Publications by authors named "Thirunavukkarasu Chinnasamy"

34 Publications

Targeting molecular signal transduction pathways in hepatocellular carcinoma and its implications for cancer therapy.

Cell Biol Int 2021 Jul 16. Epub 2021 Jul 16.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, 605 014, India.

Hepatocellular carcinoma is a substantial health concern. It is currently the third dominating cause of mortality associated with cancer worldwide. The development of hepatocellular carcinoma is an intricate process that encompasses the impairment of genetic, epigenetic, and signal transduction mechanisms contributing to an aberrant metabolic system, enabling tumorigenesis. Throughout the past decade, research has led to the revelation of molecular pathways implicated in the progression of this notorious disorder. The altered signal transduction pathways, such as the MAPK pathway, PI3K/AKT/mTOR pathway, WNT/β-catenin pathway, hepatocyte growth factor/c-MET pathway, and JAK/STAT signaling pathway is of much therapeutic significance, as targeting them may avail to revert, retard or avert hepatocarcinogenesis. The present review article sums up the contemporary knowledge of such signaling mechanisms, including their therapeutic targets and betokens that novel and efficacious therapies can be developed only by the keen understanding of their character in hepatocarcinogenesis. In additament, we address the role of consequential therapeutic agents and preclinical non-drug therapies known for combating hepatocarcinogenesis. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/cbin.11670DOI Listing
July 2021

Prevalence of microplastics in the sediments of Odisha beaches, southeastern coast of India.

Mar Pollut Bull 2021 Jun 29;167:112265. Epub 2021 Mar 29.

Departmentof Ecology and Environmental Sciences, Pondicherry University, 605014, India; School of Environmental Studies, Cochin University of Science and Technology, 682022, India. Electronic address:

The prevalence of microplastics along the coastal habitats has become a global concern owing to the increased input of plastic debris from multiple sources. The present study is the first of its kind to examine the prevalence and distribution of microplastics in Odisha coast. The average microplastic abundance in the nine stations along Odisha coastal beach is 258.7 ± 90.0 particles/kg of beach sediment. Among the stations sampled, Swargadwara was reported with the highest microplastic abundance of 378.3 ± 39.7 particles/kg of beach sediment andAbhayachandpurwas found with the lowest number of 153.3 ± 27.3 particles/kg. Different types of microplastics varying in color, size, and shape were encountered in the study. From the Raman spectroscopic analysis, twelve types of polymers including High Density Polyethylene, Polystyrene, Polyvinyl chloride, and acrylonitrile copolymer were identified.
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http://dx.doi.org/10.1016/j.marpolbul.2021.112265DOI Listing
June 2021

Prevalence and characteristics of microplastics present in the street dust collected from Chennai metropolitan city, India.

Chemosphere 2021 Apr 27;269:128757. Epub 2020 Oct 27.

Departmentof Ecology and Environmental Sciences, Pondicherry University, 605014, India; School of Environmental Studies, Cochin University of Science and Technology, 682022, India. Electronic address:

In the present study, we assessed the extent of microplastic pollution in the road dust of Chennai, the fifth largest metropolitan city in India. This study is the first of its kind to be reported from India. Sixteen different locations were selected from which road dust samples were collected. The average microplastic abundance was estimated to be 227.94 ± 91.37 per hundred grams of street dust sample. Nile Red dye was used for microplastic identification and quantification. 92.46% of the quantified microplastics were fragments. Raman spectroscopy of a representative sample identified nine types of polymers viz. polyvinyl chloride, poly(ethylene-co-vinyl-acetate), HDPE, poly(tetrafluoroethylene), cellulose microcrystalline, lyocell, superflex-200, wax-1032, and AC-395. SEM-EDS analysis highlighted the presence of various trace elements pertaining to automobile exhausts. Assessment of microplastic pollution rampant in street dust, especially in coastal cities as Chennai, is a dire need as it pertains to the concerns of human health and escape into the marine environment.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128757DOI Listing
April 2021

Quantification of microplastics using Nile Red in two bivalve species Perna viridis and Meretrix meretrix from three estuaries in Pondicherry, India and microplastic uptake by local communities through bivalve diet.

Mar Pollut Bull 2020 Apr 28;153:110982. Epub 2020 Feb 28.

Department of Ecology and Environmental Sciences, Pondicherry University, 605014, India; School of Environmental Studies, Cochin University of Science and Technology, 682022, India. Electronic address:

Microplastics ingested by two bivalve species Perna viridis and Meretrix meretrix collected from three estuaries viz. Ariyankuppam, Panithittu, and Chunnambar in Pondicherry, India was analysed for the first time in this research. Nile Red dye was used for microplastic detection. A survey of 50 local families was conducted to determine the frequency and quantity in which they consume mussels/clams. On an average, the number of microplastics per gram of soft tissue (wet weight) is 0.18 ± 0.04, 1.84 ± 0.61, and 1.76 ± 0.48; and the number of microplastics per bivalve is 0.50 ± 0.11, 1.75 ± 0.35, and 4.80 ± 1.39 respectively for Ariyankuppam, Panithittu, and Chunnambar. 61.02% and 77.42% of the particles belonged to the size group of <100 μm in M. meretrix and P. viridis respectively. A moderate positive correlation of r (18) = 0.6985, p < 0.05 was calculated between bivalve weight and microplastic particles. An average person belonging to the local community is likely to ingest 3917.79 ± 144.71 microplastic particles per year through mussel consumption.
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http://dx.doi.org/10.1016/j.marpolbul.2020.110982DOI Listing
April 2020

Curcuma longa and Trigonella foenum graecum-enriched nutrient mixture from germinated Macrotyloma uniflorum and Vigna radiate ameliorate nonalcoholic fatty liver diseases in rats.

J Food Biochem 2020 04 3;44(4):e13159. Epub 2020 Feb 3.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India.

The prevalence of nonalcoholic fatty liver is increasing due to modern lifestyle. Germinated and dehulled Macrotyloma uniflorum and Vigna radiate were shown to have enhanced nutrients. Curcuma longa and Trigonella foenum graecum were proven hepatoprotective.The supplementation of the nutrient herbal mixture to the MCD diet-induced steatosis shows reduced hepatic fat accumulation and lipid profile, and liver injury markers in serum also reserved in normal. Increased serum albumin in the treatment group indicates that the liver function is enhanced than that of steatosis. The supplementation of the herbal mixture has preserved the hepatic antioxidant. Zymographic analysis of matrix metalloproteinase, western blot determination of α-SMA, and histological evolution (H&E, Sirius red) depicted reduced fibrosis and reveled management of hepatic stellate cells in quiescent form. The present study concludes that the herbal mixture has reduced hepatocyte fat accumulation in steatotic animals, and curtailed the oxidative stress, further it prevents the progression of steatohepatitis. PRACTICAL APPLICATIONS: Fatty liver diseases can be treated by modulating the diet composition such as consuming food rich in the nutrient herbal mixture. In this study, the nutrient mixture was made with dynamic food processing techniques such as germination, dehulling, and milling to augment the nutritional contents. Besides, Macrotyloma uniflorum, Vigna radiate, Curcuma longa, and Trigonella foenum graecum were used to improve the medicinal value and antioxidant. This formulation could target the various stages of NAFLD. This study revealed that the nutrient herbal mixture reduces the steatosis of the liver and curtailed the progression of steatohepatitis from hepatic steatosis. Since the edible foodstuff was used to make the nutrient mixture, it has excellent clinical application.
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http://dx.doi.org/10.1111/jfbc.13159DOI Listing
April 2020

Nutrient mixture from germinated legumes: Enhanced medicinal value with herbs-attenuated liver cirrhosis.

J Food Biochem 2020 01 23;44(1):e13085. Epub 2019 Oct 23.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India.

Among various food processing strategies, germination and dehulling enhance the nutritional content of the food, and the addition of herbs to this could improve the medicinal value. The milled powders of germinated Macrotyloma uniflorum (horse gram) and Vigna radiata (green gram) were used to make the nutrient mixture. Further, Curcuma longa (turmeric) and Trigonella foenum graecum (fenugreek) were used to improve its medicinal value. The prepared nutrient mixture has high nutritional value, antioxidant potential, and reduced antinutrient factors. Supplementation of nutrient mixture reduced oxidative stress-mediated hepatocyte injury on the CCl -induced liver cirrhosis model. Further, histological examination (H&E and Sirius red), matrix metalloproteinase gelatin zymography, and Western blot revealed the management of hepatic stellate cells in an inactive stage thereby reduced cirrhosis. These findings conclude that the supplementation of nutrient mixture formulation protected and effectively prevented liver cirrhosis. PRACTICAL APPLICATIONS: This study has a good impact on nutritional therapy for liver diseases. Many of the chronic liver diseases are associated with severe malnutrition and hypoalbuminemia, which further worsens the condition. This study would emphasize the nutritional therapy to treat such imbalance and enriching the medicinal value of nutrition mixture with herbs could target different pathophysiological changes and provide better defense in liver disease patients. Since this nutrient mixture is from common edible natural resources, it could reach the pharmaceutical industry's attention to the highest production and marketing.
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http://dx.doi.org/10.1111/jfbc.13085DOI Listing
January 2020

Chemotherapeutic doses of arsenic trioxide delays hepatic regeneration by oxidative stress and hepatocyte apoptosis in partial hepatectomy rat.

Toxicol Appl Pharmacol 2019 11 13;382:114760. Epub 2019 Sep 13.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India. Electronic address:

The extensive regeneration potential of the liver makes use of hepatic re-sectioning and split liver transplantation for treating advanced liver diseases. Heavy metals such as cisplatin, carboplatin, and arsenic trioxide (ATO) are being practiced as chemotherapeutic agents for different cancers. Further, research is progressed on using different heavy metal nano-particles as a drug, drug carrier and diseases detective agent. Since liver is the chief organ metabolize ingested materials, the current study focuses on the involvement of ATO on acute liver injury regeneration using a partially hepatectomised (PHx) rat model. Scrutiny of serum liver markers such as albumin, AST, ALT & ALP and hepatic antioxidants like reduced glutathione, glutathione peroxidase, glutathione S-transferase, catalase & superoxide dismutase reveled ATO mediated hepatocyte injury and oxidative stress. Further, oxidative stress is confirmed with elevated TBARS and 8-OHdG in the hepatocyte nucleus in ATO supplemented healthy and regenerating liver and are co-relating with the H&E histological observations. It is noticed that ATO supplementation reduced liver regeneration potential as evidenced by reduced proliferative markers (Ki-67 and PCNA) and meanwhile increases apoptotic protein PARP-1. ICP-MS analysis displayed several-fold hiked serum and liver arsenic in ATO administrated normal and liver regenerating animals. This study concludes that ATO at a chemotherapeutic concentration augments oxidative stress and hepatocytes apoptosis, thereby delays liver regeneration potential and could affect the outcome of liver transplantation.
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http://dx.doi.org/10.1016/j.taap.2019.114760DOI Listing
November 2019

Arsenic trioxide, a cancer chemo drug hampers fibrotic liver regeneration by interrupting oxidative stress rekindling and stellate cell rejuvenation.

J Cell Physiol 2020 02 4;235(2):1222-1234. Epub 2019 Jul 4.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India.

After withdrawal of liver toxic insult, the spontaneous regenerative potential of the liver is well reported in the literature. On the other hand, various molecules have been reported to promote as well as delay such natural regeneration. This current study investigates the involvement of arsenic trioxide (ATO) medication at chemotherapeutic dose on the spontaneous regeneration of the CCl induced fibrotic liver. Liver injury markers, such as albumin and SGOT, SGPT, and ALP activities, in serum indicated that ATO supplementation during liver regeneration hampers the rejuvenation process. The hepatic architecture as well as the degree of fibrosis by hematoxylin and eosin and Sirius red staining confirms the above findings. The reduced hepatic antioxidant system and elevated oxidative stress markers, such as lipid peroxidation and 8-hydroxy deoxy-guanosine-positive hepatocytes in ATO supplied rats, display the persistence of oxidative stress when compared with healthy controls and the normal regeneration model. Immuno-histochemical localization of Ki-67 indicates that mitotically active hepatocytes were fewer in the ATO given rats when compared with normal regeneration rats. Further delay in hepatic fibrinolysis was monitored by matrix metalloproteinase zymography assay in the ATO-given animals. Poly(ADP-ribose) polymerase 1 expression demonstrates elevated hepatocyte apoptosis with ATO. Furthermore, increased α-smooth muscle actin indicates that the stellate cells are in an activated state in ATO supplemented fibrotic animals. In conclusion, it's observed that ATO supplementation to the fibrotic liver delays oxidative stress revitalization and maintains stellate cells in the active form, thereby delaying liver regeneration, and the health status of the liver must be taken into account before administering drugs like ATO.
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http://dx.doi.org/10.1002/jcp.29037DOI Listing
February 2020

Augmenter of liver regeneration enhances cell proliferation through the microRNA-26a/Akt/cyclin D1 pathway in hepatic cells.

Hepatol Res 2019 Nov 25;49(11):1341-1352. Epub 2019 Jul 25.

Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri, New Delhi, India.

Aim: Hepatocytes can proliferate and regenerate when injured by toxins, viral infections, and so on. Augmenter of liver regeneration (ALR) is a key regulator of liver regeneration, but the mechanism is unknown. The role of ALR in other cell types is not known. In the present study, we investigated the relationship between microRNA (miRNA)-26a and ALR in the Huh7 cell line and adipose tissue-derived mesenchymal cells from chronic liver disease patients and healthy individuals.

Methods: Huh7 cells were transfected independently with ALR and miRNA-26a expression vectors, and their effects on cell proliferation, the expression of miRNA-26a, and activation of the phosphatase and tensin homolog and Akt signaling pathways were determined. The experiments were repeated on mesenchymal stem cells derived from healthy individuals and chronic liver disease patients to see whether the observations can be replicated in primary cells.

Results: Overexpression of ALR or miRNA-26a resulted in an increase of the phosphorylation of Akt and cyclin D1 expression, whereas it resulted in decreased levels of p-GSK-3β and phosphatase and tensin homolog in Huh7 cells. The inhibition of ALR expression by ALR siRNA or anti-miR-26a decreased the Akt/cyclin D1 signaling pathway, leading to decreased proliferation. Mesenchymal stem cells isolated from the chronic liver disease patients had a higher ALR expression, while the mesenchymal stem cells isolated from healthy volunteers responded to the growth factor treatments for increased ALR expression. It was found that there was a significant increase in miRNA-26a expression and proliferation.

Conclusions: These data clearly showed that ALR induced the expression of miRNA-26a, which downregulated phosphatase and tensin homolog, resulting in an increased p-Akt/cyclin D1 pathway and enhanced proliferation in hepatic cells.
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http://dx.doi.org/10.1111/hepr.13404DOI Listing
November 2019

Butein protects the nonalcoholic fatty liver through mitochondrial reactive oxygen species attenuation in rats.

Biofactors 2018 May 19;44(3):289-298. Epub 2018 Apr 19.

Adipocytes and Metabolic Disorders Lab, Food Science and Nutrition Department, King Saud University, Riyadh, 11451, Saudi Arabia.

One of the worldwide metabolic health dilemma is nonalcoholic fatty liver diseases (NAFLD). Researchers are searching effective drug to manage NAFLD patients. One of the best way to manage the metabolic imperfection is through natural principal isolated from different sources. Butein, a natural compound known to have numerous pharmacological application. In the current study we assessed the therapeutic effect of butein administration on liver function tests, oxidative stress, antioxidants, lipid abnormalities, serum inflammatory cytokines, and mitochondrial reactive oxygen species levels, in rats with methionine-choline deficient (MCD) diet induced NAFLD. Male Wistar rats were treated with MCD diet with/without butein (200 mg/kg body wt. orally) for 6 weeks. The protective effect of butein, were evident from decreased transaminase activities, restoration of albumin, globulin, albumin/globulin ratio, and oxidants in serum (P < 0.01), further it improved liver antioxidant status (P < 0.01). Butein significantly lowered lipid profile parameters (P < 0.01), suppressed inflammatory cytokines (P < 0.01), and improved liver histology. Further to understand the possible mechanism behind the hepatoprotective and lipid lowering effect of butein, the activities of heme oxygenase (HO1), myeloperoxidase (MPO), and mitochondrial reactive oxygen species (ROS) were measured. We found that butein supplementation significantly decreased the activity of HO1 (P < 0.001), and increased the activity of MPO (P < 0.001). Furthermore butein attenuated mitochondrial ROS produced in NAFLD condition. Present study shows that butein supplementation restore liver function by altering liver oxidative stress, inflammatory markers, vital defensive enzyme activities, and mitochondrial ROS. In summary, butein has remarkable potential to develop effective hepato-protective drug. © 2018 BioFactors, 44(3):289-298, 2018.
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http://dx.doi.org/10.1002/biof.1428DOI Listing
May 2018

Unveiling anticancer potential of glibenclamide: Its synergistic cytotoxicity with doxorubicin on cancer cells.

J Pharm Biomed Anal 2018 May 14;154:294-301. Epub 2018 Mar 14.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India. Electronic address:

Drug repurposing has been an emerging therapeutic strategy, which involves exploration of a new therapeutic approach for the use of an existing drug. Glibenclamide (Gli) is an anti-diabetic sulfonylurea drug extensively used for the treatment of type-2 diabetes, it has also been shown to possess anti-proliferative effect against several types of tumors. The present study was executed to understand the mechanisms underlying the interaction of Gli with DNA under physiological conditions. The binding mechanism of Gli with DNA was scrutinized by UV-vis absorption spectroscopy and fluorescence emission spectroscopy. The conformational changes and electrochemical properties were analyzed by circular dichroism spectroscopy and cyclic voltammetry. Isothermal titration calorimetry was employed to examine the thermodynamic changes and molecular docking technique used to analyze the interaction mode of Gli with DNA. The spectroscopic studies revealed that Gli interacts with DNA through groove binding mode. Further, isothermal titration calorimetry depicted a stronger mode of interaction favorably groove-binding. Recently, systemic combination therapy has shown significant promise in inhibiting multiple targets simultaneously yielding high therapeutic competence with lesser side effects. With this concern, we intended to study the combined cytotoxicity of Gli with doxorubicin (Dox). The results of MTT assay and acridine orange (AO)/ethidium bromide (EtBr) staining showed synergistic cytotoxicity of Gli + Dox combination on HepG2 & A549 cells. The present study documents the intricate mechanism of Gli-DNA interaction and delivers a multifaceted access for chemotherapy by Gli + Dox combination.
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http://dx.doi.org/10.1016/j.jpba.2018.03.025DOI Listing
May 2018

Synthesis and characterisation of arsenic nanoparticles and its interaction with DNA and cytotoxic potential on breast cancer cells.

Chem Biol Interact 2018 Nov 22;295:73-83. Epub 2017 Dec 22.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India. Electronic address:

Therapeutic applications of arsenic trioxide (ATO) are limited due to their severe adverse effects. However, nanoparticles of ATO might possess inimitable biologic effects based on their structure and size which differ from their parent molecules. Based on this conception, AsNPs were synthesized from ATO and comparatively analysed for their interaction mechanism with DNA using spectroscopic & electrochemical techniques. Finally, anti-proliferative activity was assessed against different breast cancer cells (MDA-MB-231 & MCF-7) and normal non-cancerous cells (HEK-293). The DNA interaction study revealed that AsNPs and ATO exhibit binding constant values in the order of 10 which indicates strong binding interaction. Binding of AsNPs did not disturb the structural integrity of DNA, on the other hand an opposing effect was observed with ATO through biophysical techniques. Further, in vitro study, confirms cytotoxicity of ATO and AsNPs against different cells, however at particular concentration ATO exhibits more cytotoxicity than that of AsNPs. Furthermore, cytotoxicity was confirmed through acridine orange and comet assay. In conclusion, AsNPs are safer than ATO with comparable efficacy and might be a suitable candidate for the development of novel therapeutic agent against breast cancer and other solid tumours.
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http://dx.doi.org/10.1016/j.cbi.2017.12.025DOI Listing
November 2018

Nimbolide attenuate the lipid accumulation, oxidative stress and antioxidant in primary hepatocytes.

Mol Biol Rep 2017 Dec 28;44(6):463-474. Epub 2017 Nov 28.

Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, P.O. Box 2460, Riyadh, 11451, Saudi Arabia.

Nimbolide is a bioactive compound found in Azadirachta indica. This work was devised to investigate the potential effects of nimbolide on intracellular lipid deposition and its associated redox modulation in primary hepatocytes (Heps). Lipid accumulation was induced in Heps by supplementing 1 mM oleic acid for 24 h which was marked by significant accumulation of lipids. The results demonstrated that nimbolide can decrease intracellular cholesterol, free fatty acids and triglycerides. Nimbolide may also improve hepatocytes function through its antioxidant effects by inhibiting oxidative DNA damage and lipid peroxidation by curtailing the reactive oxygen species levels. Further it also restore the mitochondrial potential, improving the endogenous antioxidant levels such as GSH and antioxidant enzyme activities. Nimbolide increased (P < 0.05) liver X receptor-α (LXRα), peroxisome proliferator-activated receptor-γ (PPARγ) and sterol regulatory element-binding protein-1c (SREBP1c) gene expression in Heps. The biological significance of nimbolide may involve hypolipidemic effect, lipid peroxidation inhibition, DNA damage inhibition, ROS inhibition, restoring mitochondrial function, increases in GSH and SOD & CAT activities, and direct regulation of LXRα, PPARγ and SREBP1c gene expression. Nimbolide may be used as effective lipid lowering compound and lipid deposition-induced Heps changes.
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http://dx.doi.org/10.1007/s11033-017-4132-1DOI Listing
December 2017

Anticancer potential of ZnO nanoparticle-ferulic acid conjugate on Huh-7 and HepG2 cells and diethyl nitrosamine induced hepatocellular cancer on Wistar albino rat.

Nanomedicine 2018 02 21;14(2):415-428. Epub 2017 Nov 21.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India. Electronic address:

Drawbacks and limitations of recently available therapies to hepatocellular cancer (HCC) devoted the scientist to focus on emerging new strategies. ZnO nanoparticles (ZnONPs) based chemotherapeutics has been emanating as a promising approach to maximize therapeutic synergy facilitating the discovery of novel multitargeted combinations. In the present study we conjugated ZnONPs with ferulic acid (ZnONPs-FAC) characterized by computational, spectroscopic and microscopic techniques. In vitro anticancer potential has been evaluated by assessing cell viability, morphology, ROS generation, mitochondrial membrane permeability, comet assay, immunofluorescent staining of 8-OHdG, Ki67 and γ-H2AX, cell cycle analysis and western blot analysis and in vivo anticancer potential against DEN induced HCC was analyzed by histopathological and immunohistochemical methods. The results revealed that ZnONPs-FAC induces cell death through apoptosis and can suppress the DEN-induced HCC. Our study documents therapeutic potential of nanoparticle conjugated with phytochemicals, suggesting a new platform for combinatorial chemotherapy.
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http://dx.doi.org/10.1016/j.nano.2017.11.003DOI Listing
February 2018

Neutrophil extracellular traps in acrolein promoted hepatic ischemia reperfusion injury: Therapeutic potential of NOX2 and p38MAPK inhibitors.

J Cell Physiol 2018 04 28;233(4):3244-3261. Epub 2017 Sep 28.

Department of Biochemistry and Molecular Biology, School of life sciences, Pondicherry University, Pondicherry, India.

Neutrophil is a significant contributor to ischemia reperfusion (IR) induced liver tissue damage. However, the exact role of neutrophils in IR induced innate immune activation and liver damage is not quite clear. Our study sheds light on the role of chronic oxidative stress end products in worsening the IR inflammatory process by neutrophil recruitment and activation following liver surgery. We employed specific inhibitors for molecular targets-NOX2 (NADPH oxidase 2) and P38 MAPK (Mitogen activated protein kinase) signal to counteract neutrophil activation and neutrophil extracellular trap (NET) release induced liver damage in IR injury. We found that acrolein initiated neutrophil chemotaxis and induced NET release both in vitro and in vivo. Acrolein exposure caused NET induced nuclear and mitochondrial damage in HepG2 cells as well as aggravated the IR injury in rat liver. Pretreatment with F-apocynin and naringin, efficiently suppressed acrolein induced NET release in vitro. Notably, it suppressed the expression of inflammatory cytokines, P38MAPK-ERK activation, and apoptotic signals in rat liver exposed to acrolein and subjected to IR. Moreover, this combination effectively attenuated acrolein induced NET release and hepatic IR injury. In the current study we have shown that the acrolein accumulation in liver due to chronic stress, is responsible for neutrophil recruitment and its activation leading to NET induced liver damage during surgery. Our study shows that therapeutic targeting of NOX2 and P38MAPK signaling in patients with chronic hepatic disorders would improve post operative hepatic function and survival.
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http://dx.doi.org/10.1002/jcp.26167DOI Listing
April 2018

Troxerutin with copper generates oxidative stress in cancer cells: Its possible chemotherapeutic mechanism against hepatocellular carcinoma.

J Cell Physiol 2018 Mar 3;233(3):1775-1790. Epub 2017 Aug 3.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India.

Troxerutin (TXER) a rutin derivative is known for its anticancer effect against hepatocellular carcinoma (HCC). As part of large study, recently we have shown TXER interact with genetic material and its anti-mutagenic property. In the present study we have explored its possible mode of action in HCC. Since TXER alone did not show significant anticancer effect on Huh-7 cells, in vitro biochemical assays were performed for determining anticancer efficacy of TXER + metal complex using transition metals such as Cu, Zn, and Fe. The anticancer efficacy of TXER + Cu on Huh-7 cells were evaluated using MTT assay, DCFDA, JC-1 staining, comet assay, cell cycle analysis, immunocytochemistry, and Western blotting. Non-toxic nature of TXER was analyzed on primary rat hepatocytes. The in vivo efficacy of TXER was tested in N-nitrosodiethylamine initiated and γ-benzene hexachloride and partial hepatectomy promoted rat liver cancer. Liver markers, transition metal levels, histopathological examination, and expression levels of GST-P, 8-OHdG and Ki-67 were studied to assess the in vivo anticancer effect of TXER. We observed that TXER + Cu induced extensive cellular death on Huh-7 cells through generating free radicals and did not possess any toxic effect on normal hepatocytes. The in vivo studies revealed that TXER possess significant anti-cancer effect as assessed through improved liver markers and suppressed GST-P, 8-OHdG, and Ki-67 expression. TXER treatment reduced the hepatic Cu level in cancer bearing animals. Current study brings the putative mechanism involved in anti-cancer effect of TXER, further it will help to formulate phytoconstituents coupled anti-cancer drug for effective treatment of HCC.
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http://dx.doi.org/10.1002/jcp.26061DOI Listing
March 2018

2-Hydroxy-4-methoxy benzoic acid attenuates the carbon tetra chloride-induced hepatotoxicity and its lipid abnormalities in rats via anti-inflammatory and antioxidant mechanism.

Inflamm Res 2017 Sep 30;66(9):753-763. Epub 2017 May 30.

Adipocytes and Metabolic Disorders Lab, Food Science and Nutrition Department, King Saud University, Riyadh, Saudi Arabia.

Background And Aim: Liver inflammation stimulates various inflammatory cytokines and initiates injury through oxidative stress. The aim of this study was to curtaile the liver injury through natural principles such as 2-hydroxy-4-methoxy benzoic acid (HMBA).

Methods: The current study examines the hepatoprotective and lipid lowering effect of HMBA against carbon tetra chloride (CCl)-mediated liver toxicity in male Wistar rats.

Results: The hepatoprotective effects of HMBA against CCl-induced liver damage, were evident from low serum transaminases activities, reduced hepatic lipid peroxidation and collagen content, restoration of total glutathione, and recouping of the inflammatory cytokines, such as TNF-α, IL-1β, IL-10, and IL-6 levels. Further it was found that the treatment of HMBA, significantly lowered (P<0.01) the levels of total cholesterol, triglycerides, free fatty acids and phospholipids in serum and liver. To investigate the mechanism behind the hepatoprotective and lipid lowering effect, the activities of heme oxygenase (HO1), and myeloperoxidase (MPO) were measured and expression levels were quantified through western blot following HMBA administration. The results showed that HMBA administration significantly decreased the activity of HO1 (P<0.001), and increased the activity of MPO (P<0.001); further similar finding was observed in western analysis. The hepatoprotective, lipid lowering and shifting key defensive enzyme activities are similar to that of standard drug such as N-acetylcysteine.

Conclusion: HMBA is competent of shielding liver from CCl-induced hepatotoxicity, and this is associated with the lipid lowering, inflammatory cytokine restoration and induction of defensive enzyme activities.
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http://dx.doi.org/10.1007/s00011-017-1054-2DOI Listing
September 2017

Selenium nanoparticles synthesized in aqueous extract of Allium sativum perturbs the structural integrity of Calf thymus DNA through intercalation and groove binding.

Mater Sci Eng C Mater Biol Appl 2017 May 7;74:597-608. Epub 2017 Feb 7.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India. Electronic address:

Biomedical application of selenium nanoparticles (SeNPs) demands the eco-friendly composite for synthesis of SeNPs. The present study reports an aqueous extract of Allium sativum (AqEAS) plug-up the current need. Modern spectroscopic, microscopic and gravimetric techniques were employed to characterize the synthesized nanoparticles. Characterization studies revealed the formation of crystalline spherical shaped SeNPs. FTIR spectrum brings out the presence of different functional groups in AqEAS, which influence the SeNPs formation and stabilization. Furthermore the different aspects of the interaction between SeNPs and CT-DNA were scrutinized by various spectroscopic and cyclic voltametric studies. The results reveals the intercalation and groove binding mode of interaction of SeNPs with stacked base pair of CT-DNA. The Stern-Volmer quenching constant (K) were found to be 7.02×10M- (ethidium bromide), 4.22×10 M- (acridine orange) and 7.6×10M- (Hoechst) indicating strong binding of SeNPs with CT-DNA. The SeNPs - CT-DNA interactions were directly visualized by atomic force microscopy. The present study unveils the cost effective, innocuous, highly stable SeNPs intricate mechanism of DNA interaction, which will be a milestone in DNA targeted chemotherapy.
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http://dx.doi.org/10.1016/j.msec.2017.02.003DOI Listing
May 2017

Preconditioning methods in the management of hepatic ischemia reperfusion- induced injury: Update on molecular and future perspectives.

Hepatol Res 2017 Jan 10;47(1):31-48. Epub 2016 May 10.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India.

Hepatic IR (ischemia reperfusion) injury is a commonly encountered obstacle in the post-operative management of hepatic surgery. Hepatic IR occurs during 'Pringle maneuver' for reduction of blood loss or during a brief period of cold storage followed by reperfusion of liver grafts. The stress induced during hepatic IR, triggers a spectrum of cellular responses leading to the varying degrees of hepatic complications which in turn affect the post operative care. Different preconditioning methods either activate or subdue different sets of molecular signals, resulting in varied levels of protection against hepatic IR injury. Yet, there is a serious lacuna in the knowledge regarding the choice of preconditioning methods and the resulting molecular changes in order to assess the efficiency and choice of these methods correctly. This review provides an update on the various preconditioning approaches such as surgical/ischemic, antioxidant, pharmaceutical and genetic preconditioning strategies published during last six years (2009-2015). Further, we discuss the attenuation or inhibition of specific inflammatory, apoptotic and necrotic markers in the various experimental models of liver IR subjected to different preconditioning strategies. While enlisting the controversies in the ischemic preconditioning strategy, we bring out the uncertainties in the existing molecular targets and their reliability in the attenuation of hepatic IR injury. Future research studies would include the novel preconditioning strategies employ i) the targeted gene silencing of key molecular targets inducing IR, ii) hyper expression of beneficial molecular signals against IR via gene transfer techniques. The above studies would see the combination of these latest techniques with the established preconditioning strategies for better post-operative hepatic management.
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http://dx.doi.org/10.1111/hepr.12706DOI Listing
January 2017

Unconjugated Bilirubin exerts Pro-Apoptotic Effect on Platelets via p38-MAPK activation.

Sci Rep 2015 Oct 13;5:15045. Epub 2015 Oct 13.

DOS in Chemistry, University of Mysore, Manasagangothri, Mysuru-570 006, India.

Thrombocytopenia is one of the most frequently observed secondary complications in many pathological conditions including liver diseases, where hyperbilirubinemia is very common. The present study sought to find the cause of thrombocytopenia in unconjugated hyperbilirubinemic conditions. Unconjugated bilirubin (UCB), an end-product of heme catabolism, is known to have pro-oxidative and cytotoxic effects at high serum concentration. We investigated the molecular mechanism underlying the pro-apoptotic effect of UCB on human platelets in vitro, and followed it up with studies in phenylhydrazine-induced hyperbilirubinemic rat model and hyperbilirubinemic human subjects. UCB is indeed found to significantly induce platelet apoptotic events including elevated endogenous reactive oxygen species generation, mitochondrial membrane depolarization, increased intracellular calcium levels, cardiolipin peroxidation and phosphatidylserine externalization (p < 0.001) as evident by FACS analysis. The immunoblots show the elevated levels of cytosolic cytochrome c and caspase activation in UCB-treated platelets. Further, UCB is found to induce mitochondrial ROS generation leading to p38 activation, followed by downstream activation of p53, ultimately resulting in altered expression of Bcl-2 and Bax proteins as evident from immunoblotting. All these parameters conclude that elevated unconjugated bilirubin causes thrombocytopenia by stimulating platelet apoptosis via mitochondrial ROS-induced p38 and p53 activation.
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http://dx.doi.org/10.1038/srep15045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602209PMC
October 2015

Nutrient profile of porridge made from Eleusine coracana (L.) grains: effect of germination and fermentation.

J Food Sci Technol 2015 Sep 14;52(9):6024-30. Epub 2015 Jan 14.

Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, 605 014 India.

Porridge (koozh) is one of the traditional foods made from Eleusine coracana L. grains (Finger millet). It is a soft food prepared from processed (germinated & fermented) finger millet flour (FMF). However, in the modern world of fast food, koozh is usually prepared from non-processed (non-germinated & non-fermented) FMF. Hence, present study was undertaken to evaluate the macro and micro nutrient contents in koozh prepared from germinated (fermented & non-fermented) and non-germinated (fermented & non-fermented) FMF. Highest protein, carbohydrate and glycoprotein contents were found in koozh prepared from germinated & non-fermented FMF. The free amino acid contents are higher in germinated & fermented condition when compare to other preparations. No significant change was observed in the calorific value of all preparations. There is no statistical difference in macro-nutrients & micro-nutrients minerals such as calcium, iron, magnesium, manganese, phosphorous and zinc among all the preparations. However, copper content is higher in non-germinated condition, whereas selenium, silicon and sulphur are higher in germinated FMF when compared to others. Significant level of total phenol, total flavonoid and free radical scavenging activity was observed in all preparations, which increased further during fermentation. The present observations, lead us to conclude that koozh prepared from germinated & non-fermented FMF contains higher level of carbohydrate, protein and glycoprotein, however germinated & fermented koozh has increased aminoacids, phytochemicals and free radical scavenging activity. Hence it is suggested that the consumption of koozh made from germinated & fermented FMF may provide easily digestible and energetic nutrients for healthier life.
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http://dx.doi.org/10.1007/s13197-015-1713-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554619PMC
September 2015

Synthesis and biological evaluation of isoindoloisoquinolinone, pyroloisoquinolinone and benzoquinazolinone derivatives as poly(ADP-ribose) polymerase-1 inhibitors.

Bioorg Med Chem 2015 Feb 19;23(3):488-98. Epub 2014 Dec 19.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India. Electronic address:

A series of novel fused isoquinolinones with isoindoloisoquinolinone, pyroloisoquinolinone, and benzoquinalizinone skeletons were synthesized from corresponding phenethylimides. The isoquinolinone derivatives were evaluated for their protective effect on chicken erythrocytes subjected to oxidative damage. The effect of isoquinolinone derivatives were analysed by estimation of cell viability, antioxidant enzyme activities, DNA damage (comet assay), PARP-1 inhibition assay and molecular docking of the compounds with PARP-1 active site. The compounds CRR-271, CRR-288 and CRR-224+225 showed significant protective effect at 100 μM concentration. The PARP-1 inhibition assay revealed the IC50 values of CRR-271, CRR-288 and CRR-224+225 as <200 nM, further molecular docking studies shows higher binding energies with PARP-1 active site. Interesting findings in this study suggest that the novel isoquinolinone derivatives inhibit PARP-1 activity and protect cells against oxidative DNA damage, which could be implemented in the treatment of inflammatory diseases.
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http://dx.doi.org/10.1016/j.bmc.2014.12.017DOI Listing
February 2015

TNF-α suppression by glutathione preconditioning attenuates hepatic ischemia reperfusion injury in young and aged rats.

Inflamm Res 2015 Jan 25;64(1):71-81. Epub 2014 Nov 25.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, 605014, India.

Background And Aim: Hepatic ischemia reperfusion (I/R) stimulates Kupffer cells and initiates injury through tumor necrosis factor-α (TNF-α) upregulation. Aim of this study was to compare the variable effects of reduced glutathione (GSH) pre-treatment on I/R liver injury in young and aged rats.

Methods: Wistar male rats were sorted into young (groups I-III) and aged (groups IV-VI). All groups except sham (groups I and IV) were subjected to 90-min ischemia and 2-h reperfusion. The treatment groups received 200 mg/kg bwt (groups III and VI) of GSH, 30 min prior to I/R. Variable effects of GSH were studied by transaminase activities, thiobarbituric acid-reactive substances (TBARS), GSH level, GSH/oxidized GSH (GSSG) ratio, TNF-α level, apoptotic markers and confirmed by histopathological observations.

Results: Our findings revealed that I/R inflicted more liver damage in aged rats than young rats. The GSH treatment prior to surgery significantly lowered the serum transaminase activities, hepatic TBARS level and effectively restored the GSH/GSSG ratio in both young and aged rats more remarkably in the mitochondria. Western analysis depicted that the GSH treatment effectively suppressed TNF-α expression and apoptotic markers in both young and aged rats. These findings were further confirmed by terminal deoxynucleotide transferase dUTP nick end labeling assay and histopathological observations of liver sections of young and aged rats.

Conclusion: Restoration of GSH/GSSG ratio through GSH pre-conditioning inhibits TNF-α and apoptosis in hepatic I/R injury. Hence, GSH pre-conditioning may be utilized in both young and aged individuals during liver transplantation/surgery for better post-operative outcomes.
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http://dx.doi.org/10.1007/s00011-014-0785-6DOI Listing
January 2015

(-)-Epigallocatechin-gallate (EGCG) stabilize the mitochondrial enzymes and inhibits the apoptosis in cigarette smoke-induced myocardial dysfunction in rats.

Mol Biol Rep 2013 Dec 7;40(12):6533-45. Epub 2013 Nov 7.

Department of Biochemistry, Periyar University, Salem, 636016, Tamil Nadu, India.

The present study brings out the preventive role of (-)-epigallocatechin-gallate (EGCG) on cardiac mitochondrial metabolism and apoptosis in cigarette smoke (CS)-exposed rats. The CS-exposed rats showed significantly decreased activities of TCA cycle enzymes and mitochondrial enzymatic antioxidants, on the other hand, mitochondrial lipid peroxidation was increased and GSH level was decreased. Further, CS exposure was found to induce cardiac apoptosis through release of cytochrome c into the cytosol, cleavage of pro-caspase-3 to active caspase-3, up-regulation of pro-apoptotic (Bax) and down-regulation of antiapoptotic (Bcl-2) molecules. The CS-induced apoptosis was further confirmed by mitochondrial and nuclear ultra structural apoptotic features as evaluated by electron microscopic studies. EGCG supplementation shelters the activities of TCA cycle enzymes and antioxidant enzymes, with concomitant decrease in lipid peroxidation and increase in GSH level. EGCG administration inhibited apoptosis through the inhibition of cytochrome c release into cytosol, activation of pro-caspase-3, down regulation of Bax and significant up regulation of Bcl-2. EGCG reversed the ultra structural apoptotic alterations of mitochondria and nucleus. The present study has provided experimental evidences that the EGCG treatment enduring to cardio protection at mitochondrial level.
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http://dx.doi.org/10.1007/s11033-013-2673-5DOI Listing
December 2013

Crocin, a dietary colorant, mitigates cyclophosphamide-induced organ toxicity by modulating antioxidant status and inflammatory cytokines.

J Pharm Pharmacol 2013 Apr 4;65(4):604-14. Epub 2013 Jan 4.

Department of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, India.

Objectives: This study investigated the protective efficacy of crocin against hepatotoxicity induced by cyclophosphamide (CP) in Wistar rats.

Methods: The experimental rats were treated with crocin orally at a dose of 10 mg/kg for 6 consecutive days after the administration of a single intraperitoneal dose of CP (150 mg/kg). The ameliorative effect of crocin on organ toxicity was studied by evaluating oxidative stress enzymes, inflammatory cytokines and histological sections.

Key Findings: A single intraperitoneal CP injection significantly elevated endogenous reactive oxygen species and oxidation of lipids and proteins, which are the hallmarks of oxidative damage in liver and serum. In consequence, the primary defensive reduced glutathione, total thiol and antioxidant enzymes such as superoxide dismutase, catalase, glutathione-S-transferase and glutathione peroxidase, were significantly reduced. In addition, liver and serum aspartate aminotransferase and alanine aminotransferase along with acid and alkaline phosphatase were considerably increased. Oral administration of crocin significantly rejuvenated all the above altered markers to almost normal state. The protective efficacy of crocin was further supported by the histological assessment and restoration of CP-induced inflammatory cytokines and enzyme levels compared with the control drug.

Conclusion: The results obtained suggest the protective nature of crocin against CP-induced oxidative damage/inflammation and organ toxicity.
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http://dx.doi.org/10.1111/jphp.12016DOI Listing
April 2013

Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions.

Bioinformation 2011 20;7(1):21-8. Epub 2011 Aug 20.

The neutral sphingomyelinase (N-SMase) is considered a major candidate for mediating the stress-induced production of ceramide, and it plays an important role in cell-cycle arrest, apoptosis, inflammation, and eukaryotic stress responses. Recent studies have identified a small region at the very N-terminus of the 55 kDa tumour necrosis factor receptor (TNF-R55), designated the neutral sphingomyelinase activating domain (NSD) that is responsible for the TNF-induced activation of N-SMase. There is no direct association between TNF-R55 NSD and N-SMase; instead, a protein named factor associated with N-SMase activation (FAN) has been reported to couple the TNF-R55 NSD to N-SMase. Since the three-dimensional fold of N-SMase is still unknown, we have modeled the structure using the protein fold recognition and threading method. Moreover, we propose models for the TNF-R55 NSD as well as the FAN protein in order to study the structural basis of N-SMase activation and regulation. Protein-protein interaction studies suggest that FAN is crucially involved in mediating TNF-induced activation of the N-SMase pathway, which in turn regulates mitogenic and proinflammatory responses. Inhibition of N-SMase may lead to reduction of ceramide levels and hence may provide a novel therapeutic strategy for inflammation and autoimmune diseases. Molecular dynamics (MD) simulations were performed to check the stability of the predicted model and protein-protein complex; indeed, stable RMS deviations were obtained throughout the simulation. Furthermore, in silico docking of low molecular mass ligands into the active site of N-SMase suggests that His135, Glu48, Asp177, and Asn179 residues play crucial roles in this interaction. Based on our results, these ligands are proposed to be potent and selective N-SMase inhibitors, which may ultimately prove useful as lead compounds for drug development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163928PMC
November 2011

Molecular modeling of human alkaline sphingomyelinase.

Bioinformation 2011 Mar 26;6(2):78-82. Epub 2011 Mar 26.

Alkaline sphingomyelinase, which is expressed in the human intestine and hydrolyses sphingomyelin, is a component of the plasma and the lysosomal membranes. Hydrolase of sphingomyelin generates ceramide, sphingosine, and sphingosine 1-phosphate that have regulatory effects on vital cellular functions such as proliferation, differentiation, and apoptosis. The enzyme belongs to the Nucleotide Pyrophosphatase/Phosphodiesterase family and it differs in structural similarity with acidic and neutral sphingomyelinase. In the present study we modeled alkaline sphingomyelinase using homology modeling based on the structure of Nucleotide Pyrophosphatase/Phosphodiesterase from Xanthomonas axonopodis with which it shares 34% identity. Homology modeling was performed using Modeller9v7. We found that Cys78 and Cys394 form a disulphide bond. Further analysis shows that Ser76 may be important for the function of this enzyme, which is supported by the findings of Wu et al. (2005), that S76F abolishes the activity completely. We found that the residues bound to Zn(2+) are conserved and geometrically similar with the template. Molecular Dynamics simulations were carried out for the modeled protein to observe the effect of Zinc metal ions. It was observed that the metal ion has little effect with regard to the stability but induces increased fluctuations in the protein. These analyses showed that Zinc ions play an important role in stabilizing the secondary structure and in maintaining the compactness of the active site.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082857PMC
http://dx.doi.org/10.6026/97320630006078DOI Listing
March 2011

Constitutive release of powerful antioxidant-scavenging activity by hepatic stellate cells: protection of hepatocytes from ischemia/reperfusion injury.

Liver Transpl 2010 Dec;16(12):1400-9

Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Within the liver, reactive oxygen species produced by infiltrating blood cells and Kupffer cells (resident macrophages) can injure hepatocytes. We hypothesized that hepatocyte survival is influenced by the relatively small juxtaposed population of hepatic stellate cells (HSCs). We used cultures of primary rat hepatocytes as targets for superoxide-induced damage, which was determined by crystal violet assay and lactate dehydrogenase release. An HSC-conditioned medium prevented the superoxide-induced death of hepatocytes, and the protective factor released by HSCs was a protein or proteins (apparent molecular weight > 100 kDa) resistant to heat (70°C) and pH (4.5-8.5). The protein or proteins were partially purified on DE52 cellulose, and the active fraction contained no detectable levels of superoxide dismutase: after separation by Sephadex G-100 gel filtration, the antioxidant activity could be reconstituted by the combination of 2 protein peaks, and this reconstituted activity was protective both in vitro and against liver ischemia/reperfusion injury in intact rats. Mass spectrometry proteomic studies confirmed that this activity could not be attributed to any previously identified antioxidant protein. Thus, HSCs protect hepatocytes against oxidative damage through the production of a novel protein, the further purification of which may lead to the isolation of a powerful oxygen radical scavenger with clinical applications.
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http://dx.doi.org/10.1002/lt.22172DOI Listing
December 2010

WITHDRAWN: Attenuation of cardiac oxidative stress by (-)-epigallocatechin-gallate (EGCG) in CS exposed rats.

Biomed Pharmacother 2010 Oct 23. Epub 2010 Oct 23.

Department of Biochemistry, Periyar University, Salem 636016, Tamil Nadu, India; Department of Biochemistry, Islamiah College, Vaniyambadi, Tamil Nadu, India.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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http://dx.doi.org/10.1016/j.biopha.2010.09.025DOI Listing
October 2010

p38-MAPK- and caspase-3-mediated superoxide-induced apoptosis of rat hepatic stellate cells: reversal by retinoic acid.

J Cell Physiol 2009 Jan;218(1):157-66

Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.

Reactive oxygen species (ROS) activate retinoid-containing quiescent hepatic stellate cells (qHSCs) to retinoid-deficient fibrogenic myofibroblast-like cells (aHSCs). However, ROS also cause apoptosis of aHSCs, and apoptotic aHSCs are observed in inflammatory fibrotic liver. Here, we investigated mechanisms of the effects of oxidative stress on the survival of qHSCs and aHSCs. HSCs from normal rat liver were used after overnight culture (qHSCs), or in 3-5 passages (aHSCs). For in vivo induction of oxidative stress, tert-butylhydroperoxide was injected into control and CCl4-induced cirrhotic rats. Spontaneous caspase-3 activation and apoptosis, observed in cultured qHSCs, decreased with time and were unaffected by superoxide. In contrast, superoxide caused caspase-3 and p38-MAPK activation, reduction in Bcl-xL expression, and apoptosis in aHSCs. Inhibition of caspase-3 and p38-MAPK did not affect the viability of qHSCs in the absence or presence of superoxide, but inhibited superoxide-induced death of aHSCs. Glutathione (GSH) level and activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were lower in aHSCs than qHSCs. Superoxide increased GSH content, and activities of SOD, catalase and GPx in qHSCs but not in aHSCs. Incubation of 13-cis-retinoic acid (RA)-treated aHSCs with superoxide increased their GSH content significantly, and prevented superoxide-induced p38-MAPK and caspase-3 activation while dramatically reducing the extent of apoptosis. Finally, oxidative stress induced in vivo caused apoptosis of aHSCs in cirrhotic but not of qHSCs in control rats. These results suggest that the absence of retinoids render aHSCs susceptible to superoxide-induced apoptosis via caspase-3 and p38-MAPK activation.
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http://dx.doi.org/10.1002/jcp.21581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896034PMC
January 2009
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