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11.
Jyoti Mareddy N. Suresh C. Ganesh Kumar Ravikumar Kapavarapu A. Jayasree Sarbani Pal 《Bioorganic & medicinal chemistry letters》2017,27(3):518-523
A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 ~6–10 μM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60–70% at 10 μM) that was supported by the docking studies (PLP score 87–94) in silico. 相似文献
12.
Prachi Jain Somesh Baranwal Shengli Dong Amanda P. Struckhoff Rebecca A. Worthylake Suresh K. Alahari 《The Journal of biological chemistry》2013,288(22):15495-15509
Biallelic inactivation of LKB1, a serine/threonine kinase, has been detected in 30% of lung adenocarcinomas, and inhibition of breast tumor growth has been demonstrated. We have identified the tumor suppressor, Nischarin, as a novel binding partner of LKB1. Our mapping analysis shows that the N terminus of Nischarin interacts with amino acids 44–436 of LKB1. Time lapse microscopy and Transwell migration data show that the absence of both Nischarin and LKB1 from an invasive breast cancer cell line (MDA-MB-231) enhances migration as measured by increased distance and speed of migrating cells. Our data suggest that this is a result of elevated PAK1 and LIMK1 phosphorylation. Moreover, the absence of Nischarin and LKB1 increased tumor growth in vivo. Consistent with this, the percentage of S phase cells was increased, as demonstrated by flow cytometry and enhanced cyclin D1. The absence of Nischarin and LKB1 also led to a dramatic increase in the formation of lung metastases. Our studies, for the first time, demonstrate functional interaction between LKB1 and Nischarin to inhibit cell migration and breast tumor progression. Mechanistically, we show that these two proteins together regulate PAK-LIMK-Cofilin and cyclin D1/CDK4 pathways. 相似文献
13.
During 30-months of storage at 4°C, potato (Solanum tuberosum L.) tubers progressively lose the ability to produce superoxide in response to wounding, resist microbial infection, and
develop a suberized wound periderm. Using differentially aged tubers, we demonstrate that Strboh A is responsible for the wound-induced oxidative burst in potato and aging attenuates its expression. In vivo superoxide production
and NADPH oxidase (NOX) activity from 1-month-old tubers increased to a maximum 18–24 h after wounding and then decreased
to barely detectable levels by 72 h. Wounding also induced a 68% increase in microsomal protein within 18 h. These wound-induced
responses were lost over a 25- to 30-month storage period. Superoxide production and NOX activity were inhibited by diphenylene
iodonium chloride, a specific inhibitor of NOX, which in turn effectively inhibited wound-healing and increased susceptibility
to microbial infection and decay in 1-month-old tubers. Wound-induced superoxide production was also inhibited by EGTA-mediated
destabilization of membranes. The ability to restore superoxide production to EGTA-treated tissue with Ca+2 declined with advancing tuber age, likely a consequence of age-related changes in membrane architecture. Of the five homologues
of NOX (Strboh A-D and F), wounding induced the expression of Strboh A in 6-month-old tubers but this response was absent in tubers stored for 25–30 months. Strboh
A thus mediates the initial burst of superoxide in response to wounding of potato tubers; loss of its expression increases
the susceptibility to microbial infection and contributes to the age-induced loss of wound-healing ability. 相似文献
14.
Balabaskaran Nina P Morrisey JM Ganesan SM Ke H Pershing AM Mather MW Vaidya AB 《The Journal of biological chemistry》2011,286(48):41312-41322
The rotary nanomotor ATP synthase is a central player in the bioenergetics of most organisms. Yet the role of ATP synthase in malaria parasites has remained unclear, as blood stages of Plasmodium falciparum appear to derive ATP largely through glycolysis. Also, genes for essential subunits of the F(O) sector of the complex could not be detected in the parasite genomes. Here, we have used molecular genetic and immunological tools to investigate the localization, complex formation, and functional significance of predicted ATP synthase subunits in P. falciparum. We generated transgenic P. falciparum lines expressing seven epitope-tagged canonical ATP synthase subunits, revealing localization of all but one of the subunits to the mitochondrion. Blue native gel electrophoresis of P. falciparum mitochondrial membranes suggested the molecular mass of the ATP synthase complex to be greater than 1 million daltons. This size is consistent with the complex being assembled as a dimer in a manner similar to the complexes observed in other eukaryotic organisms. This observation also suggests the presence of previously unknown subunits in addition to the canonical subunits in P. falciparum ATP synthase complex. Our attempts to disrupt genes encoding β and γ subunits were unsuccessful, suggesting an essential role played by the ATP synthase complex in blood stages of P. falciparum. These studies suggest that, despite some unconventional features and its minimal contribution to ATP synthesis, P. falciparum ATP synthase is localized to the parasite mitochondrion, assembled as a large dimeric complex, and is likely essential for parasite survival. 相似文献
15.
Anjali V. Sahasrabudhe Suresh M. Solapure Rajeev Khurana Vepa Suryanarayan Sudha Ravishankar Sunita M. deSousa Goutam Das 《Protein expression and purification》1998,14(3):425-433
hBSSL and its truncated variant hBSSL-C cDNA clones were expressed inPichia pastorisusing two different signal peptides, native signal peptide and invertase signal peptide, respectively, to facilitate secretion of the recombinant proteins into the culture medium. Both recombinant proteins were secreted into the culture medium to a level of 45–50 mg/liter in shake flask cultures. Native signal peptide of hBSSL was recognized inP. pastorisand was cleaved at the same site as in humans. The level of expression of the hBSSL gene was found to be dependent on the number of its copies integrated into the host chromosome. The multicopy transformant clone was found to be very stable. When grown and induced in a fermentor, the level of accumulation of the recombinant hBSSL in the culture medium improved from 50 mg/liter in shake flask cultures to 300 mg/liter. The recombinant hBSSL purified from the culture supernatant was found to be similar to the native hBSSL in its biochemical properties except for the lectin-binding profile. 相似文献
16.
Patil SB Bitar KN 《American journal of physiology. Gastrointestinal and liver physiology》2006,290(1):G83-G95
Agonist-induced activation of the RhoA/Rho kinase (ROCK) pathway results in inhibition of myosin phosphatase and maintenance of myosin light chain (MLC20) phosphorylation. We have shown that RhoA/ROCKII translocates and associates with heat shock protein (HSP)27 in the particulate fraction. We hypothesize that inhibition of the 130-kDa regulatory myosin-binding subunit (MYPT) requires its association with HSP27 in the particulate fraction. Furthermore, it is not certain whether regulation of MYPT by CPI-17 or by ROCKII is due to cross talk between RhoA and PKC-alpha. Presently, we examined the cross talk between RhoA and PKC-alpha in the regulation of MYPT phosphorylation in rabbit colon smooth muscle cells. Acetylcholine induced 1) sustained phosphorylation of PKC-alpha, CPI-17, and MYPT; 2) an increase in the association of phospho-MYPT with HSP27 in the particulate fraction; 3) a decrease in myosin phosphatase activity (66.21+/-3.52 and 42.19+/-3.85% nM/ml lysate at 30 s and 4 min); and 4) an increase in PKC activity (298.12+/-46.60% and 290.59+/-22.07% at 30 s and 4 min). Inhibition of RhoA/ROCKII by Y-27632 inhibited phosphorylation of MYPT and its association with HSP27. Both Y27632 and a negative dominant construct of RhoA inhibited phosphorylation of MYPT and CPI-17. Inhibition of PKCs or calphostin C or selective inhibition of PKC-alpha by negative dominant constructs inhibited phosphorylation of MYPT and CPI-17. The results suggest that 1) acetylcholine induces activation of both RhoA and/or PKC-alpha pathways, suggesting cross talk between RhoA and PKC-alpha resulting in phosphorylation of MYPT, inhibition of myosin phosphatase activity, and maintenance of MLC phosphorylation; and 2) phosphorylated MYPT is associated with HSP27 and translocated to the particulate fraction, suggesting a scaffolding role for HSP27 in mediating the association of the complex MYPT/RhoA-ROCKII. Thus both pathways (PKC and RhoA) converge on the regulation of myosin phosphatase activities and modulate sustained phosphorylation of MLC20. 相似文献
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19.
Shahabi V Whitney G Hamid O Schmidt H Chasalow SD Alaparthy S Jackson JR 《Cancer immunology, immunotherapy : CII》2012,61(5):733-737
Ipilimumab, a fully human monoclonal antibody against cytotoxic T lymphocyte antigen-4, has demonstrated significant improvement
in overall survival in previously treated advanced melanoma patients. The BRAF inhibitor, vemurafenib, has shown up to 78%
objective response rates in melanoma patients harboring the BRAF-V600E mutation but not in patients lacking the mutation.
As an immune potentiator, the mechanism of action of ipilimumab may not be dependent of the activity of the BRAF pathway.
To test this, we investigated whether the clinical activity of ipilimumab would be affected by the BRAF-V600E mutation status
of the tumors. Thus, this retrospective analysis was carried using a set of tumor biopsies from a completed phase II clinical
trial. CA184004 was a randomized, double-blind, multicenter trial of 82 previously treated or untreated patients with unresectable
stage III/IV melanoma. Patients received ipilimumab 3 or 10 mg/kg every 3 weeks for four doses followed by maintenance dosing
in eligible patients. The BRAF-V600E mutation status for 80 patients was determined in tumor biopsies by PCR-based assays.
Data on disease control were available for 69 patients with evaluated BRAF-V600E mutation status. Rates of objective responses
and stable disease in patients with BRAF-V600E mutation positive tumors (30%) were comparable to those in patients with the
wild-type gene (~33%). Eleven patients displayed Durable Disease Control (DDC) of which 55% had BRAF-V600E mutation positive
tumors and 45% did not. In the 48 patients showing no DDC, the mutation frequency was 50%. In this study, no association between
BRAF-V600E mutation status of melanoma tumors and DDC after treatment with ipilimumab was detected. 相似文献
20.