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71.
Hung JH Lu YS Wang YC Ma YH Wang DS Kulp SK Muthusamy N Byrd JC Cheng AL Chen CS 《Cancer research》2008,68(4):1204-1212
This study was aimed at elucidating the mechanism by which FTY720, a synthetic sphingosine immunosuppressant, mediated antitumor effects in hepatocellular carcinoma (HCC) cells. The three HCC cell lines examined, Hep3B, Huh7, and PLC5, exhibited differential susceptibility to FTY720-mediated suppression of cell viability, with IC(50) values of 4.5, 6.3, and 11 mumol/L, respectively. Although FTY720 altered the phosphorylation state of protein kinase B and p38, our data refuted the role of these two signaling kinases in FTY720-mediated apoptosis. Evidence indicates that the antitumor effect of FTY720 was attributable to its ability to stimulate reactive oxygen species (ROS) production, which culminated in protein kinase C (PKC)delta activation and subsequent caspase-3-dependent apoptosis. We showed that FTY720 activated PKC delta through two distinct mechanisms: phosphorylation and caspase-3-dependent cleavage. Cotreatment with the caspase-3 inhibitor Z-VAD-FMK abrogated the effect of FTY720 on facilitating PKC delta proteolysis. Equally important, pharmacologic inhibition or shRNA-mediated knockdown of PKC delta protected FTY720-treated Huh7 cells from caspase-3 activation. Moreover, FTY720 induced ROS production to different extents among the three cell lines, in the order of Hep3B > Huh7 > PLC5, which inversely correlated with the respective glutathione S-transferase pi expression levels. The low level of ROS generation might underlie the resistant phenotype of PLC5 cells to the apoptotic effects of FTY720. Blockade of ROS production by an NADPH oxidase inhibitor protected Huh7 cells from FTY720-induced PKC delta activation and caspase-3-dependent apoptosis. Together, this study provides a rationale to use FTY720 as a scaffold to develop potent PKC delta-activating agents for HCC therapy. 相似文献
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Oluseye K. Onajole Karnishree Govender Patrick Govender Paul D. van Helden Hendrik G. Kruger Glenn E.M. Maguire Karen Muthusamy Manormoney Pillay Ian Wiid Thavendran Govender 《European journal of medicinal chemistry》2009,44(11):4297-4305
As part of an ongoing effort to develop highly potent anti-tuberculosis agents, fourteen pentacyclo-undecane (PCU) tetra-amine compounds were synthesized and screened for their in vitro anti-mycobacterial activity against two TB strains, H37Rv and XDR 194 [an extensively drug-resistant strain of tuberculosis]. Using the broth macrodilution method, nitrofuranylamide based compounds (6a and 6b) showed almost similar activities against the H37Rv strain of Mycobacterium tuberculosis when compared with the control drug, ethambutol. N-Geranyl piperazine PCU (8a) and trans–trans farnesyl piperazine PCU (8b) were 3.2 and 3.7 times more potent than commercially available ethambutol. Both isoprenyl PCU tetra-amine derivatives and N-decyl piperazine PCU (9a) were highly active against the XDR 194 strain of tuberculosis with MICs in the range of 0.63–3.02 μM. Cytotoxicities (IC50) of isoprenyl based compounds (8a, 8b) and compound 9a were tested on a mammalian cell line [MDBK (Madin Darby bovine kidney epithelium)] with values of 30, 24 and 25 μM respectively. 相似文献
74.
Harimurthi Kothandaraman Muthusamy Saroja Devi 《Macromolecular chemistry and physics.》1994,195(8):2989-3001
Kinetic studies of the polymerization of 1-octene with the Ziegler-Natta catalyst systems VOCl3—AlEt3 (I) and VOCl3—AlEt2Br (II) are reported. The effect of the various parameters such as the Al/V ratio, catalyst and monomer concentrations, reaction time, aging time and temperature on rate of reaction and molecular weight of polymer were studied. Each of these parameters has a profound effect on the polymer yield and the rate of the reaction for both systems. The rate of polymerization increases linearly with increasing temperature, catalyst and monomer concentrations. The reaction is first order with respect to both the monomer and the catalyst concentration in the two catalyst systems studied. From the Arrhenius plot the overall activation energy of polymerization for the two systems was found to be 51,2 and 43,5 kJ/mol, respectively. The mechanism of polymerization is discussed on the basis of the dependence of the polymerization rate on the alkylaluminium concentration. 相似文献
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77.
Gurpreet K Grewal Khuraijam D Singh Neha Kanojia Chitra Rawat Samiksha Kukal Ajay Jajodia Anshika Singhal Richa Misra Selvaraman Nagamani Karthikeyan Muthusamy Ritushree Kukreti 《Pharmaceutical research》2017,34(7):1444-1458
Purpose
Over expression of ATP-binding cassette transporters is considered one of the major reasons for non-responsiveness to antiepileptic drugs. Carbamazepine (CBZ), one of first line antiepileptic drug is known to influence ABCC2 expression but its exact molecular mechanism is unknown.Methods
We investigated the effect of CBZ on expression of ABCC2 and pregnane X receptor (PXR) in HepG2 cell line and compared with hyperforin (agonist of PXR) and ketoconazole (antagonist of PXR) through realtime PCR and western blot assay. Involvement of PXR was demonstrated through nuclear translocation and RNA interference and related effect of CBZ on ABCC2 through functional activity assay. Molecular docking and dynamic simulation approach was used to understand the interaction of CBZ with PXR.Results
CBZ and hyperforin increased the PXR and ABCC2 expression whereas reversed when present it in combination with ketoconazole. Experiments confirmed CBZ induced ABCC2 expression is PXR dependent. Molecular dynamic (MD) simulation and in vitro experiment indicated possibility of CBZ to be PXR agonist and PXR residue Gln285 to be important for CBZ-PXR interaction.Conclusions
CBZ alters the functional activity of ABCC2 through PXR, which in turn can interfere with therapy. Mutational analysis of residues revealed the importance of Gln285 in ligand interaction.78.
Kai Siang Chan Shanying Liang Yuan Teng Cho Yam Meng Chan Audrey Hui Min Tan Sivakami Muthuveerappa Tina Peiting Lai Cheng Cheng Goh Annie Joseph Qiantai Hong Enming Yong Li Zhang Lester Rhan Chaen Chong Glenn Wei Leong Tan Sadhana Chandrasekar Zhiwen Joseph Lo 《International wound journal》2022,19(2):436
Chronic venous insufficiency is a chronic disease of the venous system with a prevalence of 25% to 40% in females and 10% to 20% in males. Venous leg ulcers (VLUs) result from venous insufficiency. VLUs have a prevalence of 0.18% to 1% with a 1‐year recurrence of 25% to 50%, bearing significant socioeconomic burden. It is therefore important for regular assessment and monitoring of VLUs to prevent worsening. Our study aims to assess the intra‐ and inter‐rater reliability of a machine learning‐based handheld 3‐dimensional infrared wound imaging device (WoundAide [WA] imaging system, Konica Minolta Inc, Tokyo, Japan) compared with traditional measurements by trained wound nurse. This is a prospective cross‐sectional study on 52 patients with VLUs from September 2019 to January 2021 using three WA imaging systems. Baseline patient profile and clinical demographics were collected. Basic wound parameters (length, width and area) were collected for both traditional measurements and measurements taken by the WA imaging systems. Intra‐ and inter‐rater reliability was analysed using intra‐class correlation statistics. A total of 222 wound images from 52 patients were assessed. There is excellent intra‐rater reliability of the WA imaging system on three different image captures of the same wound (intra‐rater reliability ranging 0.978‐0.992). In addition, there is excellent inter‐rater reliability between the three WA imaging systems for length (0.987), width (0.990) and area (0.995). Good inter‐rater reliability for length and width (range 0.875‐0.900) and excellent inter‐rater reliability (range 0.932‐0.950) were obtained between wound nurse measurement and each of the WA imaging system. In conclusion, high intra‐ and inter‐rater reliability was obtained for the WA imaging systems. We also obtained high inter‐rater reliability of WA measurements against traditional wound measurement. The WA imaging system is a useful clinical adjunct in the monitoring of VLU wound documentation. 相似文献
79.
BACKGROUND: Surgical resection is the only curative treatment for patients with pheochromocytomas, paragangliomas, and other catecholamine-producing tumors. Patients with metastatic disease can often have significant symptoms associated with catecholamine excess. Activation of the Raf-1/MEK/ERK1/2 pathway has been shown to inhibit growth and hormone production for neuroendocrine tumors (NE) such as carcinoid and medullary thyroid cancer. However, the role of the Raf-1/MEK/ERK1/2 signaling pathway in pheochromocytomas is unknown. MATERIALS AND METHODS: Pheochromocytoma PC-12 cells were treated with varying concentrations of ZM336372, a pharmacologic Raf-1 activating drug. Levels of phosphorylated ERK1/2 and the NE marker Chromogranin A (CgA) were determined by Western blot. Cellular growth was measured by MTT cell-proliferation assay. RESULTS: At baseline, PC-12 cells had very little phosphorylated ERK1/2, similar to other NE tumors. Treatment of PC-12 cells with increasing dosages of ZM336372 resulted in increased phosphorylated ERK1/2. Importantly, ZM336372 inhibited pheochromocytoma cellular proliferation. Furthermore, Raf-1 pathway activation by ZM336372 was associated with suppression of NE marker, CgA, by the tumor cells. CONCLUSIONS: These data suggest that Raf-1/MEK/ERK1/2 pathway activation may be a novel strategy to treat pheochromocytoma and other catecholamine-producing tumors. In pheochromocytoma cells, ZM336372 blocks cellular proliferation and suppresses NE vasoactive peptide production. Thus, ZM336372 may be used for both therapeutic and palliative treatment for patients with pheochromocytomas. 相似文献
80.
Akin Akinc Michael Goldberg June Qin J Robert Dorkin Christina Gamba-Vitalo Martin Maier K Narayanannair Jayaprakash Muthusamy Jayaraman Kallanthottathil G Rajeev Muthiah Manoharan Victor Koteliansky Ingo Röhl Elizaveta S Leshchiner Robert Langer Daniel G Anderson 《Molecular therapy》2009,17(5):872-879
RNA interference therapeutics afford the potential to silence target gene expression specifically, thereby blocking production of disease-causing proteins. The development of safe and effective systemic small interfering RNA (siRNA) delivery systems is of central importance to the therapeutic application of siRNA. Lipid and lipid-like materials are currently the most well-studied siRNA delivery systems for liver delivery, having been utilized in several animal models, including nonhuman primates. Here, we describe the development of a multicomponent, systemic siRNA delivery system, based on the novel lipid-like material 98N12-5(1). We show that in vivo delivery efficacy is affected by many parameters, including the formulation composition, nature of particle PEGylation, degree of drug loading, and biophysical parameters such as particle size. In particular, small changes in the anchor chain length of poly(ethylene glycol) (PEG) lipids can result in significant effects on in vivo efficacy. The lead formulation developed is liver targeted (>90% injected dose distributes to liver) and can induce fully reversible, long-duration gene silencing without loss of activity following repeat administration. 相似文献