Vascular leakage in multiple organs is a characteristic pathological change in sepsis. Our recent study revealed that ascorbate protects endothelial barrier function in microvascular endothelial cell monolayers through inhibiting serine/threonine protein phosphatase 2A (PP2A) activation (Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, Wilson JX. Free Radic Biol Med 48: 128-135, 2010). The present study addressed the mechanism of protection by ascorbate against vascular leakage in cecal ligation and puncture (CLP)-induced septic peritonitis in mice. CLP caused NADPH oxidase activation and endothelial nitric oxide synthase (eNOS) uncoupling to produce superoxide, increased NO production by inducible NOS (iNOS) and neuronal NOS (nNOS) activity, and elevated 3-nitrotyrosine (a product of peroxynitrite) formation and PP2A activity in the hindlimb skeletal muscles at 12 h after CLP. The increase in PP2A activity was associated with decreased levels of phosphorylated serine and threonine in occludin, which was immunoprecipitated from freshly harvested endothelial cells of the septic skeletal muscles. Moreover, CLP increased the vascular permeability to fluorescent dextran and Evans blue dye in skeletal muscles. An intravenous bolus injection of ascorbate (200 mg/kg body wt), given 30 min prior to CLP, prevented eNOS uncoupling, attenuated the increases in iNOS and nNOS activity, decreased 3-nitrotyrosine formation and PP2A activity, preserved the phosphorylation state of occludin, and completely inhibited the vascular leakage of dextran and Evans blue. A delayed ascorbate injection, given 3 h after CLP, also prevented the vascular permeability increase. We conclude that ascorbate injection protects against vascular leakage in sepsis by sequentially inhibiting excessive production of NO and superoxide, formation of peroxynitrite, PP2A activation, and occludin dephosphorylation. Our study provides a scientific basis for injection of ascorbate as an adjunct treatment for vascular leakage in sepsis.
Background: The driving force behind osteoarthritis (OA) pathogenesis is an anabolic-catabolic (a/c) imbalance. Melatonin (MT) is a key player in maintaining a/c stability and mitigates OA pathogenesis, but mechanisms underlying its effects remain poorly understood.Objectives: We performed a systematic review analyzing the experimental data that support the clinical applicability of MT in the treatment of OA pathogenesis, placing particular emphasis on the regulation of circadian rhythms and a/c balance.Methods: Major electronic databases and grey literature were used to identify related original articles. Methodological quality of all selected studies was evaluated using the SYRCLE risk of bias tool. Pooled mean differences (MDs)/standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to estimate the effect size.Results: Eleven trials were included in this systematic review. Compared with the control group, MT significantly decreased the levels of interleukin-1β (IL-1β; SMD = −5.45; 95% CI [−6.78, −4.12]; p < 0.00001, and histological grading scale (SMD = −3.46; 95% CI, [−5.24, −1.68]; p < 0.0001). MT significantly increased the transforming growth factor-β1 (TGF-β1; SMD = 1.17; 95% CI [0.31, 2.03]; p < 0.0007). Furthermore, core circadian clock genes Per2 and Cry1 mRNA levels were regulated by MT treatment in OA progression.Conclusion: MT may maintain a/c balance and regulate circadian rhythms during OA development. MT could be used in as adjunct with other interventions to manage pain and OA severity.
Cerebral ischemia (CI) is a condition where blockage in an artery limits the distribution of oxygen-rich blood to the brain, and this leads to brain tissue damage. Cerebral ischemia may be caused by cardiac arrest, 1 stroke, 2 severe anemia, 3 aging, 4,5 systemic hypotension and hypoxia, 6-8 metabolic derangements, 9,10 or strangulation. 11,12 Severe CI such as stroke has a high death rate with approximately 795,000 people having a stroke each year, 13 and survivors often showing significant neurological disabilities and
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