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INTRODUCTIONAsearlyasin1948wehavefr8CtionatedisolatednucleifromnormalandtumorcellsbyextractionwithiMNaCIanddilutealkali[1].Thenuclearresiduewasthenstudiedmorethoroughly[2,3].Lateron,sillillarproteinousnuclearresidueswereisolatedbyotherworkers[46]andasstud… 相似文献
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Background
In the present study we tested the hypothesis that progression of streptozotocin (STZ)-induced diabetes (14-days to 28-days) would produce renal and vascular dysfunction that correlate with altered p38- mitogen-activated protein kinase (p38-MAPK) phosphorylation in kidneys and thoracic aorta.Methods
Male Sprague Dawley rats (350–400 g) were randomized into three groups: sham (N = 6), 14-days diabetic (N = 6) and 28-days diabetic rats (N = 6). Diabetes was induced using a single tail vein injection of STZ (60 mg/kg, I.V.) on the first day. Rats were monitored for 28 days and food, water intake and plasma glucose levels were noted. At both 14-days and 28-days post diabetes blood samples were collected and kidney cortex, medulla and aorta were harvested from each rat.Results
The diabetic rats lost body weight at both 14-days (-10%) and 28-days (-13%) more significantly as compared to sham (+10%) group. Glucose levels were significantly elevated in the diabetic rats at both 14-days and 28-days post-STZ administration. Renal dysfunction as evidenced by renal hypertrophy, increased plasma creatinine concentration and reduced renal blood flow was observed in 14-days and 28-days diabetes. Vascular dysfunction as evidenced by decreased carotid blood flow was observed in 14-days and 28-days diabetes. We observed an up-regulation of inducible nitric oxide synthase (iNOS), prepro endothelin-1 (preproET-1) and phosphorylated p38-MAPK in thoracic aorta and kidney cortex but not in kidney medulla in 28-days diabetes group.Conclusion
The study provides evidence that diabetes produces vascular and renal dysfunction with a profound effect on signaling mechanisms at later stage of diabetes. 相似文献64.
Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation 总被引:2,自引:0,他引:2
Earlier we have demonstrated that inhibition of endothelin biosynthesis ameliorates endotoxemia-induced inducible nitric oxide synthase (iNOS) activation and phosphorylation of p38-mitogen activated protein kinase (pp38-MAPK). Therefore, in the present study, we tested the hypothesis that activation of endothelin (ET)-1 biosynthesis using bigET-1 during early sepsis would upregulate iNOS and affect myocardial function in the rat. Male Sprague-Dawley rats (350–400 g) were anesthetised using Nembutal® (50 mg/kg, i.p.) and jugular vein, tail artery (Mean arterial pressure, MAP) and right carotid arteries (advanced to left ventricle, LV) were cannulated. The rats were randomly divided into saline-, bigET-1- and C-terminal fragment of bigET-1(bigET-1(22-38))-treated groups. Sepsis was induced using i.p. injection of cecal inoculum obtained from a donor rat (200 mg/kg in 5 ml 5% sterile dextrose water, D5W). Sham animals received an i.p. injection of D5W (5 ml/kg). MAP and LVP were recorded and cardiodynamic parameters were calculated at 0, 2, 6, 12 and 24 h post sham or sepsis-induction. A significant elevation in LV isovolumic relaxation rate constant (tau), LV end diastolic pressure (LVEDP) and rate pressure product (RPP) was observed in vehicle-treated septic group at 24 h. BigET-1 significantly increased concentration of LV ET-1 both in sham and septic groups. BigET-1 elevated tau and LVEDP both in sham and septic animals as early as 12 h which persisted through 24 h. However, bigET-1(22-38) elevated LVEDP in septic group at 24 h but not in sham group. BigET-1 accentuated the levels of plasma nitric oxide byproduct (NOx) levels in both sham and septic animals at 6, 12 and 24 h. Sepsis increased myocardial iNOS at 24 h. BigET-1 significantly upregulated expression of myocardial iNOS and pp38-MAPK. The data suggest that increased substrate availability for ET-1 at the time of sepsis-induction contributes in diastolic dysfunction, iNOS activation and p38-MAPK phosphorylation. (Mol Cell Biochem 271: 225–237, 2005) 相似文献
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Nonmotile cells extend and retract pseudopodia-like structures in a random manner, whereas motile cells establish a single dominant pseudopodium in the direction of movement. This is a critical step necessary for cell migration and occurs prior to cell body translocation, yet little is known about how this process is regulated. Here we show that myosin II light chain (MLC) phosphorylation at its regulatory serine 19 is elevated in growing and retracting pseudopodia. MLC phosphorylation in the extending pseudopodium was associated with strong and persistent amplification of extracellular-regulated signal kinase (ERK) and MLC kinase activity, which specifically localized to the leading pseudopodium. Interestingly, inhibition of ERK or MLC kinase activity prevented MLC phosphorylation and pseudopodia extension but not retraction. In contrast, inhibition of RhoA activity specifically decreased pseudopodia retraction but not extension. Importantly, inhibition of RhoA activity specifically blocked MLC phosphorylation associated with retracting pseudopodia. Inhibition of either ERK or RhoA signals prevents chemotaxis, indicating that both pathways contribute to the establishment of cell polarity and migration. Together, these findings demonstrate that ERK and RhoA are distinct pathways that control pseudopodia extension and retraction, respectively, through differential modulation of MLC phosphorylation and contractile processes. 相似文献
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Khambhaty Y Mody K Gandhi MR Thampy S Maiti P Brahmbhatt H Eswaran K Ghosh PK 《Bioresource technology》2012,103(1):180-185
The present study describes production of bio-ethanol from fresh red alga, Kappaphycus alvarezii. It was crushed to expel sap - a biofertilizer - while residual biomass was saccharified at 100 °C in 0.9 N H2SO4. The hydrolysate was repeatedly treated with additional granules to achieve desired reducing sugar concentration. The best yields for saccharification, inclusive of sugar loss in residue, were 26.2% and 30.6% (w/w) at laboratory (250 g) and bench (16 kg) scales, respectively. The hydrolysate was neutralized with lime and the filtrate was desalted by electrodialysis. Saccharomyces cerevisiae (NCIM 3523) was used for ethanol production from this non-traditional bio-resource. Fermentation at laboratory and bench scales converted ca. 80% of reducing sugar into ethanol in near quantitative selectivity. A petrol vehicle was successfully run with E10 gasoline made from the seaweed-based ethanol. Co-production of ethanol and bio-fertilizer from this seaweed may emerge as a promising alternative to land-based bio-ethanol. 相似文献
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Lysosphingolipids are important lipid signaling molecules that are associated predominantly with high density lipoproteins (HDL) in human plasma. Further, HDL has been shown to be a target for the reactive chlorinating species (RCS) produced by myeloperoxidase (MPO). Accordingly, RCS attack of lysosphingolipids was characterized in these studies. It was shown that RCS attack of sphingosylphosphorylcholine results in the formation of 2-hexadecenal and 1-cyano methano phosphocholine. The structures were identified and confirmed predominantly using mass spectrometric analyses. Further, it was demonstrated that RCS attack of another bioactive lysosphingolipid sphingosine 1-phosphate also results in the formation of 2-hexadecenal from its sphingosine base. Using a synthetically prepared, deuterated 2-hexadecenal internal standard, it was determined that 2-hexadecenal quickly accumulated in HDL treated with MPO/RCS generating system. Thus, the present studies characterize the formation of a novel group of lipid products generated following RCS attack of lysosphingolipids. 相似文献
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Erica H. Layer Caitlin E. Kennedy Sarah W. Beckham Jessie K. Mbwambo Samuel Likindikoki Wendy W. Davis Deanna L. Kerrigan Heena Brahmbhatt the LTC Tanzania Collaborative Study Team 《PloS one》2014,9(8)
Progression through the HIV continuum of care, from HIV testing to lifelong retention in antiretroviral therapy (ART) care and treatment programs, is critical to the success of HIV treatment and prevention efforts. However, significant losses occur at each stage of the continuum and little is known about contextual factors contributing to disengagement at these stages. This study sought to explore multi-level barriers and facilitators influencing entry into and engagement in the continuum of care in Iringa, Tanzania. We used a mixed-methods study design including facility-based assessments and interviews with providers and clients of HIV testing and treatment services; interviews, focus group discussions and observations with community-based providers and clients of HIV care and support services; and longitudinal interviews with men and women living with HIV to understand their trajectories in care. Data were analyzed using narrative analysis to identify key themes across levels and stages in the continuum of care. Participants identified multiple compounding barriers to progression through the continuum of care at the individual, facility, community and structural levels. Key barriers included the reluctance to engage in HIV services while healthy, rigid clinic policies, disrespectful treatment from service providers, stock-outs of supplies, stigma and discrimination, alternate healing systems, distance to health facilities and poverty. Social support from family, friends or support groups, home-based care providers, income generating opportunities and community mobilization activities facilitated engagement throughout the HIV continuum. Findings highlight the complex, multi-dimensional dynamics that individuals experience throughout the continuum of care and underscore the importance of a holistic and multi-level perspective to understand this process. Addressing barriers at each level is important to promoting increased engagement throughout the continuum. 相似文献
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Thomas D Walko III Valentina Di Caro Jon Piganelli Timothy R Billiar Robert SB Clark Rajesh K Aneja 《Molecular medicine (Cambridge, Mass.)》2014,20(1):612-624
Pathophysiological conditions that lead to the release of the prototypic damage-associated molecular pattern molecule high mobility group box 1 (HMGB1) also result in activation of poly(ADP-ribose) polymerase 1 (PARP1; now known as ADP-ribosyl transferase 1 [ARTD1]). Persistent activation of PARP1 promotes energy failure and cell death. The role of poly(ADP-ribosyl)ation in HMGB1 release has been explored previously; however, PARP1 is a versatile enzyme and performs several other functions including cross-talk with another nicotinamide adenine dinucleotide- (NAD+) dependent member of the Class III histone deacetylases (HDACs), sirtuin-1 (SIRT1). Previously, it has been shown that the hyperacetylation of HMGB1 is a seminal event prior to its secretion, a process that also is dependent on HDACs. Therefore, in this study, we seek to determine if PARP1 inhibition alters LPS-mediated HMGB1 hyperacetylation and subsequent secretion due to its effect on SIRT1. We demonstrate in an in vitro model that LPS treatment leads to hyperacetylated HMGB1 with concomitant reduction in nuclear HDAC activity. Treatment with PARP1 inhibitors mitigates the LPS-mediated reduction in nuclear HDAC activity and decreases HMGB1 acetylation. By utilizing an NAD+-based mechanism, PARP1 inhibition increases the activity of SIRT1. Consequently, there is an increased nuclear retention and decreased extracellular secretion of HMGB1. We also demonstrate that PARP1 physically interacts with SIRT1. Further confirmation of this data was obtained in a murine model of sepsis, that is, administration of PJ-34, a specific PARP1 inhibitor, led to decreased serum HMGB1 concentrations in mice subjected to cecal ligation and puncture (CLP) as compared with untreated mice. In conclusion, our study provides new insights in understanding the molecular mechanisms of HMGB1 secretion in sepsis. 相似文献