers. Our study for the first time demonstrated a definite increase in expression of Zyklopen at both protein and mRNA levels in term placenta, in maternal IDA. the This study will help us to understand better, the increased potential for influx of iron from mother to foetus in the condition of maternal iron deficiency. This study will help to determine how placental iron transport proteins can be regulated in response to maternal and neonatal iron status and will further our existing knowledge on relationships between maternal and neonatal iron status and mechanisms by which placental iron transport is modified in relation to these parameters.
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http://dx.doi.org/10.1080/01443615.2021.1882968DOI Listing
January 2022

Impact of ERCC1 gene polymorphisms on response to cisplatin based therapy in oral squamous cell carcinoma (OSCC) patients.

Indian J Pathol Microbiol 2020 Oct-Dec;63(4):538-543

Department of Prosthodontics, Kamineni Institute of Dental Sciences, Narketpally, Telangana, India.

Background And Objectives: Cisplatin is one of the major drugs that used in the treatment of oral cancer.Excision repair cross-complementation group 1 (ERCC1) is a key DNA repair gene in the nucleotide excision repair pathway which is activated in the repair of intra- and interstrand DNA crosslink caused by platinum-based treatment. The aim of this study was to investigate the association between polymorphisms in ERCC1 (C118T & C8092A) genes and the response to cisplatin-based chemotherapy.

Methods: ERCC1polymorphisms (C118T & C8092A) were studied using PCR-RFLP method from 150 OSCC patients as cases as well as 150 normal tissues from the same patients were collected as controls for this study. Results: Frequencies of ERCC1 C118C, C118T and T118T genotypes were 60%, 28% and 12% in OSCC patients and 78%, 19% and 3% in the controls, respectively. The C118T & T118T genotype had a 1.69 and 4.97 -folds increased risk for OSCC. Frequencies of ERCC1 C8092C, C8092A and A8092A were 78%, 18% and 4% in the OSCC patients and 89%, 10%, amd 1% in the controls, respectively. The C8092A genotype showed a 1.97-fold increased risk for OSCC.

Interpretation & Conclusions: In conclusion, this study highlights the DNA repair gene polymorphisms that might play a role in mediating susceptibility to oral squamous cell carcinoma and cisplatin therapy. Our data suggest that the ERCC1 C118T, T118T and ERCC1 C8092A genotypes are genetic risk factors for Oral squamous cell carcinoma and ERCC1 118 C/T and C8092A polymorphisms have significant influence on clinical outcome.
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http://dx.doi.org/10.4103/IJPM.IJPM_964_19DOI Listing
July 2021

Cinnamon Attenuated Long-Term IGT-Induced Retinal Abnormalities via Regulation of Glucose Homeostasis in Neonatal Streptozotocin Induced Rat Model.

Indian J Clin Biochem 2020 Oct 9;35(4):442-450. Epub 2019 Jul 9.

Lipid Chemistry Division, National Institute of Nutrition, Jamai-Osmania, Hyderabad, 500007 India.

Diabetic retinopathy (DR) is one of the major causes of blindness all over the world. According to the previous studies, impaired glucose tolerance (IGT) has been linked to retinal dysfunction/vascular damage. Decreased retinal function is an initial event of early DR. Although the biochemical and molecular events are not fully understood, glial activation, angiogenesis and oxidative stress are some of the pathways associated with early retinal abnormalities. Since IGT is associated with development of retinal dysfunction/vascular damage; as a preventive strategy, we have studied beneficial effect of Cinnamon as a hypoglycaemic agent on long-term IGT induced retinal abnormalities using neonatal streptozotocin (nSTZ) rat model. Control, IGT rats were maintained on AIN-93M diet alone and another set of IGT rats were maintained on AIN-93M diet with 3% Cinnamon for 8 months. At the end of the study, untreated IGT rats developed retinal functional abnormalities as assessed by electroretinogram (ERG) and the retinal structure did not alter as assessed by H&E staining. Further, increase in expressions of GFAP, VEGF and decreased expression of rhodopsin in untreated IGT rat retinas. 4-HNE, a marker of oxidative stress was also elevated in IGT state. Supplementation of Cinnamon to IGT rats had lowered fasting and postprandial glucose levels and also prevented retinal functional abnormalities. Further, Cinnamon protected photoreceptor cell damage, suppressed glial activation, angiogenesis and oxidative stress as there was an improved rhodopsin expression, inhibited elevated expressions of GFAP, VEGF and 4-HNE respectively. In conclusion, Cinnamon attenuated IGT induced retinal abnormalities probably through its hypoglycemic property.
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http://dx.doi.org/10.1007/s12291-019-00842-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502638PMC
October 2020

Expression of iron transport protein Divalent metal transporter 1 (DMT1) increases in response to maternal iron deficiency anemia in near term to term placenta.

J Matern Fetal Neonatal Med 2020 Mar 29:1-9. Epub 2020 Mar 29.

National Institute of Nutrition, Pathology and Microbiology Division, National Institute of Nutrition, Hyderabad, India.

Iron deficiency anemia (IDA) is the most prevalent nutritional deficiency disorder in pregnant women. During pregnancy, placental transport protein Divalent metal transporter1 (DMT1) plays a crucial role in transit of iron across placenta. The developing fetus is observed to be immune to anemia despite presence of anemia in the mother. Hence, we planned the present study to explore the effect of maternal IDA on the expression of DMT1 in the placenta. Two hundred pregnant women recruited, were divided into anemic and nonanemic groups based on their predelivery hemoglobin levels (<11 g/dL and ≥11 g/dL respectively). After delivery, placental expression of DMT1 was studied by immunohistochemistry and mRNA analysis and neonatal anthropometry was performed. Of the 200 women recruited, 58.8% were anemic with 60.35% having moderate anemia. Most of the red cell parameters were observed to be higher in cord blood than mothers. DMT1 protein immunohistochemical expression showed a statistically significant increase with increasing severity of anemia. Similarly, placental mRNA expression levels of DMT1 gene were observed to be higher in anemic mothers in comparison with nonanemic mothers. Our study thus demonstrated a definite increase in expression of DMT1 at both protein and mRNA levels in term placenta, in maternal IDA.
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http://dx.doi.org/10.1080/14767058.2020.1742317DOI Listing
March 2020

Effect of Maternal Iron Deficiency Anaemia on the Expression of Iron Transport Proteins in the Third Trimester Placenta.

Fetal Pediatr Pathol 2021 Dec 25;40(6):581-596. Epub 2020 Feb 25.

Pathology and Microbiology Division, National Institute of Nutrition, Hyderabad, India.

During pregnancy, iron is transferred from mother to fetus with placental iron transport proteins (Transferrin receptor, Divalent metal transporter/DMT1, ferroportin/FPN1 and Zyklopen). The aim of the study was to evaluate the effect of maternal iron deficiency anemia on placental iron transporters. Two hundred pregnant women, in third trimester of pregnancy were divided into anemic (Hemoglobin/Hb < 11g/dl) and non-anemic groups (Hb ≥ 11 g/dl). After delivery, placental expression of iron transport proteins were studied by immunohistochemistry and by mRNA analysis. Of the 200 subjects, 59% were anemic. All 3 placental proteins showed statistically significant increase in immunohistochemical expression, proportionate to the severity of maternal anemia. The mRNA expression of DMT-1 gene was only significantly elevated in placentas of anemic mothers. Although in our study mRNA expression of only the DMT-1 gene was significantly high, immunohistochemically however all the 3 proteins showed significantly higher expression in placentas of anemic mothers.
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http://dx.doi.org/10.1080/15513815.2020.1725942DOI Listing
December 2021

Vitamin A deficiency increases the oleic acid (C18:1) levels in the kidney of high fructose diet-fed rats.

Indian J Med Res 2019 12;150(6):620-629

Divisions of Lipid Biochemistry, ICMR-National Institute of Nutrition, Hyderabad, Telangana, India.

Background & Objectives: Stearoyl-CoA desaturase 1 (SCD1) is a key lipogenic enzyme responsible for endogenous synthesis of monounsaturated fatty acids (MUFA) and plays a key role in various pathophysiology, including fatty liver diseases. In this experimental study the impact of vitamin A deficiency was assessed on SCD1 regulation in relation to kidney biology, under high fructose (HFr) diet-fed condition in rats.

Methods: Forty male weanling (21 day old) Wistar rats were divided into four groups control, vitamin A-deficient (VAD), HFr, VAD with HFr consisting of eight rats each, except 16 for the VAD group. The groups received one of the following diets: control, VAD, HFr and VAD with HFr for 16 wk, except half of the VAD diet-fed rats were shifted to HFr diet, after eight week period.

Results: Feeding of VAD diet (alone or with HFr) significantly reduced the kidney retinol (0.51, 0.44 μg/g vs. 2.1 μg/g; P < 0.05), while increased oleic (C18:1) and total MUFA levels (23.3, 22.2% and 27.3, 25.4% respectively vs. 14.7 and 16.6%; P < 0.05) without affecting the SCD1, both at protein and mRNA levels, when compared with HFr. Comparable, immunohistological staining for SCD1 was observed in the distal convoluted tubules. Despite an increase in MUFA, morphology, triglyceride content and markers of kidney function were not affected by VAD diet feeding.

Interpretation & Conclusions: Feeding of VAD diet either alone or under HFr condition increased the kidney oleic acid (C18:1) levels and thus total MUFA, which corroborated with elevated SCD1 activity index, without affecting its expression status. However, these changes did not alter the kidney morphology and function. Thus, nutrient-gene regulation in kidney biology seems to be divergent.
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http://dx.doi.org/10.4103/ijmr.IJMR_1574_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038806PMC
December 2019

Vitamin A and its metabolic pathway play a determinant role in high-fructose-induced triglyceride accumulation of the visceral adipose depot of male Wistar rats.

Cell Biochem Funct 2019 Dec 9;37(8):578-590. Epub 2019 Sep 9.

Lipid Biochemistry Division, ICMR-National Institute of Nutrition, Hyderabad, India.

Here, we tested a hypothesis that vitamin A and/or its metabolic pathways are involved in the high-fructose-mediated alteration in adipose tissue biology. For this purpose, weanling male Wistar rats were provided with one of the following diets: control (C), control with vitamin A deficiency (C-VAD), high fructose (HFr), and HFr with VAD (HFr-VAD) for 16 weeks, except that half of the C-VAD diet-fed rats were shifted to HFr diet (C-VAD(s)HFr), after 8-week period. Compared with control, feeding of HFr diet significantly increased the triglyceride content (P ≤ .01) and thus adipocyte size (hypertrophy) (P ≤ .001) in visceral adipose depot; retroperitoneal white adipose tissue (RPWAT) and these changes were corroborated with de novo lipogenesis, as evidenced by the increased glycerol-3-phosphate dehydrogenase activity (P ≤ .01) and up-regulation of lipogenic pathway transcripts, fructose transporter, and aldehyde dehydrogenase 1 A1. On the contrary, the absence of vitamin A in the HFr diet (HFr-VAD) failed to exert these changes; however, it induced adipocyte hyperplasia. Further, vitamin A deficiency-mediated changes were reversed by replenishment, as evident from the group that was shifted from C-VAD to HFr diet. In conclusion, vitamin A and its metabolic pathway play a key determinant role in the high-fructose-induced triglyceride accumulation and adipocyte hypertrophy of visceral white adipose depot. SIGNIFICANCE OF THE STUDY: Here, we report the metabolic impact of high-fructose feeding under vitamin A-sufficient and vitamin A-deficient conditions. Feeding of high-fructose diet induced triglyceride accumulation and adipocyte hypertrophy of the visceral white adipose depots. These changes corroborated with augmented expression of vitamin A and lipid metabolic pathway genes. Contrarily, absence of vitamin A in the high-fructose diet did not elicit such responses, while vitamin A replenishment reversed the changes exerted by vitamin A deficiency. To our knowledge, this is the first study to report the role of vitamin A and its metabolic pathway in the high-fructose-induced triglyceride synthesis and its accumulation in visceral adipose depot and thus provide a new insight and scope to understand these nutrients interaction in clinical conditions.
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http://dx.doi.org/10.1002/cbf.3434DOI Listing
December 2019

Study on the Effect of Severity of Maternal Iron Deficiency Anemia on Regulators of Angiogenesis in Placenta.

Fetal Pediatr Pathol 2019 Oct 25;38(5):361-375. Epub 2019 May 25.

National Institute of Nutrition, Pathology and Microbiology , Tarnaka , Hyderabad, Telangana , India.

In this study, we hypothesized that maternal anemia leads to altered expression of angiogenic proteins vascular endothelial growth factor (VEGF), placental growth factor (PLGF), nitrotyrosine (NT) residues, and endothelial nitric oxide synthase (e-NOS) in the placenta. Hence, we study the expression of the abovementioned proteins in the placentas of mothers with different grades of anemia. Our study was conducted in 48 pregnant women (36-40 weeks of gestation), who were divided into four groups-normal, mild, moderate, and severe anemia. After delivery, the expression of the angiogenic proteins was studied in their placentas by immunohistochemistry. In our study, 58.3% of the pregnant women were anemic, among which 20.83% had mild anemia, 18.75% had moderate anemia, and 18.75% had severe anemia. Immunohistochemical staining intensity for VEGF, PLGF, NT residues, and e-NOS proteins was observed to be higher in the placentas of anemic women when compared with the non-anemic women. Our study showed that there is an increased expression of angiogenic proteins in the placentas of anemic mothers, which probably is an adaptive response leading to changes in placental vessels.
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http://dx.doi.org/10.1080/15513815.2019.1587120DOI Listing
October 2019

High-Fat Diet Elevates Liver Docosahexaenoic Acid Possibly through Over-Expression of Very Long-Chain Fatty Acid Elongase 2 in C57BL/6J Mice.

Int J Vitam Nutr Res 2019 Jul 8;89(1-2):62-72. Epub 2019 Apr 8.

1Lipid Biochemistry Division, National Institute of Nutrition, Jamai Osmania, Hyderabad, India.

The liver is the main site of lipid metabolism and vitamin A storage. Dietary factors are known to affect liver function, thereby leading to metabolic abnormalities. Here, we assessed the impact of long-term feeding of a high-fat diet on hepatic vitamin A status and lipid metabolism. For this purpose, 14 male and 14 female 35-day-old mice (strain C57BL/6J) were each divided into 2 groups of 7 animals and fed either a stock diet or a high-fat (HF) diet for 26 weeks. In addition to increased body weight/weight gain, the HF diet induced hypertriglyceridemia in both (p < 0.01). However, liver triglyceride levels were comparable among groups, which could be partly explained by unaltered expression of various lipogenic pathway proteins such as sterol regulatory element binding protein 1 (SREBP1), fatty acid synthase (FAS), microsomal triglyceride transfer protein (MTTP), and glycerol 3-phosphate acyl transferase (GPAT). On the other hand, hepatic retinol stores increased significantly in both sexes, whereas males displayed elevated circulatory retinol levels. Notably, long-term feeding of a HF diet elevated n-3 polyunsaturated fatty acid (PUFA) and docosahexaenoic acid (DHA, C22:6) levels in the liver (p ≤ 0.001), which is in line with the over-expression of very long-chain fatty acid elongase 2 (ELOVL2) protein in both sexes of mice (p < 0.01). In conclusion, very long-term feeding of a HF diet increased hepatic retinol stores and induced hypertriglyceridemia. However, it had no effect on hepatic triglyceride accumulation, possibly due to increased DHA levels arising from the ELOVL2-mediated elongation pathway.
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http://dx.doi.org/10.1024/0300-9831/a000432DOI Listing
July 2019

Coconut oil consumption improves fat-free mass, plasma HDL-cholesterol and insulin sensitivity in healthy men with normal BMI compared to peanut oil.

Clin Nutr 2019 12 29;38(6):2889-2899. Epub 2018 Dec 29.

Lipid Biochemistry Division, National Institute of Nutrition, Jamai Osmania, Hyderabad, 500 007, Telangana, India. Electronic address:

Background & Aims: The existing scientific evidence on coconut oil consumption and its health effects remains inconclusive due to varied reasons. In this context, we conducted a well-controlled metabolic study, eliminating some of the confounding factors and assessed the effects of the consumption of coconut oil-based diet on various anthropometric, biochemical and inflammatory markers and compared with peanut oil-diet.

Methods: Nine healthy male volunteers with BMI ≤25 kg/m were enrolled for this study and given balanced diets prepared with coconut oil (CO; ~35 g) for a period of eight weeks. After a wash-out period of six weeks, the same subjects were provided with diets prepared with peanut oil (~35 g) for eight weeks. Except fat source, the composition of the diets was identical in all aspects.

Results: Compared to basal values, there were significant increases in fat-free mass (p ≤ 0.022), plasma HDL-cholesterol (HDL-C) (p ≤ 0.047) and insulin sensitivity of the subjects at the end of CO-consumption. Further, compared to peanut oil, increase in plasma HDL-C was significant (p = 0.004) in CO treatment. On the other hand, plasma inflammatory markers-associated with cardiovascular diseases (CVD), namely soluble vascular cell adhesion molecule 1 (sVCAM1) and matrix metalloproteinase levels were reduced significantly by CO-intake. Further, these subjects displayed elevated levels of myristic acid (14:0) in plasma phospholipids at the end of CO-consumption, which correlated positively with HDL-C and negatively with sVCAM1. However, no such changes were observed after peanut oil diet consumption.

Conclusions: In conclusion, compared to peanut oil, the consumption of coconut oil in a balanced diet resulted in increased fat-free mass, plasma HDL-C, elicited favourable changes on insulin sensitivity and CVD risk-associated parameters in healthy men with normal BMI.
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http://dx.doi.org/10.1016/j.clnu.2018.12.026DOI Listing
December 2019

Substitution of linoleic acid with α-linolenic acid or long chain n-3 polyunsaturated fatty acid prevents Western diet induced nonalcoholic steatohepatitis.

Sci Rep 2018 Jul 19;8(1):10953. Epub 2018 Jul 19.

Department of Lipid Chemistry, National Institute of Nutrition, Hyderabad, India.

Imbalance in the n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA in the Western diet may increase the risk of nonalcoholic fatty liver disease (NAFLD). This study investigates the impact of substitution of linoleic acid with α-linolenic acid (ALA) or long chain (LC) n-3 PUFA and hence decreasing n-6:n-3 fatty acid ratio on high fat, high fructose (HFHF) diet induced nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were divided into four groups and fed control diet, HFHF diet (n-6:n-3 ratio of 200), HFHF diet with ALA (n-6:n-3 ratio of 2) or HFHF diet with LC n-3 PUFA (n-6:n-3 ratio of 5) for 24 weeks. Rats fed HFHF diet with n-6:n-3 ratio of 200 resulted in hepatic steatosis, induced glucose intolerance, insulin resistance and oxidative stress accompanied by increase in markers of inflammation, plasma lipids and aminotransferase levels. Histopathological examination of liver further confirmed the establishment of NASH. ALA and LC n-3 PUFA supplementation prevented hepatic steatosis and dyslipidemia by inhibiting lipogenesis and increasing insulin sensitivity. Furthermore, n-3 PUFA supplementation attenuated hepatic oxidative stress by restoring antioxidant status, decreased inflammation and preserved hepatic architecture. These finding suggest that decreasing n-6:n-3 ratio prevented HFHF induced NASH by attenuating oxidative stress and inflammation.
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http://dx.doi.org/10.1038/s41598-018-29222-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053361PMC
July 2018

Chronic consumption of fructose in combination with trans fatty acids but not with saturated fatty acids induces nonalcoholic steatohepatitis with fibrosis in rats.

Eur J Nutr 2018 Sep 4;57(6):2171-2187. Epub 2017 Jul 4.

Department of Lipid Chemistry, National Institute of Nutrition, Hyderabad, India.

Purpose: Consumption of Western diet high in fat and fructose has been attributed to the recent epidemic of nonalcoholic fatty liver disease (NAFLD). However, the impact of specific fatty acids on the progression of NAFLD to nonalcoholic steatohepatitis (NASH) is poorly understood. In the present study, we investigated the chronic effects of consumption of fructose in combination with saturated fatty acids (SFA) or trans fatty acids (TFA) on the development of NAFLD.

Methods: Male Sprague-Dawley rats were randomly assigned to six isocaloric starch/high fructose (44% of calories), high fat (39% calories) diet containing either starch-peanut oil, fructose-peanut oil, fructose-palmolein, fructose-clarified butter, fructose-coconut oil or fructose-partially hydrogenated vegetable oil and fed for 24 weeks. Palmolein, clarified butter and coconut oil were used as the source of SFA whereas partially hydrogenated vegetable oil was used as the source of TFA. Peanut oil was used as the reference oil.

Results: Long-term feeding of fructose in combination with SFA or TFA induced hepatic steatosis of similar extent associated with upregulation of stearoyl CoA desaturase-1. In contrast, fructose in combination with TFA induced NASH with fibrosis as evidenced by upregulation of hepatic proinflammatory cytokine and fibrogenic gene expression, increased hepatic oxidative stress and adipocytokine imbalance. Histopathological analysis revealed the presence of NASH with fibrosis. Further, peanut oil prevented the development of NAFLD in fructose-fed rats.

Conclusion: Fructose in combination with TFA caused NASH with fibrosis by inducing oxidative stress and inflammation, whereas, fructose in combination with SFA caused simple steatosis, suggesting that the type of fatty acid is more important for the progression of NAFLD.
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http://dx.doi.org/10.1007/s00394-017-1492-1DOI Listing
September 2018

Chronic transgenerational vitamin B12 deficiency of severe and moderate magnitudes modulates adiposity-probable underlying mechanisms.

Biofactors 2017 May 10;43(3):400-414. Epub 2017 Feb 10.

Endocrinology and Metabolism Division, National Institute of Nutrition (NIN), ICMR, Hyderabad, 500007, India.

We have demonstrated previously that severe but not moderate vitamin B12 deficiency altered body composition and induced adiposity in female C57BL/6 mice. This study aims to elucidate the effects of chronic transgenerational dietary vitamin B12 restriction on body composition and various biochemical parameters in the F1 generation offspring of our mouse models of severe and moderate vitamin B12 deficiency established earlier. Female weanling C57BL/6 mice received, ad libitum, for 4 weeks a (i) control diet, (ii) vitamin B12-restricted diet with pectin as dietary fiber (severely deficient diet), or (iii) vitamin B12-restricted diet with cellulose as dietary fiber (moderately deficient diet) and then mated with control males. The offspring of control and severely deficient dams continued on the respective diets of their mothers. Few moderately deficient dams were rehabilitated to control diet from parturition and their pups were weaned to control diet. Also, some offspring born to moderately B12 deficient dams were weaned to control diet, while others continued on the same diet as their mothers. Various parameters were determined in the F1 offspring after 12 and 36 weeks of feeding. The results indicate that both severe and moderate maternal vitamin B12 restrictions were associated with accelerated catch-up growth, increased body fat percentage, visceral adiposity, dyslipidemia, fasting hyperglycemia and insulin resistance in the F1 offspring. Inflammation, increased glucocorticoid and oxidative stress and poor antioxidant defence probably underlie these adverse effects. Rehabilitation from parturition but not weaning was beneficial in delaying the onset of the adverse outcomes in the offspring. © 2016 BioFactors, 43(3):400-414, 2017.
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http://dx.doi.org/10.1002/biof.1350DOI Listing
May 2017

Transcriptome profiling of visceral adipose tissue in a novel obese rat model, WNIN/Ob & its comparison with other animal models.

Indian J Med Res 2016 Sep;144(3):409-423

Department of Biochemistry, National Institute of Nutrition (ICMR), Hyderabad, India.

Background & Objectives: Adipose tissue dysfunction in obesity is linked to the development of type 2 diabetes and cardiovascular diseases. We studied the differential gene expression in retroperitoneal adipose tissue of a novel obese rat model, WNIN/Ob, to understand the possible underlying transcriptional changes involved in the development of obesity and associatedcomorbidities in this model.

Methods: Four month old, male WNIN/Ob lean and obese rats were taken, blood was collected and tissues were dissected. Body composition analysis and adipose tissue histology were performed. Global gene expression in retroperitoneal adipose tissue of lean and obese rats was studied by microarray using Affymetrix GeneChips.

Results: One thousand and seventeen probe sets were downregulated and 963 probe sets were upregulated (more than two-fold) in adipose tissue of WNIN/Ob obese rats when compared to that of lean rats. Small nucleolar RNA (SnoRNA) made most of the underexpressed probe sets, whereas immune system-related genes werethe most overexpressed in the adipose tissues of obese rats. Genes coding for cytoskeletal proteinswere downregulated, whereas genes related to lipid biosynthesis were elevated in the adipose tissue of obese rats.

Interpretation & Conclusions: Majority of the altered genes and pathways in adipose tissue of WNIN/Ob obese rats were similar to the observations in other obese animal models and human obesity. Based on these observations, it is proposed that WNIN/Ob obese rat model may be a good model to study the mechanisms involved in the development of obesity and its comorbidities. Downregulation of SnoRNA appears to be a novel feature in this obese rat model.
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http://dx.doi.org/10.4103/0971-5916.198667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320847PMC
September 2016

Transient Decrease in Circulatory Testosterone and Homocysteine Precedes the Development of Metabolic Syndrome Features in Fructose-Fed Sprague Dawley Rats.

J Nutr Metab 2016 12;2016:7510840. Epub 2016 Oct 12.

Department of Biochemistry, National Institute of Nutrition, Indian Council of Medical Research, Jamai Osmania PO, Hyderabad, Andhra Pradesh 500 604, India.

. Increased fructose consumption is linked to the development of metabolic syndrome (MS). Here we investigated the time course of development of MS features in high-fructose-fed Sprague Dawley rats along with circulatory testosterone and homocysteine levels. . Rats were divided into control and experimental groups and fed with diets containing 54.5% starch and fructose, respectively, for 4, 12, and 24 weeks. Plasma testosterone and homocysteine levels were measured along with insulin, glucose, and lipids. Body composition, insulin resistance, and hepatic lipids were measured. . Increase in hepatic triglyceride content was first observed in metabolic disturbance followed by hypertriglyceridemia and systemic insulin resistance in fructose-fed rats. Hepatic lipids were increased in time-dependent manner by fructose-feeding starting from 4 weeks, but circulatory triglyceride levels were increased after 12 weeks. Fasting insulin and Homeostatis Model Assessment of Insulin Resistance (HOMA-IR) were increased after 12 weeks of fructose-feeding. Decreased visceral adiposity, circulatory testosterone, and homocysteine levels were observed after 4 weeks of fructose-feeding, which were normalized at 12 and 24 weeks. . We conclude that transient decrease in circulatory testosterone and homocysteine levels and increased hepatic triglyceride content are the earliest metabolic disturbances that preceded hypertriglyceridemia and insulin resistance in fructose-fed SD rats.
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http://dx.doi.org/10.1155/2016/7510840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080489PMC
October 2016

Carrot Juice Administration Decreases Liver Stearoyl-CoA Desaturase 1 and Improves Docosahexaenoic Acid Levels, but Not Steatosis in High Fructose Diet-Fed Weanling Wistar Rats.

Prev Nutr Food Sci 2016 Sep 30;21(3):171-180. Epub 2016 Sep 30.

Lipid Biochemistry Division, National Institute of Nutrition, Jamai Osmania, Hyderabad 500007, India.

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases associated with an altered lifestyle, besides genetic factors. The control and management of NAFLD mostly depend on lifestyle modifications, due to the lack of a specific therapeutic approach. In this context, we assessed the effect of carrot juice on the development of high fructose-induced hepatic steatosis. For this purpose, male weanling Wistar rats were divided into 4 groups, fed either a control (Con) or high fructose (HFr) diet of AIN93G composition, with or without carrot juice (CJ) for 8 weeks. At the end of the experimental period, plasma biochemical markers, such as triglycerides, alanine aminotransferase, and β-hydroxy butyrate levels were comparable among the 4 groups. Although, the liver injury marker, aspartate aminotransferase, levels in plasma showed a reduction, hepatic triglycerides levels were not significantly reduced by carrot juice ingestion in the HFr diet-fed rats (HFr-CJ). On the other hand, the key triglyceride synthesis pathway enzyme, hepatic stearoyl-CoA desaturase 1 (SCD1), expression at mRNA level was augmented by carrot juice ingestion, while their protein levels showed a significant reduction, which corroborated with decreased monounsaturated fatty acids (MUFA), particularly palmitoleic (C16:1) and oleic (C18:1) acids. Notably, it also improved the long chain n-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA; C22:6) content of the liver in HFr-CJ. In conclusion, carrot juice ingestion decreased the SCD1-mediated production of MUFA and improved DHA levels in liver, under high fructose diet-fed conditions. However, these changes did not significantly lower the hepatic triglyceride levels.
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http://dx.doi.org/10.3746/pnf.2016.21.3.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063201PMC
September 2016

Protein kinase C-mediated sodium glucose transporter 1 activation in precondition-induced cardioprotection.

Drug Des Devel Ther 2016 14;10:2929-2938. Epub 2016 Sep 14.

Division of Medicinal Chemistry and Pharmacology, Indian Institute of Chemical Technology, Hyderabad, India; Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, India.

The concept of cardioprotection through preconditioning against ischemia-reperfusion (I/R) injury is well known and established. However, among different proposed mechanisms regarding the concept of ischemic preconditioning, protein kinase C (PKC)-mediated cardioprotection through ischemic preconditioning plays a key role in myocardial I/R injury. Thus, this study was designed to find the relationship between PKC and sodium glucose transporter 1 (SGLT1) in preconditioning-induced cardioprotection, which is ill reported till now. By applying a multifaceted approach, we demonstrated that PKC activates SGLT1, which curbed oxidative stress and apoptosis against I/R injury. PKC activation enhances cardiac glucose uptake through SGLT1 and seems essential in preventing I/R-induced cardiac injury, indicating a possible cross-talk between PKC and SGLT1.
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http://dx.doi.org/10.2147/DDDT.S105482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028101PMC
April 2017

Carrot juice ingestion attenuates high fructose-induced circulatory pro-inflammatory mediators in weanling Wistar rats.

J Sci Food Agric 2017 Mar 25;97(5):1582-1591. Epub 2016 Aug 25.

Lipid Biochemistry Division, National Institute of Nutrition, Jamai Osmania, Hyderabad, 500007, India.

Background: Adipose tissue, an endocrine organ, plays a vital role not only in energy homeostasis, but also in the development and/or progression of various metabolic diseases, such as insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), via several factors and mechanisms, including inflammation. This study tested, whether carrot juice administration affected the adipose tissue development and its inflammatory status in a high fructose diet-induced rat model. For this purpose, male weanling Wistar rats were divided into four groups and fed either control or high fructose diet of AIN-93G composition with or without carrot juice ingestion for an 8 week period.

Results: Administration of carrot juice did not affect the adiposity and cell size of visceral fat depot; retroperitoneal white adipose tissue (RPWAT), which was corroborated with unaltered expression of genes involved in adipogenic and lipogenic pathways. However, it significantly reduced the high fructose diet-induced elevation of plasma free fatty acid (FFA) (P ≤ 0.05), macrophage chemoattractant protein 1 (MCP1) (P ≤ 0.01) and high sensitive C-reactive protein (hsCRP) (P ≤ 0.05) levels.

Conclusion: Carrot juice administration attenuated the high fructose diet-induced elevation of levels of circulatory FFA and pro-inflammatory mediators; MCP1 and hsCRP without affecting the adiposity and cell size of visceral fat depot; RPWAT. © 2016 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.7906DOI Listing
March 2017

Inhibition of SGLT1 abrogates preconditioning-induced cardioprotection against ischemia-reperfusion injury.

Biochem Biophys Res Commun 2016 Apr 23;472(2):392-8. Epub 2016 Feb 23.

Division of Medicinal Chemistry and Pharmacology, Indian Institute of Chemical Technology, Hyderabad, India. Electronic address:

Background: Recently, we reported Na+/glucose co-transporter (SGLT1) expression in mouse and human heart. We speculated that SGLT1 might play an important role in ischemic preconditioning-induced cardioprotection. Therefore, the present study was designed to find the role of SGLT1 in ischemic preconditioning-induced cardioprotection.

Methods: Hearts isolated from SD male rats were subjected to either ischemia-reperfusion injury (I/R) (15 min global ischemia followed by 20 min reperfusion) or ischemic preconditioning (IPC) (3 cycles of 2 min global ischemia separated by 3 min reperfusion) followed by I/R in presence and absence of phlorizin, an SGLT1 inhibitor.

Results: IPC increased membrane SGLT1 expression in rat heart as observed by immunoblotting and immunohistochemistry. Hearts from I/R group showed significant increase in oxidative stress levels and marked myocardial injury as compared to control. We also observed significant increase in apoptotic parameters in I/R heart, as measured by caspase-3 activity, TUNEL positive nuclei and gene expression analysis. Significant improvement in oxidative stress, apoptosis parameters and cardiac injury was observed in I/R hearts when subjected to IPC. However, all beneficial effects of preconditioning were lost when hearts were pre-treated with phlorizin.

Conclusion: Present study indicated that inhibition of SGLT1 by phlorizin abrogated the beneficial effect of ischemic-preconditioning and for the first time, provides evidence that SGLT1 plays a crucial role in ischemic preconditioning-induced cardioprotection.
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http://dx.doi.org/10.1016/j.bbrc.2016.02.016DOI Listing
April 2016

Severe but Not Moderate Vitamin B12 Deficiency Impairs Lipid Profile, Induces Adiposity, and Leads to Adverse Gestational Outcome in Female C57BL/6 Mice.

Front Nutr 2016 22;3. Epub 2016 Jan 22.

Endocrinology and Metabolism Division, National Institute of Nutrition, Indian Council of Medical Research , Hyderabad , India.

Vitamin B12 deficiency is widely prevalent in women of childbearing age, especially in developing countries. In the present study, through dietary restriction, we have established mouse models of severe and moderate vitamin B12 deficiencies to elucidate the impact on body composition, biochemical parameters, and reproductive performance. Female weanling C57BL/6 mice were fed for 4 weeks: (a) control AIN-76A diet, (b) vitamin B12-restricted AIN-76A diet with pectin as dietary fiber (severe deficiency group, as pectin inhibits vitamin B12 absorption), or (c) vitamin B12-restricted AIN-76A diet with cellulose as dietary fiber (moderate deficiency group as cellulose does not interfere with vitamin B12 absorption). After confirming deficiency, the mice were mated with male colony mice and maintained on their respective diets throughout pregnancy, lactation, and thereafter till 12 weeks. Severe vitamin B12 deficiency increased body fat% significantly, induced adiposity and altered lipid profile. Pregnant dams of both the deficient groups developed anemia. Severe vitamin B12 deficiency decreased the percentage of conception and litter size, pups were small-for-gestational-age and had significantly lower body weight at birth as well as weaning. Most of the offspring born to severely deficient dams died within 24 h of birth. Stress markers and adipocytokines were elevated in severe deficiency with concomitant decrease in antioxidant defense. The results show that severe but not moderate vitamin B12 restriction had profound impact on the physiology of C57BL/6 mice. Oxidative and corticosteroid stress, inflammation and poor antioxidant defense seem to be the probable underlying mechanisms mediating the deleterious effects.
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http://dx.doi.org/10.3389/fnut.2016.00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722109PMC
February 2016

Vitamin A deficiency suppresses high fructose-induced triglyceride synthesis and elevates resolvin D1 levels.

Biochim Biophys Acta 2016 Mar 18;1861(3):156-65. Epub 2015 Nov 18.

Lipid Biochemistry Division, National Institute of Nutrition, Jamai Osmania, Hyderabad 500007, India. Electronic address:

Background/aims: Vitamin A and its metabolites are known to regulate lipid metabolism. However so far, no study has assessed, whether vitamin A deficiency per se aggravates or attenuates the development of non-alcoholic fatty liver disease (NAFLD). Therefore, here, we tested the impact of vitamin A deficiency on the development of NAFLD.

Methods: Male weanling Wistar rats were fed one of the following diets; control, vitamin A-deficient (VAD), high fructose (HFr) and VAD with HFr (VADHFr) of AIN93G composition, for 16weeks, except half of the VAD diet-fed rats were shifted to HFr diet (VAD(s)HFr), at the end of 8(th) week.

Results: Animals fed on VAD diet with HFr displayed hypotriglyceridemia (33.5mg/dL) with attenuated hepatic triglyceride accumulation (8.2mg/g), compared with HFr diet (89.5mg/dL and 20.6mg/g respectively). These changes could be partly explained by the decreased activity of glycerol 3-phosphate dehydrogenase (GPDH) and the down-regulation of stearoyl CoA desaturase 1 (SCD1), both at gene and protein levels, the key determinants of triglyceride biosynthesis. On the other hand, n-3 long chain polyunsaturated fatty acid, docosahexaenoic acid and its active metabolite; resolvin D1 (RvD1) levels were elevated in the liver and plasma of VAD diet-fed groups, which was negatively associated with triglyceride levels. All these factors confer vitamin A deficiency-mediated protection against the development of hepatic steatosis, which was also evident from the group shifted from VAD to HFr diet.

Conclusions: Vitamin A deficiency attenuates high fructose-induced hepatic steatosis, by regulating triglyceride synthesis, possibly through GPDH, SCD1 and RvD1.
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http://dx.doi.org/10.1016/j.bbalip.2015.11.005DOI Listing
March 2016

Evaluation of neonatal streptozotocin induced diabetic rat model for the development of cataract.

Oxid Med Cell Longev 2014 19;2014:463264. Epub 2014 Nov 19.

Department of Biochemistry, National Institute of Nutrition, Jamai-Osmania, Hyderabad 500007, India.

Type 2 diabetes (T2D) generally follows prediabetes (PD) conditions such as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Although studies reported an association of IGT or IFG with cataract, the experimental basis for PD associated cataract is not known. Hence, we evaluated neonatal streptozotocin (nSTZ) induced rat model to study PD associated cataractogenesis by injecting STZ to two-day old rats. While majority (70%) of nSTZ injected pups developed IGT (nSTZ-PD) by two months but not cataract even after seven months, remaining (30%) nSTZ rats developed hyperglycemia (nSTZ-D) by two months and mature cataract by seven months. Lens biochemical analysis indicated increased oxidative stress as indicated by increased SOD activity, lipid peroxidation, and protein carbonyl levels in nSTZ-D cataractous lens. There was also increased polyol pathway as assessed by aldose reductase activity and sorbitol levels. Though nSTZ-PD animals have not shown any signs of lenticular opacity, insolubilization of proteins along with enhanced polyol pathway was observed in the lens. Further there was increased oxidative stress in lens of IGT animals. These results suggest that oxidative stress along with increased polyol pathway might play a role in IGT-associated lens abnormalities. In conclusion, nSTZ-PD rat model could aid to investigate IGT-associated lens abnormalities.
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http://dx.doi.org/10.1155/2014/463264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253707PMC
June 2015

Improvement of bioavailability and anti-inflammatory potential of curcumin in combination with emu oil.

Inflammation 2014 Dec;37(6):2139-55

National Institute of Pharmaceutical Education & Research, Balanagar, Hyderabad, 500037, A.P., India.

The purpose of the present study is to evaluate the effect of emu oil on bioavailability of curcumin when co-administered and to evaluate the property that enhances the anti-inflammatory potential of curcumin. Oral bioavailability of curcumin in combination with emu oil was determined by measuring the plasma concentration of curcumin by HPLC. The anti-inflammatory potential was evaluated in carrageenan-induced paw edema model (acute model) and in Freund's complete adjuvant (FCA)-induced arthritis model (chronic model) in male SD rats. The anti-inflammatory potential of curcumin in combination with emu oil has been significantly increased in both acute and chronic inflammatory models as evident from inhibition of increase in paw volume, arthritic score, and expression of pro-inflammatory cytokines. The increased anti-inflammatory activity in combination therapy is due to enhanced bioavailability (5.2-fold compared to aqueous suspension) of curcumin by emu oil. Finally, it is concluded that the combination of emu oil with curcumin will be a promising approach for the treatment of arthritis.
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http://dx.doi.org/10.1007/s10753-014-9948-4DOI Listing
December 2014

Carnosic acid promotes myocardial antioxidant response and prevents isoproterenol-induced myocardial oxidative stress and apoptosis in mice.

Mol Cell Biochem 2014 Sep 6;394(1-2):163-76. Epub 2014 Jun 6.

Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500 007, India.

Unlabelled: Carnosic acid is a well-known antioxidant. Recently, it has been identified as modulator of nuclear factor erythroid 2-related factor 2 (Nrf2). The effect of carnosic acid in the context of cardiovascular disorders has not been studied. In the present study, we investigated the beneficial effect and the underlying cardioprotective mechanism of carnosic acid by using mouse model of isoproterenol (ISO)-induced myocardial stress. Elevated serum levels of Troponin I, CK-MB, LDH, SGOT and SGPT, and myofibrillar degeneration with necrotic damage, and the presence of epicardial inflammatory infiltrate (H & E staining) confirmed the ISO-induced myocardial stress. Myocardial content of vitamin C, reduced glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase,

Nad(p)h: quinine oxidoreductase 1, superoxide dismutase, catalase, nuclear translocation of Nrf2 and protein expression heme oxygenase-1 were evaluated. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and myocardial expression of cleaved caspase-3, caspase-9, p53, Bax, and Bcl-2 were investigated to assess the apoptotic cell death. Pretreatment with carnosic acid attenuated ISO-induced elevated serum levels of Troponin I, CK-MB, LDH, SGOT and SGPT, and histopathological alterations in heart. Moreover, carnosic acid enhanced the nuclear translocation of Nrf2 and up-regulated the phase II/antioxidant enzyme activities. Furthermore, TUNEL assay and apoptosis-related protein analysis indicated that carnosic acid prevented ISO-induced cardiomyocyte apoptosis. Isoproterenol-induced myocardial lipid peroxidation and protein oxidation were also significantly decreased by carnosic acid pretreatment. The overall results clearly indicate that therapeutic application of carnosic acid might be beneficial in treating cardiovascular disorders.
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http://dx.doi.org/10.1007/s11010-014-2092-5DOI Listing
September 2014

Cardioprotective effect of ritonavir, an antiviral drug, in isoproterenol induced myocardial necrosis: a new therapeutic implication.

J Transl Med 2013 Mar 26;11:80. Epub 2013 Mar 26.

Division of Medicinal Chemistry and Pharmacology, Indian Institute of Chemical Technology (IICT), Hyderabad, India.

Background: Ritonavir is a HIV protease inhibitor. In addition to its antiviral effect, Ritonavir directly inhibits the insulin-regulated glucose transporter GLUT4 and blocks glucose entry into fat and muscle cells. However, the effect of Ritonavir on cardiac GLUT4 inhibition during myocardial necrosis is not investigated. In the present study, we evaluated the role of Ritonavir in isoproterenol-induced myocardial necrosis in vivo and compared the effect with Phlorizin, a nonslective SGLTs inhibitor.

Methods: Isoproterenol (ISO) (150 mg/kg/day, i.p for 2 consecutive days) was administered to mice to cause myocardial necrosis. Phlorizin (400 mg/kg/day i.p twice daily for 2 days) and Ritonavir (10 mg/kg/day i.p twice daily for 2 days) were administered in two different groups of mice before isoproterenol administration.

Results And Discussion: Isoproterenol (ISO) (150 mg/kg/day, i.p for 2 consecutive days) administration caused significant (p < 0.05) increase in heart/body weight ratio, and myocardial necrosis as evident by significant (p < 0.05) increase in serum markers i.e. SGOT and CK; and cardiac histopathological changes. Significant (p < 0.05) reduction in myocardial SOD and catalase activities, and GSH level along with a significant (p < 0.05) rise in myocardial TBARS and nitric oxide levels were observed after ISO administration. However, administration of phlorizin, a SGLT1 inhibitor has been found to exhibit partial protection in ISO induced myocardial necrosis, as observed by significant decrease in heart/body weight ratio and myocardial nitric oxide level; significant increase in myocardial SOD and catalase activities along with no histopathological alterations. On the other hand, administration of ritonavir, a nonspecific GLUT inhibitor has been found to exhibit complete protection as observed by normalisation of heart/body weight ratio, serum markers, antioxidant enzymes activities and histopathological alterations. In vitro study with heart homogenate confirmed no antioxidant effect of ritonavir and phlorizin in the absence and presence of isoproterenol.

Conclusions: Our study concluded that ritonavir, a nonspecific GLUT inhibitors showed complete protection in catecholamine induced myocardial necrosis.
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http://dx.doi.org/10.1186/1479-5876-11-80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623744PMC
March 2013

Effect of metformin against cisplatin induced acute renal injury in rats: a biochemical and histoarchitectural evaluation.

Exp Toxicol Pathol 2013 Sep 8;65(6):933-40. Epub 2013 Feb 8.

Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India.

Although cisplatin has been a mainstay for cancer therapy, its use is limited mainly because of nephrotoxicity. Accumulating literature suggest the antioxidant and cytoprotective effect of metformin, a first line antidiabetic drug. With this background, we investigated the effect of metformin on the cisplatin induced nephrotoxicity in rats. A single injection of cisplatin (7.5 mg/kg, i.p.) caused marked renal damage, characterized by a significant increase in blood urea nitrogen (BUN), serum creatinine (Cr) and abnormal histo-architecture of kidney. These were accompanied by significant elevation of malondialdehyde (MDA), total reactive oxygen species (tROS) and caspase-3 levels and decreased antioxidant levels. Metformin treatment significantly attenuated the increase in malondialdehyde and tROS generation and restores the decrease in both enzymatic and non-enzymatic antioxidants. However metformin treatment did not prevent the cisplatin induced renal injury as there was no significant difference of renal function parameters (BUN and Cr), kidney histopathology as well as caspase-3 activity between cisplatin per se and metformin plus cisplatin treated rats. Histopathology studies revealed that similar glomerular and tubular pathological architecture in both cisplatin per se and cisplatin plus metformin group. In conclusion, the present study demonstrated that metformin is not an adjuvant drug to treat nephrotoxicity associated with cisplatin therapy.
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http://dx.doi.org/10.1016/j.etp.2013.01.007DOI Listing
September 2013

Carbenoxolone treatment ameliorated metabolic syndrome in WNIN/Ob obese rats, but induced severe fat loss and glucose intolerance in lean rats.

PLoS One 2012 17;7(12):e50216. Epub 2012 Dec 17.

Department of Biochemistry, National Institute of Nutrition, Indian Council of Medical Research, Jamai Osmania PO, Hyderabad, Andhra Pradesh, India.

Background: 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11β-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11β-HSD inhibitor, carbenoxolone (CBX) on obesity and associated comorbidities in obese rats of WNIN/Ob strain, a new animal model for genetic obesity.

Methodology/principal Findings: Subcutaneous injection of CBX (50 mg/kg body weight) or volume-matched vehicle was given once daily for four weeks to three month-old WNIN/Ob lean and obese rats (n = 6 for each phenotype and for each treatment). Body composition, plasma lipids and hormones were assayed. Hepatic steatosis, adipose tissue morphology, inflammation and fibrosis were also studied. Insulin resistance and glucose intolerance were determined along with tissue glycogen content. Gene expressions were determined in liver and adipose tissue. CBX significantly inhibited 11β-HSD1 activity in liver and adipose tissue of WNIN/Ob lean and obese rats. CBX significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia, insulin resistance in obese rats. CBX ameliorated hepatic steatosis, adipocyte hypertrophy, adipose tissue inflammation and fibrosis in obese rats. Tissue glycogen content was significantly decreased by CBX in liver and adipose tissue of obese rats. Severe fat loss and glucose- intolerance were observed in lean rats after CBX treatment.

Conclusions/significance: We conclude that 11β-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11β-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11β-HSD1 inhibition may lead to insulin resistance in normal conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050216PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524236PMC
June 2013

Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity.

Food Chem Toxicol 2011 Dec 6;49(12):3090-7. Epub 2011 Sep 6.

National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, India.

Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5mg/kg) caused marked renal damage, characterized by a significant (P<0.05) increase in serum creatinine, blood urea nitrogen (BUN) and relative weight of kidney with higher kidney MDA (malondialdehyde), tROS (total reactive oxygen species), caspase 3, GSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (P<0.05) attenuated the increase in lipid peroxidation, caspase-3 and ROS generation and enhanced the levels of reduced glutathione, tissue nitrite level and activities of SOD, CAT, GSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties.
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http://dx.doi.org/10.1016/j.fct.2011.08.018DOI Listing
December 2011

Nitric oxide synthase inhibition abrogates hydrogen sulfide-induced cardioprotection in mice.

Mol Cell Biochem 2012 Jan 31;360(1-2):61-9. Epub 2011 Aug 31.

Division of Pharmacology and Chemical Biology, Indian Institute of Chemical Technology, Hyderabad, India.

The cardioprotective property of hydrogen sulfide (H(2)S) is recently reported. However, cellular signaling cascades mediated by H(2)S are largely unclear. This study was undertaken to explore the molecular mechanism of H(2)S-induced cardioprotection in mouse heart by utilizing in vivo model of cardiac injury. We report here that intraperitoneal administration of sodium hydrogen sulfide (NaHS, 50 μmol kg(-1 )day(-1) for 2 days), a H(2)S donor, significantly (P ≤ 0.05) increased nitric oxide levels in serum as well as myocardium without any sign of myocardial injury. Typical characteristics of myocardial injury induced by isoproterenol (ISO) administration was significantly (P ≤ 0.05) abrogated by NaHS administration as evidenced from reduction in elevated thiobarbituric acid reactive substances (TBARS) and normalization of glutathione (GSH), glutathione peroxidase, superoxide dismutase (SOD), and catalase activity. Further, decrease in TNF-α expression and improvement in myocardial architecture was also observed. However, co-administration of N-nitro-L-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor, and Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor along with NaHS and ISO abrogated the beneficial effect of H(2)S differentially. Inhibition of NOS significantly (P ≤ 0.05) increased serum creatine kinase, lactate dehydrogenase, serum glutamic oxaloacetic transaminase activity and myocardial TBARS, along with significant (P ≤ 0.05) reduction of myocardial GSH, SOD, and catalase. This was followed by increase in TNF-α expression and histopathological changes. Our results revealed that H(2)S provides myocardial protection through interaction with NOS and COX-2 pathway and inhibition of NOS completely abrogates the hydrogen sulfide-induced cardioprotection in mice.
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http://dx.doi.org/10.1007/s11010-011-1044-6DOI Listing
January 2012
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