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41.
Christoph Kleinschnitz Henrike Grund Kirstin Wingler Melanie E. Armitage Emma Jones Manish Mittal David Barit Tobias Schwarz Christian Geis Peter Kraft Konstanze Barthel Michael K. Schuhmann Alexander M. Herrmann Sven G. Meuth Guido Stoll Sabine Meurer Anja Schrewe Lore Becker Valérie Gailus-Durner Helmut Fuchs Thomas Klopstock Martin Hrabé de Angelis Karin Jandeleit-Dahm Ajay M. Shah Norbert Weissmann Harald H. H. W. Schmidt 《PLoS biology》2010,8(9)
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4
−/−) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4
−/− mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. 相似文献
42.
Anurag K. Sinha Theetha L. Pavankumar Srinivasulu Kamisetty Pragya Mittal Malay K. Ray 《Molecular microbiology》2013,89(4):792-810
Chromosomal damage was detected previously in the recBCD mutants of the Antarctic bacterium Pseudomonas syringae Lz4W, which accumulated linear chromosomal DNA leading to cell death and growth inhibition at 4°C. RecBCD protein generally repairs DNA double‐strand breaks by RecA‐dependent homologous recombination pathway. Here we show that ΔrecA mutant of P. syringae is not cold‐sensitive. Significantly, inactivation of additional DNA repair genes ruvAB rescued the cold‐sensitive phenotype of ΔrecBCD mutant. The ΔrecA and ΔruvAB mutants were UV‐sensitive as expected. We propose that, at low temperature DNA replication encounters barriers leading to frequent replication fork (RF) arrest and fork reversal. RuvAB binds to the reversed RFs (RRFs) having Holliday junction‐like structures and resolves them upon association with RuvC nuclease to cause linearization of the chromosome, a threat to cell survival. RecBCD prevents this by degrading the RRFs, and facilitates replication re‐initiation. This model is consistent with our observation that low temperature‐induced DNA lesions do not evoke SOS response in P. syringae. Additional studies show that two other repair genes, radA (encoding a RecA paralogue) and recF are not involved in providing cold resistance to the Antarctic bacterium. 相似文献
43.
Sweety Mittal Mohini Bhadwal Sudipta Chakraborty H.D. Sarma Sharmila Banerjee M.R.A. Pillai 《Bioorganic & medicinal chemistry letters》2013,23(6):1808-1812
Radiolabeled Arg-Gly-Asp (RGD) peptides are promising agents for non invasive imaging of αvβ3 expression in malignant tumors. The integrin αvβ3 binding affinity and consequent tumor uptake could be improved when a dimeric RGD peptide is used as the targeting moiety instead of a monomer. Towards this, a novel approach was envisaged to synthesize a 99mTc labeled dimeric RGD derivative using a RGD monomer and [99mTcN]+2 intermediate. The dithiocarbamate derivative of cyclic RGD peptide G3-c(RGDfK) (G3 = Gly-Gly-Gly, f = Phe, K = Lys) was synthesized and radiolabeled with [99mTcN]+2 intermediate to form the 99mTcN-[G3-c(RGDfK)]2 complex in high yield (~98%). Biodistribution studies carried out in C57/BL6 mice bearing melanoma tumors showed good tumor uptake [4.61 ± 0.04% IA/g at 30 min post-injection] with fast clearance of the activity from non-target organs/tissue. Scintigraphic imaging studies showed visible accumulation of activity in the tumor with appreciable target to background ratio. 相似文献
44.
Vaishali A. Kilor Nidhi P. Sapkal Jasmine G. Awari Bharti D. Shewale 《AAPS PharmSciTech》2010,11(1):336-343
In the present study, an attempt was made to prepare immediate-release enteric-coated pellets of aceclofenac, a poorly soluble
nonsteroidal anti-inflammatory drug that has a gastrointestinal intolerance as its serious side effect. Formulation of enteric-coated
pellets with improved solubility of aceclofenac could address both of these problems. To achieve these goals, pellets were
prepared by extrusion–spheronization method using pelletizing agents that can contribute to the faster disintegration and
thereby improve the solubility of the drug. Different disintegrants like β-cyclodextrin, kollidon CL, Ac-Di-Sol, and sodium
starch glycolate were tried in order to further improve disintegration time. The pellets were characterized for drug content,
particle size distribution, flow properties, infrared spectroscopy, surface morphology, disintegration rate, and dissolution
profile. The formulations, which showed best disintegration and dissolution profiles, were coated with Eudragit L100-55, an
enteric-coated polymer which does not dissolve at gastric pH but dissolves at intestinal pH, releasing the drug immediately
in the dissolution medium. The optimized enteric-coated formulation containing 20% κ-carrageenan, lactose, and sodium starch
glycolate as a disintegrant did inhibit the release of the drug for 2 h in 0.1 N HCl, whereas 87% of the drug was released
within 45 min. The improvement was substantial when it was compared with solubility of pure drug under the same conditions.
Thus, dissolution profiles suggested that combination of κ-carrageenan and sodium starch glycolate resulted into fast-disintegrating,
immediate-release pellets, overcoming the bioavailability problem of the poorly soluble drug, aceclofenac, and enteric coating
of these pellets avoids the exposure of aceclofenac to ulcer-prone areas of the gastrointestinal tract. 相似文献
45.
Kim JS Romero R Tarca AL LaJeunesse C Han YM Kim MJ Suh YL Draghici S Mittal P Gotsch F Kusanovic JP Hassan S Kim CJ 《Journal of cellular and molecular medicine》2008,12(4):1317-1330
There is a difference in the susceptibility to inflammation between the umbilical vein (UV) and the umbilical arteries (UAs). This led us to hypothesize that there is an intrinsic difference in the pro-inflammatory response between UA and UV. Real-time quantitative RT-PCR and microarray analysis revealed higher expression of interleukin (IL)-1β and IL-8 mRNA in the UV and differential expression of 567 genes between the UA and UV associated with distinct biological processes, including the immune response. Differential expression of human leukocyte antigen (HLA)-DRA mRNA between the UA and UV was due to unexpected HLA-DR+ cells migrating via the umbilical vessels into Wharton's jelly, more frequently in the UV. A significant proportion of these cells co-expressed CD45 and type I pro-collagen, and acquired CD163 or α-smooth muscle actin immunoreactivity in Wharton's jelly. Migrating cells were also found in the chorionic and stem villous vessels. Furthermore, the extent of migration increased with progression of gestation, but diminished in intrauterine growth restriction (IUGR). The observations herein strongly suggest that circulating foetal fibrocytes, routing via umbilical and placental vessels, are a reservoir for key cellular subsets in the placenta. This study reports fibrocytes in the human umbilical cord and placenta for the first time, and a novel role for both circulating foetal cells and the umbilical vessels in placental development, which is deranged in IUGR. 相似文献
46.
Padda BS Jung SA Pretorius D Nager CW Den-Boer D Mittal RK 《American journal of physiology. Gastrointestinal and liver physiology》2007,292(2):G565-G571
The role of pelvic floor muscle contraction in the genesis of anal canal pressure is not clear. Recent studies have suggested that vaginal distension increases pelvic floor muscle contraction. We studied the effects of vaginal distension on anal canal pressure in 15 nullipara asymptomatic women. Anal pressure, rest, and squeeze were measured using station pull-through manometry techniques with no vaginal probe, a 10-mm vaginal probe, and a 25-mm vaginal probe in place. Rest and squeeze vaginal pressures were significantly higher when measured with the 25-mm probe compared with the 10-mm probe, suggesting that vaginal distension enhances pelvic floor contraction. In the presence of the 25-mm vaginal probe, rest and squeeze anal pressures in the proximal part of the anal canal were significantly higher compared with no vaginal probe or the 10-mm vaginal probe. On the other hand, distal anal pressures were not affected by any of the vaginal probes. Ultrasound imaging of the pelvic floor revealed that vaginal distension increased the anterior-posterior length of the puborectalis muscle. Atropine at 15 micro g/kg had no influence on the rest and squeeze anal pressures with or without vaginal distension. Our data suggest that pelvic floor contractions increase pressures in the proximal part of the anal canal, which is anatomically surrounded by the puborectalis muscle. We propose that pelvic floor contraction plays an important role in the fecal continence mechanism by increasing anal canal pressure. 相似文献
47.
Saxena AK Ram S Saxena M Singh N Prathipati P Jain PC Singh HK Anand N 《Bioorganic & medicinal chemistry》2003,11(9):2085-2090
A series of nineteen substituted 1,2,3,4,6,7,12,12a-octahydropyrazino[2',1':6,1]pyrido[3, 4-b]indoles analogues of neuroleptic drug, Centbutindole have been studied using quantitative structure-activity relationship analysis. The derived models display good fits to the experimental data (r>or=0.75) having good predictive power (r(cv)>or=0.688). The best model describes a high correlation between predicted and experimental activity data (r=0.967). Statistical analysis of the equation populations indicates that hydrophobicity (as measured by pi(R), logP(o/w) and SlogP_VSA8), dipole y and structural parameters in terms of indicator variable, (In(1)) and globularity are important variables in describing the variation in the neuroleptic activity in the series. 相似文献
48.
Summary Studies were conducted in 22 non-calcareous soils (India) to evaluate various extractants,viz. (6N HCl, 0.1N HCl, EDTA (NH4)2CO3, EDTA NH4OAc, DTPA+CaCl2 and 1M MgCl2) to find critical levels of soil and plant Zn for green gram (Phaseolus aureus Roxb.). The order of extractability by the different extractants was 6N HCl>0.1N HCl>EDTA (NH4)2CO3<EDTA NH4OAc DTPA+CaCl2>1M MgCl2.
Critical levels of 0.48 ppm DTPA × CaCl2 extractable Zn, 0.80 ppm EDTA NH4OAc extractable Zn, 0.70 ppm EDTA (NH4)2CO3 extractable Zn, and 2.2 ppm 0.1N HCl extractable Zn were estimated for the soils tested. The critical Zn concentration in 6 weeks old plants was found to
be 19 ppm. The 0.1N HCl method gave the best correlation (r=0.588**) between extractable Zn and Bray's per cent yield, while with DTPA+CaCl2, it was slightly low (r=0.542**). The DTPA + CaCl2 method gave significant (r=0.73**) correlation with plant Zn concentration. The 0.1N HCl gave the higher correlation with Zn uptake (r=0.661**) than DTPA (r=0.634**) 6N HCl and 1M MgCl2 method gave nonsignificant positive relationship with Bray's per cent yield. For noncalcareous soils apart from the common
use of DTPA+CaCl2, 0.1N HCl can also be used for predicting soil available Zn. The use of 0.1N HCl would be much cheaper than DTPA and other extractants used in the study. 相似文献
49.
Rishein Gupta Harsh Vardhan Pragya Srivastava Sudha Salhan Aruna Mittal 《Reproductive biology and endocrinology : RB&E》2009,7(1):84-13
Background
Chlamydial Inclusion membrane proteins (Incs), are involved in biochemical interactions with host cells and infecting Chlamydiae. We have previously reported the role of two Chlamydia trachomatis (CT) Incs, namely IncB and IncC in generating host immunity in CT infected women. Emerging data shows involvement of Inc stimulated CD4 positive T cells in aiding host immunity in infected fertile and infertile women through the secretion of interferon gamma. However the lack of data on the intra-cytokine interplay to these Incs in infected cell milieu prompted us to investigate further. 相似文献50.