Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.
Ischemia/reperfusion (I/R) injury is a significant cause of mortality and long-term disability worldwide. Recent evidence has proved that pyroptosis, a novel cell death form, contributes to inflammation-induced neuron death and neurological function impairment following ischemic stroke. Gasdermin D (GSDMD) is a newly discovered key molecule of cell pyroptosis, but its biological function and precise role in ischemic stroke are still unclear. The present study investigates the cleavage activity of GSDMD, localization of pyroptotic cells, and global neuroinflammation in gsdmd−/− mice after I/R. The level of cell pyroptosis around the infarcted area was significantly increased in the acute phase of cerebral I/R injury. The ablation of GSDMD reduced the infraction volume and improved neurological function against cerebral I/R injury. Furthermore, we confirmed I/R injury induced cell pyroptosis mainly in microglia. Knockdown of GSDMD effectively inhibited the secretion of mature IL-1β and IL-18 from microglia cells but did not affect the expression of caspase-1/11 in vitro and in vivo. In summary, blocking GSDMD expression might serve as a potential therapeutic strategy for ischemic stroke.
Blood glucose fluctuations have higher risk than absolute blood glucose level in diabetic chronic complications. At present, “dawn phenomenon” is well known by clinicians, but “dusk phenomenon” has not been recognized. This study explored the objective existence of “dusk phenomenon” (spontaneous and transient predinner hyperglycemia) and its clinical significance.The data of 54 patients with diabetes, who received routine insulin pump therapy between December 2010 and October 2012 in our hospital, were retrospectively analyzed. These patients included 4 patients with type 1 diabetes mellitus (DM) (T1DM) and 50 patients with type 2 DM (T2DM). According to the difference between predinner and postlunch blood glucose levels, the 50 patients with T2DM were divided into dusk phenomenon group (4 patients, all the differences ≥0 mmol/L during insulin pump therapy), nondusk phenomenon group (12 patients, all the differences <0 mmol/L during insulin pump therapy), and suspicious group (34 patients, the differences were uncertain during insulin pump therapy). In the 4 patients with T1DM of this study, the differences all were more than 0 mmol/L during insulin pump therapy. The changes in blood glucose levels were observed, and the correlations of blood glucose level with other factors were analyzed in T1DM and T2DM patients, respectively.In T1DM patients, blood glucose level was significantly higher in predinner than in prebreakfast and prelunch (all P < 0.01), and in postdinner 2 hour than in postlunch 2 hour (P = 0.021). The predinner blood level had no significant correlations with the blood glucose level at other time points and insulin dosages (all P > 0.05). In T2DM patients, the predinner blood glucose level was significantly higher in dusk phenomenon group than in suspicious group and nondusk phenomenon group (all P < 0.05). In dusk phenomenon group, the blood glucose level remained rising from predinner to prebed, and the predinner blood glucose level was only significantly correlated with postdinner 2-hour blood glucose level (P < 0.05).The “dusk phenomenon” (spontaneous and transient predinner hyperglycemia) is an objective existence in some patients with diabetes. The predinner hyperglycemia can affect blood glucose control between postdinner and prebed. Awareness of the “dusk phenomenon” has important clinical significance.
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