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Malkapuram S.,SAI Life science Ltd. | Venkataraman K.,Vellore Institute of Technology | Tongaonkar R.,SAI Life science Ltd. | Taran S.,SAI Life science Ltd. | And 2 more authors.
Research Journal of Medicinal Plant | Year: 2016

Green Coffee Extract (GCE), an extract of Coffea arabica bean is a popular health supplement employed for anti-obesity and anti-diabetic effects. Here a hydroalcoholic extract of Green Coffee (GCE) was evaluated for its potential as a cardioprotective agent against Doxorubicin (Dox) induced cardiac insult in a H9C2 rat cardiomyocyte in vitro model system. The GCE was tested in an MTT viability assay using 1 μM Dox with and without GCE pretreatment at 50, 100 and 250 μg mL-1 concentrations. GCE was also tested for its free radical scavenging ability in a DPPH assay at 10 concentrations (500 μg mL-1 maximum concentration). To understand the mechanism of action of cardioprotection, mitochondrial membrane potential (Δψm) was compared between Dox treated cells with and without GCE pretreatment, using the JC-1 dye. Finally, the activation of caspase-3/7 was quantitated. Findings from the above experiments demonstrated that GCE rescued H9C2 cardiomyocytes from Dox induced loss of cell viability in a dose-dependent manner. While Dox treatment caused a clear decrease in the JC-1 ratio from 2 to 1.6 due to loss of Δψm, pre- treatment with GCE at 25, 50 and 100 μg mL-1 restored the JC-1 ratio to 1.6, 1.9 and 2.0, respectively. Dox treatment potently induced caspase 3/7 activity by 5 fold and pre-treatment with GCE at 100 and 500 μg mL-1 reduced this activation to 3.5 and 1.5 fold, respectively. This data clearly demonstrates that GCE is strongly cardioprotective against Dox induced cardiac insult and the mechanism of action is by blocking activation of intrinsic apoptotic pathway. © 2016 Academic Journals Inc.

Zhao P.,Boston Childrens Hospital | Zhao P.,Harvard University | Zhao P.,Methodist Hospital Research Institute | Hou L.,Boston Childrens Hospital | And 7 more authors.
Journal of Leukocyte Biology | Year: 2014

SerpinB1 is an endogenous inhibitor of serine proteases recognized for its anti-inflammatory and host-protective properties. Although loss of serpinB1 in mice does not result in gross immune deregulation, serpinb1a-/- mice display increased mortality and inflammation-associated morbidity upon challenge with influenza virus. Here, we show that IL-17A+ γδ and CD4+ Th17 cells are already expanded in the lungs of serpinb1a-/- mice at steady-state. Both γδ and αβ+ CD4+ CCR6+ T cells isolated from the lungs of naive serpinb1a-/- mice displayed a skewed transcriptional profile relative to WT cells, including increased Th17 signature transcripts [Il17a, l17f, and Rorc (RORγt)] and decreased Th1 signature transcripts [Ifng, Cxcr3, and Tbx21 (T-bet)] in γδ T cells. In addition to the lung, IL-17A+ γδ and CD4+ Th17 cells were increased in the spleen of naive serpinb1a-/- mice, despite normal αβ and γδ T cell development in the thymus. Within the γδ T cell compartment, loss of serpinb1a prompted selective expansion of Vγ4+ and Vγ6/Vδ1+ cells, which also displayed elevated expression of the proliferating cell nuclear antigen, Ki-67, and IL-17A. Given that serpinb1a is preferentially expressed in WT IL-17A+ γδ and CD4+ Th17 cell subsets vis-à-vis other T cell lineages, our findings reveal a novel function of serpinB1 in limiting untoward expansion of lymphocytes with a Th17 phenotype. © Society for Leukocyte Biology.

Malkapuram S.,Sai Life science Ltd. Pune | Taran S.,Sai Life science Ltd. Pune | Venkataraman K.,Vellore Institute of Technology | Rajagopalan L.,Discovery Biology
International Journal of Pharma and Bio Sciences | Year: 2016

Green Coffee Extract (GCE) is a popular health supplement known for its anti-obesity & anti-diabetic effects. Here we tested GCE for its capacity to activate J774.1 mouse macrophages and protect against Doxorubicin induced apoptosis. J774.1 cells treated for 24 h with 100 and 500 μg/ml GCE showed increased production of IL-6, TNF-α and nitric oxide (NO) in a dose dependent manner. GCE upregulated production of these molecules by inducing transcription of the IL-6, TNF-α and iNOS genes. In addition, GCE was able to restore viability of J774.1 cells treated with Doxorubicin. Pre-treatment of cells with GCE for 1 h abrogated Dox induced loss of cell viability. While Dox robustly induced caspase 3/7 activity within 6 h of treatment, pretreatment with GCE for 1 h was enough to attenuate this induction. The results we report here suggest that GCE activates J774.1 macrophages and is cytoprotective against Dox induced apoptosis.

Rinne J.O.,University of Turku | Frantzen J.,University of Turku | Leinonen V.,Kuopio University Hospital | Leinonen V.,University of Eastern Finland | And 18 more authors.
Neurodegenerative Diseases | Year: 2014

Backgound/Objective: To determine the level of association between uptake of the amyloid positron emission tomography (PET) imaging agent [ 18F]flutemetamol and the level of amyloid-β measured by immunohistochemical and histochemical staining in a frontal cortical region biopsy site. Methods: Seventeen patients with probable normal pressure hydrocephalus (NPH) underwent prospective [18F]flutemetamol PET and subsequent frontal cortical brain biopsy during ventriculoperitoneal shunting. Tissue amyloid-β was evaluated using the monoclonal antibody 4G8, thioflavin S and Bielschowsky silver stain. Results: Four of the 17 patients (23.5%) had amyloid-β pathology based on the overall pathology read and also showed increased [18F]flutemetamol uptake. [18F] Flutemetamol standardized uptake values from the biopsy site were significantly associated with biopsy specimen amyloid-β levels (Pearson's r = 0.67; p = 0.006). There was also good correlation between the biopsy specimen amyloid-β level and uptake of [18F]flutemetamol in the region contralateral to the biopsy site (r = 0.67; p = 0.006), as well as with composite cortical [18F]flutemetamol uptake (r = 0.65; p = 0.008). The blinded visual read showed a high level of agreement between all readers (κ = 0.88). Two of 3 readers were in full agreement on all images; 1 reader disagreed on 1 of the 17 NPH cases. Blinded visual assessments of PET images by 1 reader were associated with 100% sensitivity to the overall pathology read, and assessments by the 2 others were associated with 75% sensitivity (overall sensitivity by majority read was 75%); specificity of all readers was 100%. Conclusions: [18F]Flutemetamol detects brain amyloid-β in vivo and shows promise as a valuable tool to study and possibly facilitate diagnosis of Alzheimer's disease both in patients with suspected NPH and among the wider population. © 2013 S. Karger AG, Basel.

Qiao J.X.,P.O. Box 4000 | Wang T.C.,P.O. Box 4000 | Adam L.P.,Discovery Biology | Chen A.Y.A.,Discovery Biology | And 29 more authors.
Journal of Medicinal Chemistry | Year: 2015

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies. © 2015 American Chemical Society.

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