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1.
Biomed Res Int ; 2020: 3712536, 2020.
Article in English | MEDLINE | ID: mdl-32685475

ABSTRACT

The second most biggest cancer worldwide is breast cancer. There is an increasing need for safer, effective, and affordable drug candidates from natural sources to treat breast cancer. In the present investigation, the anticancer effect of Cucurbita ficifolia Bouché (C. ficifolia) fruit extract was tested on the human breast cancer cells such as MCF-7. The cells were exposed with different doses of C. ficifolia, for the assessment of IC50 concentrations on the MCF-7 cell lines for 24 hs. The effect of C. ficifolia fruit extract on morphological and apoptotic changes were evaluated by specific fluorescence staining techniques and real-time PCR in a time-dependent manner for 24 hs and 48 hs. The IC50 value for C. ficifolia fruit extract was found to be 90 µg/mL. Morphological alteration and apoptotic distinctiveness aspect like chromatin condensation and nuclear fragmentation were noticed in C. ficifolia extract exposed breast cancer cells. Further, we observed that C. ficifolia extract-induced programmed cell death in the MCF-7 cells were mediated with the elevated expression of the tumor suppressor gene such as p53 and apoptotic markers such as caspase-8, caspase-9, caspase-3, fatty acid synthase (FAS), Fas-associated protein with death domain (FADD), Bcl-2 homologous antagonist/killer (BAK), and Bcl-2-associated X protein (BAX). These observations established that C. ficifolia significantly concealed the cell division and provoked p53/caspase-mediated programmed cell death. Further, we noticed that this cell death in MCF-7 cells is concentration and time dependent. As evaluated through the comet assay, C. ficifolia induced DNA damage; further upon increasing the duration of the treatment, the DNA damage was higher than before. Thus, our study concludes that C. ficifolia could serve as an effective anticancer agent through vital gene modulation.


Subject(s)
Apoptosis/drug effects , Breast Neoplasms/pathology , Caspases/metabolism , Cucurbita/chemistry , Fruit/chemistry , Plant Extracts/pharmacology , Tumor Suppressor Protein p53/metabolism , Apoptosis/genetics , Breast Neoplasms/genetics , Caspases/genetics , DNA Damage , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Staining and Labeling
2.
Saudi J Biol Sci ; 26(4): 744-751, 2019 May.
Article in English | MEDLINE | ID: mdl-31048999

ABSTRACT

Prevention and management of obesity through dietary modification is one of the top way to trim down its consequences. Development of adipose tissue requires the differentiation of less specialized cells, such as human mesenchymal stem cells (hMSCs), into adipocytes. Since food constituents play a major role in the cell differentiation and proliferation, we sought to determine if various extracts of Cucurbita ficifolia (C. ficifolia), could affect the adipogenic differentiation of hMSCs. Flow cytometry analysis with quantitative and qualitative Nile red, and quantitative PCR methods were employed to evaluate the C. ficifolia effect on hMSCs adipogenesis. Results revealed that, chloroform extract exhibits significant adipogenic inhibition than that of hexane and methanol extracts. Chloroform extract treated cells display the down-regulation of ADIPOQ, FABP4, PPARGC1A, CEBPB & LPL and up-regulation of ACACB & CEBPA genes. Further, various phytoconstituents present in the chloroform extract of C. ficifolia were analyzed though LC-MS and GC-MS. Our results indicates that chloroform extract of C. ficifolia might be used as a food supplement to control obesity and its related consequences.

3.
Biofactors ; 44(3): 289-298, 2018 May.
Article in English | MEDLINE | ID: mdl-29672963

ABSTRACT

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.


Subject(s)
Chalcones/pharmacology , Choline Deficiency/drug therapy , Diet/adverse effects , Hypolipidemic Agents/pharmacology , Liver/drug effects , Non-alcoholic Fatty Liver Disease/drug therapy , Administration, Oral , Albumins/metabolism , Animals , Choline/metabolism , Choline Deficiency/etiology , Choline Deficiency/metabolism , Choline Deficiency/pathology , Globulins/metabolism , Heme Oxygenase (Decyclizing)/antagonists & inhibitors , Heme Oxygenase (Decyclizing)/metabolism , Liver/metabolism , Liver/pathology , Male , Methionine/deficiency , Mitochondria/drug effects , Mitochondria/metabolism , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Peroxidase/antagonists & inhibitors , Peroxidase/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Transaminases/antagonists & inhibitors , Transaminases/metabolism
4.
J Pharm Biomed Anal ; 154: 294-301, 2018 May 30.
Article in English | MEDLINE | ID: mdl-29567572

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Cytotoxins/pharmacology , Doxorubicin/pharmacology , Glyburide/pharmacology , A549 Cells , Calorimetry/methods , Cell Line, Tumor , Circular Dichroism/methods , DNA/drug effects , Drug Synergism , Fluorescence , Hep G2 Cells , Humans , Molecular Docking Simulation/methods , Spectrometry, Fluorescence/methods , Thermodynamics
5.
Mol Biol Rep ; 44(6): 463-474, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29185131

ABSTRACT

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.


Subject(s)
Hepatocytes/drug effects , Hepatocytes/metabolism , Limonins/pharmacology , Lipid Metabolism/drug effects , Animals , Antioxidants/pharmacology , Cells, Cultured , Humans , Hypolipidemic Agents/pharmacology , Lipid Peroxidation/drug effects , Liver X Receptors/metabolism , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , PPAR gamma/metabolism , Reactive Oxygen Species/metabolism , Triglycerides/metabolism
6.
Inflamm Res ; 66(9): 753-763, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28560522

ABSTRACT

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 (CCl4)-mediated liver toxicity in male Wistar rats. RESULTS: The hepatoprotective effects of HMBA against CCl4-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-1ß, 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 CCl4-induced hepatotoxicity, and this is associated with the lipid lowering, inflammatory cytokine restoration and induction of defensive enzyme activities.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Benzoates/therapeutic use , Chemical and Drug Induced Liver Injury/drug therapy , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Benzoates/pharmacology , Carbon Tetrachloride , Chemical and Drug Induced Liver Injury/blood , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Collagen/metabolism , Cytokines/blood , Glutathione/metabolism , Heme Oxygenase-1/metabolism , Hydroxyproline/metabolism , Lipid Metabolism/drug effects , Lipid Peroxidation/drug effects , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Peroxidase/metabolism , Rats, Wistar
7.
Pak J Pharm Sci ; 29(4): 1133-8, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27393448

ABSTRACT

The aim of the study was to asses the anti-inflammatory effects of corosolic acid on the carbon tetrachloride (CCL4) toxicity in rats. Liver toxicity was induced by administered CCL4 (single dose (1:1 in liquid paraffin) orally at 1.25 ml/kg. Rats were pretreated with CRA for 7 days before made CCL(4) toxicity at 20 mg/kg BW. The mRNA levels of TNF-α, IL-6, iNOS, COX-2 and NF-kB were assayed by reverse transcriptase PCR analysis. The mRNA levels of proinflammatory cytokines such as TNF-α, IL-6, and the inflammatory markers such as iNOS, COX-2 and NF-kB were significantly up regulated in CCl(4) induced rats and treatment with corosolic acid significantly reduced the expression of the above indicators. Our results suggest that the inhibition of TNF-α, IL-6, iNOS, COX-2 and NF-κB by corosolic acid, a potential candidate could possess anti-inflammatory activity besides its hepatoprotective effect in CCl4 liver toxicity in rats.


Subject(s)
Chemical and Drug Induced Liver Injury/genetics , Liver/drug effects , Triterpenes/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Carbon Tetrachloride , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Liver/metabolism , Male , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/genetics
8.
Pak J Pharm Sci ; 28(5): 1647-53, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26408884

ABSTRACT

Obesity is the excessive fat accumulation in human body leading to increases a risk of various chronic diseases such as diabetes, cardiovascular diseases, cancer and osteoarthritis. Several flavonoids are known to have lipolytic activity influencing lipolysis and adipogenesis in adipose cells. To explore mechanism of the association of flavonoids in obesity and obesity associated protein (FTO), molecular docking studies were done for FTO with flavonoids, with orlistat (antiobesity drug) as a control. Autodock tools were used for docking flavonoids and orlistat with FTO. The results were visualized by PyMol and Discovery studio visualizer. Upon docking simulation, it was observed that flavonoid quercetin showed highest binding affinity (most negative δG), whereas daidzein was least affinity towards FTO. The binding affinity of other flavonoids was in the order of Exemestane >Kaempherol >Letrozole >Rutin. This study concludes that flavonoids primarily, quercetin ameliorates obesity by establishing a physical interaction with FTO. Interactions were also observed between FTO and other flavonoids and were of not greater inhibition compared to quercetin.


Subject(s)
Adipose Tissue/metabolism , Flavonoids/chemistry , Molecular Docking Simulation , Proteins/chemistry , Alpha-Ketoglutarate-Dependent Dioxygenase FTO , Humans , Lactones/chemistry , Orlistat
9.
Article in English | WPRIM (Western Pacific) | ID: wpr-820541

ABSTRACT

OBJECTIVE@#To unravel the mechanism of anti-inflammatory activity of carvacrol in D-galactosamine (D-GalN)-induced hepatotoxic rats.@*METHODS@#The mRNA and protein expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and nuclear factor kappa-B (NF-κB) were assayed by semi-quantitative reverse transcriptase polymerase chain reaction (RTPCR) and western blot analysis.@*RESULTS@#We found that the mRNA and protein expressions of TNF-α, IL-6, iNOS, COX-2 and NF-κB were significantly up-regulated in D-galactosamine induced hepatotoxic rats and treatment with carvacrol significantly down-regulated the expressions of these genes showing the mechanism behind the anti-inflammatory activity of carvacrol.@*CONCLUSIONS@#All above results reveal that the carvacrol well known anti-inflammatory activities in D-galactosamine induced hepatotoxic rats.


Subject(s)
Animals , Male , Rats , Blotting, Western , Cyclooxygenase 2 , Metabolism , Cymenes , Galactosamine , Toxicity , Interleukin-6 , Metabolism , Liver Cirrhosis, Experimental , Genetics , Metabolism , Monoterpenes , Pharmacology , NF-kappa B , Metabolism , Nitric Oxide Synthase Type II , Metabolism , Protective Agents , Pharmacology , RNA, Messenger , Metabolism , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Methods , Silymarin , Pharmacology , Tumor Necrosis Factor-alpha , Metabolism
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