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81.
Ranjit K. Mehta Sushmita Shukla Susmita G. Ramanand Vishal Somnay Alexander J. Bridges Theodore S. Lawrence Mukesh K. Nyati 《Translational oncology》2021,14(8)
Disruptin is a cell-permeable decoy peptide designed to destabilize activated EGFR, both by inhibiting Hsp90 chaperoning and dissociating the active asymmetric EGFR dimer, which leads to an increase in engagement of activated EGFR with the proteolytic degradation machinery and subsequent loss from the cells. Disruptin is an N-terminally biotinylated nonadecapeptide, with 8 amino acids from the αC-helix-β4 sheet loop of EGFR (S767-C774) fused to a TAT undecapeptide. The S767-R775 loop is at the interface with juxtamembrane domains in the active EGFR dimers and is a binding site for Hsp90. Cellular studies in EGFR-activated tumor cells demonstrated that Disruptin causes the disappearance of EGFR protein from cells over a few hours, a growth inhibitory effect, similar but more effective than the EGFR kinase inhibition. Interestingly, cells without activated EGFR remained unaffected. In vivo studies showed that Disruptin slowed the growth of small tumors. Larger tumors responded to intratumoral injections but did not respond to systemic administration at tolerated doses. Investigation of these results revealed that systemic administration of Disruptin has acute toxicities, mainly related to its TAT peptide moiety. Therefore, we conclude that although the efficacy of both in vitro and in vivo intratumoral injection of Disruptin supports the therapeutic strategy of blocking activated EGFR dimerization, Disruptin is not suitable for further development. These studies also highlight the importance of the chosen models and drug-delivery methods for such investigations. 相似文献
82.
83.
Iron chelators for the treatment of malaria have proven therapeutic activity in vitro and in vivo in both humans and mice, but their clinical use is limited by the unsuitable absorption and pharmacokinetic properties of the few available iron chelators. FBS0701, (S)3"-(HO)-desazadesferrithiocin-polyether [DADFT-PE], is an oral iron chelator currently in Phase 2 human studies for the treatment of transfusional iron overload. The drug has very favorable absorption and pharmacokinetic properties allowing for once-daily use to deplete circulating free iron with human plasma concentrations in the high μM range. Here we show that FBS0701 has inhibition concentration 50% (IC(50)) of 6 μM for Plasmodium falciparum in contrast to the IC(50) for deferiprone and deferoxamine at 15 and 30 μM respectively. In combination, FBS0701 interfered with artemisinin parasite inhibition and was additive with chloroquine or quinine parasite inhibition. FBS0701 killed early stage P. falciparum gametocytes. In the P. berghei Thompson suppression test, a single dose of 100 mg/kg reduced day three parasitemia and prolonged survival, but did not cure mice. Treatment with a single oral dose of 100 mg/kg one day after infection with 10 million lethal P. yoelii 17XL cured all the mice. Pretreatment of mice with a single oral dose of FBS0701 seven days or one day before resulted in the cure of some mice. Plasma exposures and other pharmacokinetics parameters in mice of the 100 mg/kg dose are similar to a 3 mg/kg dose in humans. In conclusion, FBS0701 demonstrates a single oral dose cure of the lethal P. yoelii model. Significantly, this effect persists after the chelator has cleared from plasma. FBS0701 was demonstrated to remove labile iron from erythrocytes as well as enter erythrocytes to chelate iron. FBS0701 may find clinically utility as monotherapy, a malarial prophylactic or, more likely, in combination with other antimalarials. 相似文献
84.
Gustavo Palacios Mady Hornig Daniel Cisterna Nazir Savji Ana Valeria Bussetti Vishal Kapoor Jeffrey Hui Rafal Tokarz Thomas Briese Elsa Baumeister W. Ian Lipkin 《PloS one》2009,4(12)
Background
Initial reports in May 2009 of the novel influenza strain H1N1pdm estimated a case fatality rate (CFR) of 0.6%, similar to that of seasonal influenza. In July 2009, however, Argentina reported 3056 cases with 137 deaths, representing a CFR of 4.5%. Potential explanations for increased CFR included virus reassortment or genetic drift, or infection of a more vulnerable population. Virus genomic sequencing of 26 Argentinian samples representing both severe and mild disease indicated no evidence of reassortment, mutations associated with resistance to antiviral drugs, or genetic drift that might contribute to virulence. Furthermore, no evidence was found for increased frequency of risk factors for H1N1pdm disease.Methods/Principal Findings
We examined nasopharyngeal swab samples (NPS) from 199 cases of H1N1pdm infection from Argentina with MassTag PCR, testing for 33 additional microbial agents. The study population consisted of 199 H1N1pdm-infected subjects sampled between 23 June and 4 July 2009. Thirty-nine had severe disease defined as death (n = 20) or hospitalization (n = 19); 160 had mild disease. At least one additional agent of potential pathogenic importance was identified in 152 samples (76%), including Streptococcus pneumoniae (n = 62); Haemophilus influenzae (n = 104); human respiratory syncytial virus A (n = 11) and B (n = 1); human rhinovirus A (n = 1) and B (n = 4); human coronaviruses 229E (n = 1) and OC43 (n = 2); Klebsiella pneumoniae (n = 2); Acinetobacter baumannii (n = 2); Serratia marcescens (n = 1); and Staphylococcus aureus (n = 35) and methicillin-resistant S. aureus (MRSA, n = 6). The presence of S. pneumoniae was strongly correlated with severe disease. S. pneumoniae was present in 56.4% of severe cases versus 25% of mild cases; more than one-third of H1N1pdm NPS with S. pneumoniae were from subjects with severe disease (22 of 62 S. pneumoniae-positive NPS, p = 0.0004). In subjects 6 to 55 years of age, the adjusted odds ratio (OR) of severe disease in the presence of S. pneumoniae was 125.5 (95% confidence interval [CI], 16.95, 928.72; p<0.0001).Conclusions/Significance
The association of S. pneumoniae with morbidity and mortality is established in the current and previous influenza pandemics. However, this study is the first to demonstrate the prognostic significance of non-invasive antemortem diagnosis of S. pneumoniae infection and may provide insights into clinical management. 相似文献85.
Kumar Ritesh Khungar Lisha Shimphrui Rinchuila Tiwari Lalit Dev Tripathi Gayatri Sarkar Neelam K. Agarwal Surekha-Katiyar Agarwal Manu Grover Anil 《Journal of plant biochemistry and biotechnology.》2020,29(4):715-732
Journal of Plant Biochemistry and Biotechnology - Caseinolytic protease (Clp)/Hsp100 proteins are members of the AAA+ (ATPase associated with a variety of cellular activities) family of proteins... 相似文献
86.
Ashish K. Mehta Yogendra Bhati Chakra D. Tripathi Krishna K. Sharma 《Neurochemical research》2014,39(8):1433-1439
Despite immense advances in the treatment strategies, management of neuropathic pain remains unsatisfactory. Piracetam is a prototype of nootropic drugs, used to improve cognitive impairment. The present study was designed to investigate the effect of piracetam on peripheral neuropathic pain in rats. Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, piracetam was intraperitoneally administered for 2 weeks in doses of 50, 100 and 200 mg/kg, and pain was assessed by employing the behavioural tests for thermal hyperalgesia (hot plate and tail flick tests) and cold allodynia (acetone test). After the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of piracetam (50 mg/kg) did not have any significant effect on all the behavioural tests. Further, piracetam (100 mg/kg) also had no effect on the hot plate and tail flick tests; however it significantly decreased the paw withdrawal duration in the acetone test. Piracetam in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot plate and tail flick latencies, and decreased paw withdrawal duration (in acetone test). Therefore, the present study suggests the potential use of piracetam in the treatment of neuropathic pain, which merits further clinical investigation. 相似文献
87.
Cropping on jhum fallows in north-eartern India is predominantly done for one year in a jhum cycle. If second year cropping
is done, expanse of the forest land required for slashing and burning could be reduced significantly. We tested this hypothesis
in a young (6 yr) and an old (20 yr) jhum fallow. We also evaluated if the productivity during second year cropping could
be alleviated by auxiliary measures such as tilling the soil or application of fertilizers (chemical or farm-yard manure or
both in combination). The results demonstrate that the ecosystem productivity (total dry matter production) and economic yield
(rice grain production) decline with shortening of jhum cycle. Second year cropping causes a further decline in ecosystem
productivity in old jhum field, but not in young jhum field. Economic yield from second year cropping in its traditional form
(without any fertilizer treatment) is not much lower than that in the first year, and can be improved further by manuring
the soil. Tilling of soil improves neither ecosystem productivity nor economic yield. Different fertilization treatments respond
differently; while inorganic manuring enhances ecosystem productivity, a combination of inorganic and organic manuring improves
economic yield 相似文献
88.
Satyendra Chandra Tripathi Ajay Matta Jatinder Kaur Jorg Grigull Shyam Singh Chauhan Alok Thakar Nootan Kumar Shukla Ritu Duggal Siddhartha DattaGupta Ranju Ralhan K. W. Michael Siu 《PloS one》2010,5(8)
Background
Tissue proteomic analysis of head and neck squamous cell carcinoma (HNSCC) and normal oral mucosa using iTRAQ (isobaric tag for relative and absolute quantitation) labeling and liquid chromatography-mass spectrometry, led to the identification of a panel of biomarkers including S100A7. In the multi-step process of head and neck tumorigenesis, the presence of dysplastic areas in the epithelium is proposed to be associated with a likely progression to cancer; however there are no established biomarkers to predict their potential of malignant transformation. This study aimed to determine the clinical significance of S100A7 overexpression in HNSCC.Methodology
Immunohistochemical analysis of S100A7 expression in HNSCC (100 cases), oral lesions (166 cases) and 100 histologically normal tissues was carried out and correlated with clinicopathological parameters and disease prognosis over 7 years for HNSCC patients. Overexpression of S100A7 protein was significant in oral lesions (squamous cell hyperplasia/dysplasia) and sustained in HNSCC in comparison with oral normal mucosa (ptrend<0.001). Significant increase in nuclear S100A7 was observed in HNSCC as compared to dysplastic lesions (p = 0.005) and associated with well differentiated squamous cell carcinoma (p = 0.031). Notably, nuclear accumulation of S100A7 also emerged as an independent predictor of reduced disease free survival (p = 0.006, Hazard ratio (HR = 7.6), 95% CI = 1.3−5.1) in multivariate analysis underscoring its relevance as a poor prognosticator of HNSCC patients.Conclusions
Our study demonstrated nuclear accumulation of S100A7 may serve as predictor of poor prognosis in HNSCC patients. Further, increased nuclear accumulation of S100A7 in HNSCC as compared to dysplastic lesions warrants a large-scale longitudinal study of patients with dysplasia to evaluate its potential as a determinant of increased risk of transformation of oral premalignant lesions. 相似文献89.
Douglas B. Kintner Xinzhi Chen Julia Currie Vishal Chanana Peter Ferrazzano Akemichi Baba Toshio Matsuda Mike Cohen John Orlowski Shing-Yan Chiu Jack Taunton Dandan Sun 《The Journal of biological chemistry》2010,285(45):35155-35168
Neuronal dendrites are vulnerable to injury under diverse pathological conditions. However, the underlying mechanisms for dendritic Na+ overload and the selective dendritic injury remain poorly understood. Our current study demonstrates that activation of NHE-1 (Na+/H+ exchanger isoform 1) in dendrites presents a major pathway for Na+ overload. Neuronal dendrites exhibited higher pHi regulation rates than soma as a result of a larger surface area/volume ratio. Following a 2-h oxygen glucose deprivation and a 1-h reoxygenation, NHE-1 activity was increased by ∼70–200% in dendrites. This elevation depended on activation of p90 ribosomal S6 kinase. Moreover, stimulation of NHE-1 caused dendritic Na+i accumulation, swelling, and a concurrent loss of Ca2+i homeostasis. The Ca2+i overload in dendrites preceded the changes in soma. Inhibition of NHE-1 or the reverse mode of Na+/Ca2+ exchange prevented these changes. Mitochondrial membrane potential in dendrites depolarized 40 min earlier than soma following oxygen glucose deprivation/reoxygenation. Blocking NHE-1 activity not only attenuated loss of dendritic mitochondrial membrane potential and mitochondrial Ca2+ homeostasis but also preserved dendritic membrane integrity. Taken together, our study demonstrates that NHE-1-mediated Na+ entry and subsequent Na+/Ca2+ exchange activation contribute to the selective dendritic vulnerability to in vitro ischemia. 相似文献
90.
Vishal Gupta A. J. Bijo Manoj Kumar C. R. K. Reddy Bhavanath Jha 《Marine biotechnology (New York, N.Y.)》2012,14(6):692-700
Regeneration of protoplasts into de novo plants was reported for a large number of seaweed species. The regeneration of protoplasts into different morphotypes as a result of epigenetic variations was discussed for the first time in this study. The loci assessed for methylation modifications in normal filamentous thalli showed a frequency of 32.43% as unmethylated DNA, 24.32% as a hemimethylated, and 20.27% as a methylation of internal cytosine at both the strands. The corresponding methylation values for disk-type thalli were 27.02%, 32.43%, and 14.86%, respectively. The hypermethylation condition was apparent in the disk-type thalli with methylation ratio of 72.97% compared to that of normal filamentous thalli with 67.56%. The frequency of methylation polymorphic sites among the two morphotypes was 53%. The present study reveals the distinct expression of cytosine methylation and is thus correlated to differential morphogenesis of plants regenerated from cultured cells. The number of protoplasts regenerating into filamentous thalli declined with increasing temperature from 15°C, 20°C, 25°C, and 30°C. The disk-type variant had higher thermal stability at 30°C over normal filamentous thalli. Further, this variant could maintain itself for more than a year in the laboratory indicating its suitability for in vitro germplasm maintenance and propagation. 相似文献