PHARMACOPHORE MODELLING FOR THE DISCOVERY OF SYSTEM XC- ANTIPORTER INHIBITORS

Cancer is one of the major disorders with increasing rates of morbidity and mortality. Recent drug discovery of anti cancer drug has identified several molecular targets and tried to achieve a goal of therapeutic effecative and safe molecule. Amongst these, system xc- antiporter is a novel promising target to control cancer progression. This antiporter is found to be over expressed in majority of cancer cells and functions by transporting amino acids, cystine and glutamate, in opposite directions. System xc- antiporter uptakes one molecule of cystine with the release of one molecule of glutamate in extracellular space. As already known cystine is precursor for the synthesis of glutathione, an in vivo antioxidant which is utilized by cancer cells to combat oxidative stress. At the other side the released glutamate (an excitatory neurotransmitter), when released in higher concentration, may over excite neurones (specifically and brain tumour) causing cell death to metastasise cancer cells. Therefore, through inhibition of system xc- antiporter, it is possible to kill cancer cells by disturbing their redox status along with through prevention of excitotoxcity by glutamate. In context to this, several researches have reported diverse molecules having system xc- antiporter inhibition potential. Amongst these molecules, erastin and its analogues are most potent system xc- antiporter inhibitors but it lacks preclinical data. Moreover, sulfasalazine, a FDA approved drug also showed good inhibition potential against this antiporter and therefore in our study we have attempted to construct pharmacophore model using this series to aid in the discovery of potent inhibitors with desirable safety. Results of this study exhibited successful development of pharmacophore model with phase survival score. Additionally, fit scores of sulfasalazine analogues were also in acceptable range. Hence, the developed pharmacophore model may be used for design of potent System xc- antiporter inhibitors

Amelioration of Abnormalities Associated with the Metabolic Syndrome by Spinacia oleracea

The present study evaluates the protective effects of an antioxidant-rich extract of Spinacea oleracea (NAOE) in abnormalities associated with the metabolic syndrome (MetS) in rats. HPTLC of NAOE revealed the presence of 13 total antioxidants, 14 flavonoids, and 10 phenolic acids. Rats administered with fructose (20% w/v) in drinking water for 45 days to induce abnormalities of MetS received NAOE (200 and 400 mg/kg, po), the standard drug gemfibrozil (60 mg/kg, po), aerobic exercise (AE), and a combination of NAOE 400 mg/kg and AE (NAOEAE) daily for 45 days. All treatments significantly altered the lipid profile and attenuated the fructose-elevated levels of uric acid, C-reactive protein, homocysteine, and marker enzymes (AST, LDH, and CK-MB) in serum and malondialdehyde in the heart and restored the fructose-depleted levels of glutathione and antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase). A significant decrease in blood glucose and insulin levels decreased insulin resistance, and improved glucose tolerance was observed in the treatment animals when compared with the fructose-fed animals. The best mitigation of MetS was shown by the NAOEAE treatment indicating that regular exercise along with adequate consumption of antioxidant-rich foods such as spinach in diet can help control MetS

Antioxidants of Phyllanthus emblica

Phyllanthus emblica L. (amla) has been used in Ayurveda as a potent rasayan for treatment of hepatic disorders. Most of the pharmacological studies, however, are largely focused on PE fruit, while the rest of the parts of PE, particularly, bark, remain underinvestigated. Therefore, we aimed to investigate the protective effect of the hydroalcoholic extract of Phyllanthus emblica bark (PEE) in ethanol-induced hepatotoxicity model in rats. Total phenolic, flavonoid, and tannin content and in vitro antioxidant activities were determined by using H2O2 scavenging and ABTS decolorization assays. Our results showed that PEE was rich in total phenols (99.523±1.91 mg GAE/g), total flavonoids (389.33±1.25 mg quercetin hydrate/g), and total tannins (310±0.21 mg catechin/g), which clearly support its strong antioxidant potential. HPTLC-based quantitative analysis revealed the presence of the potent antioxidants gallic acid (25.05 mg/g) and ellagic acid (13.31 mg/g). Moreover, one-month PEE treatment (500 and 1000 mg/kg, p.o.) followed by 30-day 70% ethanol (10 mL/kg) administration showed hepatoprotection as evidenced by significant restoration of ALT (p<0.01), AST (p<0.001), ALP (p<0.05), and TP (p<0.001) and further confirmed by liver histopathology. PEE-mediated hepatoprotection could be due to its free radical scavenging and antioxidant activity that may be ascribed to its antioxidant components, namely, ellagic acid and gallic acid. Thus, the results of the present study support the therapeutic claims made in Ayurveda about Phyllanthus emblica

<b>Protective role of flavonoids in cardiovascular diseases </b>

166-176Flavonoids are low molecular weight, polyphenolic compounds present in all vascular plants. They are primarily recognized as the pigments responsible for autumnal burst of hues and yellow, orange and red shades in flowers and fruits. Flavonoids have been shown to possess a variety of biological activities at nontoxic concentrations in living organisms. Compelling data from various in vivo and in vitro experimental and several epidemiological studies have demonstrated the beneficial effects of dietary flavonoids. The mechanisms of their cardioprotective effect have been thought to stem from their free radical scavenging, antioxidant, anti-thrombotic, anti-apoptotic and anti-hypertensive effects. Based on the results of clinical studies, it would be suffice to say that flavonoids could be promising cardio-protective agent

Metabolomics and EMT Markers of Breast Cancer: A Crosstalk and Future Perspective

Cancer cells undergo transient EMT and MET phenomena or vice versa, along with the parallel interplay of various markers, often correlated as the determining factor in decoding metabolic profiling of breast cancers. Moreover, various cancer signaling pathways and metabolic changes occurring in breast cancer cells modulate the expression of such markers to varying extents. The existing research completed so far considers the expression of such markers as determinants regulating the invasiveness and survival of breast cancer cells. Therefore, this manuscript is crosstalk among the expression levels of such markers and their correlation in regulating the aggressiveness and invasiveness of breast cancer. We also attempted to cover the possible EMT-based metabolic targets to retard migration and invasion of breast cancer

Cardioprotection by <i style="">Inula racemosa </i>Hook in experimental model of myocardial ischemic reperfusion injury

918-924 To evaluate the cardioprotective potential of Inula racemosa in myocardial ischemic-reperfusion injury, Wistar male albino rats were randomly divided into four groups. The group I and II animals were administered saline orally {(sham, ischemia- reperfusion (I-R) control group)} and animals of group III and group IV received I. racemosa extract (100 mg/kg) for 30 days. On the 30th day, animals of I-R control and I. racemosa treated groups were underwent 45 min of ligation of left anterior descending coronary artery and were thereafter re-perfused for 60 min. In the I-R control group, a significant decrease of mean arterial pressure (MAP), heart rate (HR), contractility, (+)LVdP/dt and relaxation, (-)LVdP/dt and an increase of left ventricular end diastolic pressure (LVEDP) were observed. Subsequent to haemodynamic impairment and left ventricular contractile dysfunction, a significant decline was observed in endogenous myocardial antioxidants; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH). Increased lipid peroxidation characterized by malonaldialdehyde (MDA) formation along with depletion of cardiomyocytes specific enzymes, creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH) in I-R control group compared to sham group revealed I-R injury of heart. However, treatment with I. racemosa significantly restored the myocardial antioxidant status evidenced by increased SOD, CAT, GPx and GSH and prevented leakage of cardio-specific enzymes; CK-MB and LDH and favorably modulated the altered MAP, HR, (+)LVdP/dt, (-)LVdP/dt and LVEDP as compared to I-R control. Furthermore, I-R induced lipid peroxidation was significantly inhibited by I. racemosa treatment. These beneficial cardioprotective effects translated into significant improvement in cardiac function. In conclusion, our study has demonstrated that the cardioprotective effect of I. racemosa likely resulted to improved antioxidant status, haemodynamic and left ventricular contractile function subsequent to suppression of oxidative stress</smarttagtype

Aspirin May Promote Mitochondrial Biogenesis Via The Production Of Hydrogen Peroxide And The Induction Of Sirtuin1/Pgc-1Α Genes

Based on the rapid hydrolysis of acetyl salicylic acid (ASA, Aspirin) to salicylic acid (SA), the ability of SA to form dihydroxy benzoic acid (DBA), and the latter\u27s redox reactions to yield hydrogen peroxide (H2O 2), we predicted that ASA may have the potential to induce Sirtuin1 (Sirt1) and its downstream effects. We observed that treatment of cultured liver cells with ASA resulted in the induction of Sirt1, peroxisome proliferator-activated receptor-gamma co-activator-1α (PGC-1α), and NAD(P)H quinone oxidoreductase 1 (Nqo1) genes. Paraoxonase 1 (PON1) and Aryl hydrocarbon receptor (AhR) siRNA transfections inhibited the induction of gene expressions by ASA suggesting the need for the acetyl ester hydrolysis and hydroxylation to DHBA. The latter also induced Sirt1, confirming the proposed pathway. As predicted, ASA and SA treatment resulted in the production of H 2O2, a known inducer of Sirt1 and confirmed in the current studies. More importantly, ASA treatment resulted in an increase in mitochondria as seen by tracking dyes. We suggest that DHBA, generated from ASA, via its oxidation/reduction reactions mediated by Nqo1 might be involved in the production of O2-. and H2O2. As Sirt1 and PGC-1α profoundly affect mitochondrial metabolism and energy utilization, ASA may have therapeutic potential beyond its ability to inhibit cyclooxygenases. © 2012 Elsevier B.V. All rights reserved

The Effect of Parthenolide, a NLRP3 Inflammasome Inhibitor on Insulin Resistance in High-Fat Diet-Obese Mice

The activation of Nod-like receptor proteins containing pyrin domain (NLRP3) inflammasome is a hallmark behind the pathogenesis of metabolic disorders. Inhibition of NLRP3 inflammasome by means of phytoconstituents is attempted as one of the strategy. Therefore, present study was aimed to evaluate the efficacy of a NLRP3 inflammasome inhibitor, i.e., parthenolide (PN; 5 mg/kg i.p.) against inflammation and insulin resistance in high-fat diet (HFD)-obese mice. PN and Pioglitazone (PIO; 30 mg/kg p.o.) treatment attenuated the lipopolysaccharide- (LPS; 1ng/ml) induced elevated tumor necrosis factor-α and interleukin-1β in mouse peritoneal macrophages in dose-dependent manner. The sixty days of PN and PIO treatment in HFD-obese mice marginally reduced the obesity-induced insulin resistance. PN treatment also decreased the blood glucose from 14th to 60thday, supporting the hypothesis of simultaneous attenuation of inflammation and insulin sensitivity in obese mice. Thus, PN treatment was also evident with the significant improvement in glucose tolerance and peripheral insulin resistance validated through the respective tolerance tests. Therefore, the present study results suggest that PN, a NLRP3 inflammasome inhibitor, could be a possible therapeutic agent in attenuating obesity-induced insulin resistance.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Antioxidants of Phyllanthus emblica L. Bark Extract Provide Hepatoprotection against Ethanol-Induced Hepatic Damage: A Comparison with Silymarin

Phyllanthus emblica L. (amla) has been used in Ayurveda as a potent rasayan for treatment of hepatic disorders. Most of the pharmacological studies, however, are largely focused on PE fruit, while the rest of the parts of PE, particularly, bark, remain underinvestigated. Therefore, we aimed to investigate the protective effect of the hydroalcoholic extract of Phyllanthus emblica bark (PEE) in ethanol-induced hepatotoxicity model in rats. Total phenolic, flavonoid, and tannin content and in vitro antioxidant activities were determined by using H 2 O 2 scavenging and ABTS decolorization assays. Our results showed that PEE was rich in total phenols (99.523 ± 1.91 mg GAE/g), total flavonoids (389.33 ± 1.25 mg quercetin hydrate/g), and total tannins (310 ± 0.21 mg catechin/g), which clearly support its strong antioxidant potential. HPTLC-based quantitative analysis revealed the presence of the potent antioxidants gallic acid (25.05 mg/g) and ellagic acid (13.31 mg/g). Moreover, one-month PEE treatment (500 and 1000 mg/kg, p.o.) followed by 30-day 70% ethanol (10 mL/kg) administration showed hepatoprotection as evidenced by significant restoration of ALT ( &lt; 0.01), AST ( &lt; 0.001), ALP ( &lt; 0.05), and TP ( &lt; 0.001) and further confirmed by liver histopathology. PEE-mediated hepatoprotection could be due to its free radical scavenging and antioxidant activity that may be ascribed to its antioxidant components, namely, ellagic acid and gallic acid. Thus, the results of the present study support the therapeutic claims made in Ayurveda about Phyllanthus emblica

Circulating Platelet Aggregates Damage Endothelial Cells In Culture

Background Presence of circulating endothelial cells (CECs) in systemic circulation may be an indicator of endothelial damage and/or denudation, and the body\u27s response to repair and revascularization. Thus, we hypothesized that aggregated platelets (AgPlts) can disrupt/denude the endothelium and contribute to the presence of CEC and EC-derived particles (ECDP). Methods Endothelial cells were grown in glass tubes and tagged with/without 0.5 μm fluorescent beads. These glass tubes were connected to a mini-pump variable-flow system to study the effect of circulating AgPlts on the endothelium. ECs in glass tube were exposed to medium alone, nonaggregated platelets (NAgPlts), AgPlts, and 90 micron polystyrene beads at a flow rate of 20 mL/min for various intervals. Collected effluents were cultured for 72 h to analyze the growth potential of dislodged but intact ECs. Endothelial damage was assessed by real time polymerase chain reaction (RT-PCR) for inflammatory genes and Western blot analysis for von Willebrand factor. Results and conclusion No ECs and ECDP were observed in effluents collected after injecting medium alone and NAgPlts, whereas AgPlts and Polybeads drastically dislodged ECs, releasing ECs and ECDP in effluents as the time increased. Effluents collected when endothelial cell damage was seen showed increased presence of von Willebrand factor as compared to control effluents. Furthermore, we analyzed the presence of ECs and ECDPs in heart failure subjects, as well as animal plasma samples. Our study demonstrates that circulating AgPlts denude the endothelium and release ECs and ECDP. Direct mechanical disruption and shear stress caused by circulating AgPlts could be the underlying mechanism of the observed endothelium damage