Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-κ B-regulated gene products

Manu, K. A.,Shanmugam, M. K.,Li, F.,Chen, L.,Siveen, K. S.,Ahn, K. S.,Kumar, A. P.,Sethi, G. Springer Science + Business Media 2014 Journal of molecular medicine Vol.92 No.3

Negative regulation of signal transducer and activator of transcription-3 signalling cascade by lupeol inhibits growth and induces apoptosis in hepatocellular carcinoma cells

Siveen, K S,Nguyen, A H,Lee, J H,Li, F,Singh, S S,Kumar, A P,Low, G,Jha, S,Tergaonkar, V,Ahn, K S,Sethi, G Nature Publishing Group 2014 The British journal of cancer Vol.111 No.7

<P><B>Background:</B></P><P>Constitutive activation of signal transducer and activator of transcription signalling 3 (STAT3) has been linked with survival, proliferation and angiogenesis in a wide variety of malignancies including hepatocellular carcinoma (HCC).</P><P><B>Methods:</B></P><P>We evaluated the effect of lupeol on STAT3 signalling cascade and its regulated functional responses in HCC cells.</P><P><B>Results:</B></P><P>Lupeol suppressed constitutive activation of STAT3 phosphorylation at tyrosine 705 residue effectively in a dose- and time-dependent manner. The phosphorylation of Janus-activated kinases (JAKs) 1 and 2 and Src was also suppressed by lupeol. Pervanadate treatment reversed the downregulation of phospho-STAT3 induced by lupeol, thereby indicating the involvement of a phosphatase. Indeed, we observed that treatment with lupeol increased the protein and mRNA levels of SHP-2, and silencing of SHP-2 abolished the inhibitory effects of lupeol on STAT3 activation. Treatment with lupeol also downregulated the expression of diverse STAT3-regulated genes and decreased the binding of STAT3 to VEGF promoter. Moreover, the proliferation of various HCC cells was significantly suppressed by lupeol, being associated with substantial induction of apoptosis. Depletion of SHP-2 reversed the observed antiproliferative and pro-apoptotic effects of lupeol.</P><P><B>Conclusions:</B></P><P>Lupeol exhibited its potential anticancer effects in HCC through the downregulation of STAT3-induced pro-survival signalling cascade.</P>

BLOOD METABOLITES LEVELS IN RELATION TO AGE AND LIVE WEIGHT IN YOUNG BUFFALO CALVES

Sikka, P.,Sethi, R.K.,Tomer, A.K.S.,Chopra, S.C. Asian Australasian Association of Animal Productio 1994 Animal Bioscience Vol.7 No.2

Thirty buffalo calves were randomly categorized into three groups on the basis of age, i.e. birth to 6 months; 6 to 12 months and 12-24 months. Blood samples were collected to monitor certain vital metabolites in relation to age and prediction of performance in growing buffalo calves. Amongst the various blood parameters estimated the serum glucose, cholesterol and gamma globulins have shown highly significant correlations with age and live weight-gain of the animal as well. However, the multiple regression analysis clearly indicated the influence of age and live body weight on blood metabolites in buffalo calves.

Microwave Assisted Energy Efficient Biodiesel Production from Crude Pongamia pinnata (L.) Oil Using Homogeneous Catalyst

Ritesh Kumar,A. K. Sethy 강원대학교 산림과학연구소 2015 Journal of Forest Science Vol.31 No.1

Microwave assisted biodiesel production from crude Pongamia pinnata oil using homogeneous base catalyst (KOH) was unsuccessful because of considerable soap formation. Therefore, a two step process of biodiesel production from high free fatty acid (FFA) oil was investigated. In first step, crude P. pinnata oil was acid catalyzed using H2SO4 and acid value of oil was reduced to less than 4 mg KOH/g. Effect of sulfuric acid concentration, alcohol-oil molar ratio and microwave irradiation time on acid value of oil was studied. Result suggested that 1.5% H2SO4 (w/w), 6:1 methanol oil molar ratio and 3 min microwave irradiation time was sufficient to reduce the acid value of oil from 12 and 22 mg KOH/g to 2.9 and 3.9 mg/KOH/g, respectively. Oil obtained after pretreatment was subsequently used for microwave assisted alkali catalyzed transesterification. A higher biodiesel yield (99.0%) was achieved by adopting two step processes. Microwave energy efficiency during alkali catalyzed transesterification was also investigated. The results suggested a significant energy saving because of reduced reaction time under microwave heating.

Microwave Assisted Energy Efficient Biodiesel Production from Crude Pongamia pinnata (L.) Oil Using Homogeneous Catalyst

Kumar, Ritesh,Sethy, A.K. Institute of Forest Science 2015 Journal of Forest Science Vol.31 No.1

Microwave assisted biodiesel production from crude Pongamia pinnata oil using homogeneous base catalyst (KOH) was unsuccessful because of considerable soap formation. Therefore, a two step process of biodiesel production from high free fatty acid (FFA) oil was investigated. In first step, crude P. pinnata oil was acid catalyzed using $H_2SO_4$ and acid value of oil was reduced to less than 4 mg KOH/g. Effect of sulfuric acid concentration, alcohol-oil molar ratio and microwave irradiation time on acid value of oil was studied. Result suggested that 1.5% $H_2SO_4$ (w/w), 6:1 methanol oil molar ratio and 3 min microwave irradiation time was sufficient to reduce the acid value of oil from 12 and 22 mg KOH/g to 2.9 and 3.9 mg/KOH/g, respectively. Oil obtained after pretreatment was subsequently used for microwave assisted alkali catalyzed transesterification. A higher biodiesel yield (99.0%) was achieved by adopting two step processes. Microwave energy efficiency during alkali catalyzed transesterification was also investigated. The results suggested a significant energy saving because of reduced reaction time under microwave heating.

Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer

Shrimali, D.,Shanmugam, M.K.,Kumar, A.P.,Zhang, J.,Tan, B.K.H.,Ahn, K.S.,Sethi, G. Elsevier Science Ireland 2013 Cancer letters Vol.341 No.2

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a natural occurring anthraquinone derivative isolated from roots and barks of numerous plants, molds, and lichens. It is found as an active ingredient in different Chinese herbs including Rheum palmatum and Polygonam multiflorum, and has diuretic, vasorelaxant, anti-bacterial, anti-viral, anti-ulcerogenic, anti-inflammatory, and anti-cancer effects. The anti-inflammatory effects of emodin have been exhibited in various in vitro as well as in vivo models of inflammation including pancreatitis, arthritis, asthma, atherosclerosis and glomerulonephritis. As an anti-cancer agent, emodin has been shown to suppress the growth of various tumor cell lines including hepatocellular carcinoma, pancreatic, breast, colorectal, leukemia, and lung cancers. Emodin is a pleiotropic molecule capable of interacting with several major molecular targets including NF-κB, casein kinase II, HER2/neu, HIF-1α, AKT/mTOR, STAT3, CXCR4, topoisomerase II, p53, p21, and androgen receptors which are involved in inflammation and cancer. This review summarizes reported anti-inflammatory and anti-cancer effects of emodin, and re-emphasizes its potential therapeutic role in the treatment of inflammatory diseases and cancer.

Mutations of <i>ADAMTS9</i> Cause Nephronophthisis-Related Ciliopathy

Choi, Yo Jun,Halbritter, Jan,Braun, Daniela A.,Schueler, Markus,Schapiro, David,Rim, John Hoon,Nandadasa, Sumeda,Choi, Won-il,Widmeier, Eugen,Shril, Shirlee,Kö,rber, Friederike,Sethi, Sidharth K. Elsevier 2019 American journal of human genetics Vol.104 No.1

<P>Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two <I>ADAMTS9</I> mutations (c.4575_4576del [p.Gln1525Hisfs<SUP>∗</SUP>60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of <I>Adamts9</I> in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of <I>adamts9</I> in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in <I>ADAMTS9</I> cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia.</P>

Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells

Baek, S.H.,Ko, J.H.,Lee, H.,Jung, J.,Kong, M.,Lee, J.w.,Lee, J.,Chinnathambi, A.,Zayed, M.,Alharbi, S.A.,Lee, S.G.,Shim, B.S.,Sethi, G.,Kim, S.H.,Yang, W.M.,Um, J.Y.,Ahn, K.S. G. Fischer 2016 Phytomedicine Vol.23 No.5

<P>Background: Signal transducer and activator of transcription 3 (STAT3) is persistently activated in squamous cell carcinoma of the head and neck (SCCHN) and can cause uncontrolled cellular proliferation and division. Hypothesis: Thus, its targeted abrogation could be an effective strategy to reduce the risk of SCCHN. Resveratrol is known for its anti-cancer efficacy in a variety of cancer models. Study design: The effect resveratrol on STAT3 activation, associated protein kinases, phosphatases, cellular proliferation and apoptosis was investigated. Methods: We evaluated the effect of resveratrol on STAT3 signaling cascade and its regulated functional responses in SCCHN cells. Results: We found that HN3 and FaDu cells expressed strongly phosphorylated STAT3 on both tyrosine 705 and serine 727 residues as compared to other SCCHN cells. The phosphorylation was completely suppressed by resveratrol in FaDu cells, but not substantially in HN3 cells. STAT3 suppression was mediated through the inhibition of activation of upstream JAK2, but not of JAK1 and Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the resveratrol-induced down-regulation of STAT3, thereby indicating a critical role for a PTP. We also found that resveratrol induced the expression of the SOCS-1 protein and mRNA. Further, deletion of SOCS-1 gene by siRNA suppressed the induction of SOCS-1, and reversed the inhibition of STAT3 activation. Resveratrol down-regulated various STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced the cell accumulation in the sub-G1 phase and caused apoptosis. Beside, this phytoalexin also exhibited the enhancement of apoptosis when combined with ionizing radiation treatment. Conclusion: Our results suggest that resveratrol blocks STAT3 signaling pathway through induction of SOCS-1, thus attenuating STAT3 phosphorylation and proliferation in SCCHN cells. (C) 2016 Elsevier GmbH. All rights reserved.</P>