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1.
Oxid Med Cell Longev ; 2020: 9568278, 2020.
Article in English | MEDLINE | ID: mdl-32952852

ABSTRACT

Cardiac hypertrophy is the underlying cause of heart failure and is characterized by excessive oxidative stress leading to collagen deposition. Therefore, understanding the signalling mechanisms involved in excessive extracellular matrix deposition is necessary to prevent cardiac remodelling and heart failure. In this study, we hypothesized that hesperetin, a flavanone that elicits the activation of Nrf2 signalling and thereby suppresses oxidative stress, mediated pathological cardiac hypertrophy progression. A cardiac hypertrophy model was established with subcutaneous injection of isoproterenol in male Wistar rats. Oxidative stress markers, antioxidant defense status, and its upstream signalling molecules were evaluated to discover the impacts of hesperetin in ameliorating cardiac hypertrophy. Our results implicate that hesperetin pretreatment resulted in the mitigation of oxidative stress by upregulating antioxidant capacity of the heart. This curative effect might be owing to the activation of the master regulator of antioxidant defense system, known as Nrf2. Further, analysis of Nrf2 revealed that hesperetin enhances its nuclear translocation as well as the expression of its downstream targets (GCLC, NQO1, and HO-1) to boost the antioxidative status of the cells. To support this notion, in vitro studies were carried out in isoproterenol-treated H9c2 cells. Immunocytochemical analysis showed augmented nuclear localization of Nrf2 implicating the action of hesperetin at the molecular level to maintain the cellular redox homeostasis. Thus, it is conceivable that hesperetin could be a potential therapeutic candidate that enhances Nrf2 signalling and thereby ameliorates pathological cardiac remodelling.


Subject(s)
Cardiomegaly/drug therapy , Cardiomegaly/metabolism , Hesperidin/therapeutic use , Homeostasis , NF-E2-Related Factor 2/metabolism , Signal Transduction , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Biomarkers/metabolism , Cardiomegaly/chemically induced , Cardiomegaly/pathology , Cell Line , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cytoprotection/drug effects , Gene Expression Regulation/drug effects , Hesperidin/pharmacology , Homeostasis/drug effects , Isoproterenol , Male , NF-E2-Related Factor 2/genetics , Oxidation-Reduction , Oxidative Stress/drug effects , Protein Transport/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Wistar , Signal Transduction/drug effects , Superoxides/metabolism
2.
Free Radic Biol Med ; 160: 227-238, 2020 11 20.
Article in English | MEDLINE | ID: mdl-32768570

ABSTRACT

Diabetic nephropathy (DN), a progressive kidney disease afflicts more than 20 and up to 40% of the diabetic population and it is characterized by persistent microalbuminuria declined glomerular filtration rate. The interesting feature associated with DN is that, even though the progression of the disease correlates with oxidative stress, Nrf2, the master regulator of antioxidant defense system involved in counteracting oxidative stress is also upregulated in the diabetic kidneys of both human as well as experimental animals in early stages of DN. Despite the increased expression, the ability of this protein to get translocated into the nucleus is diminished signifying the functional impairment of Nrf2, implying redox imbalance. Hence, it is understood that agents that boost the translocation of Nrf2 might be beneficial rather than those that quantitatively overexpress Nrf2 in treating DN. The deleterious effects of synthetic Nrf2 activators have instigated the researchers to search for phytochemicals that have ambient Nrf2 boosting ability with no side effects, one such phytochemical is Epigallocatechin-3-gallate (EGCG) and it has shown beneficial effects by preventing the progression of DN via influencing Nrf2/ARE pathway, however, the modus operandi is unclear, despite speculations. This study was designed to find out whether supplementation of Nrf2 booster like EGCG at the crucial time of Nrf2 dysfunction can mitigate the progression of DN. Based on the findings of the present study, it might be concluded that the beneficial effect of EGCG in mitigating DN is mediated mainly through its ability to activate the Nrf2/ARE signaling pathway at multiple stages i.e., by downregulating Keap1 and boosting the nuclear Nrf2 level by disrupting Nrf2-Keap1 interaction. These results emphasize that supplementation of EGCG might be more beneficial at an early stage of DN, where dysfunctional Nrf2 accumulation occurs, which should be further validated.


Subject(s)
Catechin/analogs & derivatives , Diabetes Mellitus , Diabetic Nephropathies , Animals , Catechin/pharmacology , Catechin/therapeutic use , Diabetic Nephropathies/drug therapy , Humans , Kelch-Like ECH-Associated Protein 1/genetics , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Oxidative Stress
3.
Oxid Med Cell Longev ; 2019: 8285730, 2019.
Article in English | MEDLINE | ID: mdl-31885819

ABSTRACT

BACKGROUND: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized low-density lipoprotein (Ox-LDL) in the aorta of aged rats. Ox-LDL initiates LOX-1 activation in the endothelium of lipid-accumulating sites of both animal and human subjects of hypercholesterolemia. Targeting LOX-1 may provide a novel diagnostic strategy towards hypercholesterolemia and vascular diseases. HYPOTHESIS: This study was planned to address whether aegeline (AG) could bind to LOX-1 with a higher affinity and modulate the uptake of Ox-LDL in hypercholesterolemia. STUDY DESIGN: Thirty-six Wistar rats were divided into six groups. The pathology group rats were fed with high-cholesterol diet (HCD) for 45 days, and the treatment group rats were fed with HCD and aegeline/atorvastatin (AV) for the last 30 days. In vivo and in vitro experiments were carried out to assay the markers of atherosclerosis like Ox-LDL and LOX-1 levels. Histopathological examination was performed. Oil Red O staining was carried out in the IC-21 cell line. Docking studies were performed. RESULTS: AG administration effectively brought down the lipid levels induced by HCD. The lowered levels of Ox-LDL and LOX-1 in AG-administered rats deem it to be a potent antihypercholesterolemic agent. Compared to AV, AG had a pronounced effect in downregulating the expression of lipids evidenced by Oil Red O staining. AG binds with LOX-1 at a higher affinity validated by docking. CONCLUSION: This study validates AG to be an effective stratagem in bringing down the lipid stress induced by HCD and can be deemed as an antihypercholesterolemic agent.


Subject(s)
Amides/metabolism , Atherosclerosis/drug therapy , Hypercholesterolemia/metabolism , Macrophages/physiology , Scavenger Receptors, Class E/metabolism , Amides/therapeutic use , Animals , Anticholesteremic Agents/therapeutic use , Atorvastatin/therapeutic use , Cell Line , Diet, High-Fat , Disease Models, Animal , Humans , Hypercholesterolemia/drug therapy , Lipoproteins, LDL/metabolism , Male , Mice , Molecular Targeted Therapy , Rats , Rats, Wistar
4.
J Agric Food Chem ; 65(36): 8028-8036, 2017 Sep 13.
Article in English | MEDLINE | ID: mdl-28823168

ABSTRACT

Apoptosis is an active response of cells to altered microenvironments, which is characterized by cell shrinkage, chromatin condensation, and DNA fragmentation, in a variety of cell types such as renal epithelial cells, endothelial cells, mesangial cells, and podocytes. Hyperglycemia is among the microenvironmental factors that may facilitate apoptosis, which plays a decisive role in the initiation of diabetic nephropathy. Transforming growth factor-ß emerges as a powerful fibrogenic factor in the development of renal hypertrophy. Although, a number of potential treatment strategies exist for diabetic nephropathy, considering the ease of use and bioavailability, phytochemicals stands distinct as the preeminent option. EGCG, a green tea catechin is one such phytochemical which possesses hypoglycemic and antifibrotic activity. The present study aims to explore the potential of EGCG to prevent apoptosis in a high-fat diet and STZ induced diabetic nephropathy rats by assessing renal function, pro-fibrotic marker, and the expression of apoptotic and antiapoptotic proteins. Our results validate EGCG as a potential antiapoptotic agent evidently by improving renal function via down regulating TGF-ß, consequently ameliorating diabetic nephropathy. In accordance with this, EGCG might be regarded as a prospective therapeutic candidate in modulating diabetic nephropathy, thus being a promising treatment.


Subject(s)
Apoptosis/drug effects , Catechin/analogs & derivatives , Diabetic Nephropathies/drug therapy , Animals , Catechin/administration & dosage , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/physiopathology , Fibrosis , Humans , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Prospective Studies , Rats , Rats, Sprague-Dawley , Transforming Growth Factor beta/metabolism
5.
Food Funct ; 7(2): 922-37, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26697948

ABSTRACT

Parkinson's disease is a progressive neurodegenerative movement disorder with the cardinal symptoms of bradykinesia, resting tremor, rigidity, and postural instability, which lead to abnormal movements and lack of activity, which in turn cause muscular damage. Even though studies have been carried out to elucidate the causative factors that lead to muscular damage in Parkinson's disease, apoptotic events that occur in the skeletal muscle and a therapeutical approach to culminate the muscular damage have not been extensively studied. Thus, this study evaluates the impact of rotenone-induced SNPc lesions on skeletal muscle apoptosis and the efficacy of an ethyl acetate extract of Morinda citrifolia in safeguarding the myocytes. Biochemical assays along with apoptotic markers studied by immunoblot and reverse transcription-polymerase chain reaction in the current study revealed that the supplementation of Morinda citrifolia significantly reverted alterations in both biochemical and histological parameters in rotenone-infused PD rats. Treatment with Morinda citrifolia also reduced the expression of pro-apoptotic proteins Bax, caspase-3 and caspase-9 and blocked the release of cytochrome c from mitochondria induced by rotenone. In addition, it augmented the expression of Bcl2 both transcriptionally and translationally. Thus, this preliminary study paves a way to show that the antioxidant and anti-apoptotic activities of Morinda citrifolia can be exploited to alleviate skeletal muscle damage induced by Parkinsonism.


Subject(s)
Apoptosis , Cytochromes c/metabolism , Muscle, Skeletal/drug effects , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Rotenone/toxicity , Animals , Antioxidants/pharmacology , Aspartate Aminotransferases/blood , Caspase 3/genetics , Caspase 3/metabolism , Caspase 9/genetics , Caspase 9/metabolism , Creatine Kinase/blood , Cytochromes c/antagonists & inhibitors , Disease Models, Animal , L-Lactate Dehydrogenase/blood , Male , Mitochondria/drug effects , Mitochondria/metabolism , Morinda/chemistry , Muscle, Skeletal/metabolism , Oxidative Stress/drug effects , Parkinsonian Disorders/chemically induced , Pars Compacta/drug effects , Pars Compacta/pathology , Proto-Oncogene Proteins c-bcl-2/genetics , Rats , Rats, Sprague-Dawley , Up-Regulation , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
6.
Exp Gerontol ; 57: 96-103, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24844145

ABSTRACT

SCOPE: Increased fat consumption in industrialized countries has resulted in hepatic steatosis that upregulates atherogenic aspirant genes, leading to atherosclerosis and mortality. Although extensive studies have been carried out to elucidate the atheroprotective efficacy of epigallocatechin-3-gallate (EGCG), the effect of EGCG on hepatic steatosis has not been studied comprehensively. Hence, the current study was designed to find out the effect of EGCG on hepatic events that prelude atherosclerosis with special reference to macrophage infiltration. METHODS AND RESULTS: Male albino rats of Wistar strain were used in this study. Basic biochemical assays along with the protein expression of CAMs, NF-κB, TNF-α and NF-AT were assayed in the current study. EGCG supplementation significantly reverted the alterations in both biochemical and histological parameters and is shown to reduce the TNF-α mediated NF-AT expression and thereby its downstream targets like ICAM-1 and E-selectin expression to a greater extent than NF-κB mediated downstream targets like VCAM-1 and P-selectin in hypercholesterolemic rat liver. CONCLUSION: Our results suggest that EGCG influences the early events of atherosclerosis that occur; thereby modulating the NF-AT pathway and thereby mitigating the hypercholesterolemic stress.


Subject(s)
Antioxidants/therapeutic use , Catechin/analogs & derivatives , Fatty Liver/drug therapy , Macrophages/drug effects , NFATC Transcription Factors/metabolism , Animals , Antioxidants/pharmacology , Catechin/pharmacology , Catechin/therapeutic use , Cell Adhesion Molecules/metabolism , Cholesterol, Dietary/adverse effects , Down-Regulation/drug effects , Drug Evaluation, Preclinical , Fatty Liver/immunology , Fatty Liver/metabolism , Liver/metabolism , Male , NF-kappa B/metabolism , Phytotherapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Rats, Wistar , Tumor Necrosis Factor-alpha/metabolism
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