Purpose: To investigate the protective effect of sevoflurane against lipopolysaccharide (LPS)-induced acute liver injury (ALI) in amice model.Methods: Seven week-old female BalB/C mice were used. Lung water content and cell count were estimated by standard protocols. Cytokine and chemokine analysis was performed using commercially available kits. Myeloperoxidase activity was evaluated spectrophotometrically while histopathological analysis was carried out by H and E staining.Results: The results revealed that sevoflurane treatment significantly improved gaseous exchange, and reduced lung water content and lung inflammation as evidenced by a decrease in neutrophil migration into BALF (p < 0.01). Sevoflurane also significantly reversed the LPS-triggered suppression of IL-10 in the lung tissues of LPS-treated mice, when compared to saline-treated controls (p < 0.01). It reversed LPS-induced oxidative stress, as demonstrated by increase in total antioxidant capacity (T-AC), catalase (CAT) and superoxide dismutase-1 (SOD-1), as well as an increase in reduced/oxidized glutathione (GSH/GSSG) ratio. In addition, sevoflurane blocked LPS-induced lung tissue injury in ALI mice, and exerted protective effects against acute LPS-induced lung injury.Conclusion: These results suggest that sevoflurane improves gaseous exchange and exerts a protective effect against LPS-triggered lung injury in mice model, most probably due to its antiinflammatory and antioxidant properties.Keywords: Lung injury, Sevoflurane, Respiratory distress, Superoxide dismutase, Liposaccharide
MicroRNAs (miRNAs) have been shown to have complicated implications in the pathogenesis of Parkinson's disease (PD). However, the role of miR-29c and the underlying mechanism in the development of PD remain not well understood. In this work, the MPTP-treated mice or MPP+ -intoxicated SH-SY5Y cells were established as an in vivo or in vitro PD model. Then the specific agomir of miR-29c was employed to examine its biological function on PD progress. We found that miR-29c was down-expressed but SP1 was high-expressed in substantia nigra pars compacta (SNpc) of MPTP-induced PD mice. Overexpression of miR-29c attenuated dopaminergic neuron loss and α-synuclein accumulation in SNpc of PD mice. Furthermore, the increments of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and TUNEL-positive apoptotic cells in MPTP-treated mice were ameliorated by miR-29c. Similarly, in SH-SY5Y cell models of PD, we also found that miR-29c inhibited inflammatory cytokine production, reduced apoptotic rate and suppressed pro-apoptotic regulator activity. In addition, the increased expression of SP1 in PD models was found to be inhibited by miR-29c. Luciferase reporter assay confirmed that SP1 was complementary with miR-29c. Knockdown of SP1 with siRNA restored α-synuclein accumulation, inflammation and apoptosis in MPP+ -induced SH-SY5Y cells. Collectively, this current work presents that miR-29c may directly target SP1 to protect against the neuroinflammatory and apoptotic responses in PD, providing a potential biomarker for PD diagnosis and treatment.
Microglial inflammation is identified as a key process associated with Parkinson's disease (PD) pathogenesis. Our previous study showed that miR-29c-3p (miR-29c) exhibited anti-inflammatory properties in PD animal and neuronal models. However, the specific role and regulatory mechanism of miR-29c played in microglia are still unclear. In this study, lipopolysaccharide (LPS)-stimulated BV-2 cells were used to establish a cellular model of microglial activation for investigating PD. The results showed a decreased expression of miR-29c in LPS-induced BV-2 cells. Over-expression of miR-29c suppressed LPS-triggered Iba-1 increment, pro-inflammatory cytokine release, and NF-кB and TXNIP/NLRP3 inflammasome activation. Silence of miR-29c induced similar effects with LPS on microglial inflammation. In addition, we found that NFAT5 was negatively correlated with miR-29c. Knockdown of NFAT5 blocked the aggravated inflammation in microglia treated by miR-29c inhibitor. Thus, these findings suggest that miR-29c modulates NLRP3 inflammasome to impair microglial inflammatory responses by targeting NFAT5, which represents a promising therapeutic target for PD.
Objective:To study the function of apoptosis regulating protein Bax,Bcl-2,Fas,caspase-3 in the pathogenesis of premature rupture of fetal membranes and to determine whether the expression of these apoptosis regulating proteins is correlated with infection.Methods:Human fetal membrane samples were collected from 51 nulliparous women,including premature rupture of membranes of term,preterm premature rupture of membranes and intact membranes as controls,who underwent cesarean delivery before labor.The expression of Bax,Bcl-2,Fas,caspase-3 in tissue sections of fetal membranes was documented with immunohistochemistry.Routine HE staining was used to perform fetal membranes histology,and TUNEL technology to label apoptotic cells in situ in order to detect apoptosis index of sections.Results:The positive expression rate of Bax,Fas,caspas-3 in fetal membranes in the premature rupture of membranes group(respectively 91.18%,88.24%,85.29%) was significantly higher than those in control(58.82%,52.94%,23.53%,P=0.018,0.014,0.000),whereas antiapoptotic Bcl-2 expression between two groups was not significant(P=0.105).Fetal membranes histology indicated: not only cases complicated with chorioamnionitis but also cellular apoptosis index of sections in the premature rupture of membranes group were significantly greater than those in control group(P=0.035,0.000).There were not statistically significant differences in Bax,Bcl-2,caspase-3 expression between with and without chorioamnionitis groups(P=0.846,0.332,0.334).In contrast a significant increase was seen in Fas expression from chorioamnionitis group compared with the without chorioamnionitis group(P=0.039),and mean apoptosis index of chorioamnionitis group also was significantly greater than that without chorioamnionitis group(P=0.000).Conclusion:Premature rupture of membranes is associated with increased apoptotic cells.Proapoptotic protein Bax,Fas,caspase-3 expression are significantly up-regulated in fetal membranes with premature rupture of membranes,regardless of infection,and the over expression of Fas is correlated with inflammation reaction.The increased apoptotic cells by gene-environment interaction may be another pathogenesis of premature rupture of membranes,and apoptosis may be a single major risk factor or take synergistic effect together with infection in the etiology of premature rupture of membranes.
Chondrocyte apoptosis contributes to the pathogenesis of cartilage degeneration in osteoarthritis (OA). We found that isopsoralen pretreatment significantly reversed the increase in DNA fragmentation and apoptosis rate, and significantly decreased the caspase-3 activity and PARP cleavage in IL-1β-treated chondrocytes. Isopsoralen pretreatment markedly inhibited disruption of matrix proteins. Moreover, the expressions of LC3-II and LAMP-1 were markedly increased but the expression of p62/SQSTM1 was remarkably decreased by isopsoralen pretreatment. Importantly, the protective effects of isopsoralen against IL-1β were blocked by pretreatment with autophagy inhibitor 3-MA and bafilomycin A1. These results suggest that isopsoralen ameliorates chondrocyte apoptosis by promoting autophagy flux.[Formula: see text].
Objective In order to obtain high purity of primary culture of dopaminergic neurons in rat fetus,we tried to modify the culture procedure.Using improved techniques,we compared the growth status of dopaminergic neurons cultured on Matrigel and PLL(Poly\|L\|Lysine)substrates. Methods The DA neurons were obtained from the ventral mesencephalon of SD rat embryos(E13) by using a different dissecting method and then plated in plastic dishes coated with Matrigel and PLL substrates in high density (1×10\+5/cm\+2).After cultured for 5 days in vitro, TH immunocytochemical staining was performed and length of TH immunoreactive neurites was measured. Results and Conclusions 1\^Cultured dopaminergic neurons in high\|purity(dopaminergic neuron/all neuron=15%) could be got by using this improved culture method.2\^ Matrigel substrate promoted neurites outgrowth of cultured neurons more potently than PLL substrate,but did not increase the survival of the neurons.\;
Quercetin was previously reported to exhibit significant anti-proliferative activities, and its major effect on tumors was to induce cell apoptosis or autophagy. However, the specific mechanism remains controversial. In this study, autophagy induced by quercetin was determined with various methods. Intracellular Ca2+ ([Ca2+]i) was measured after being incubated with Fluo-3 acetoxymethyl (AM). At the same time, the relationship between the intracellular Ca2+ and autophagy induced by quercetin was further analyzed. These results showed that autophagy induced by quercetin (0-50 µg/ml) in HepG2 cells was in a dose-dependent manner. Meanwhile, when autophagy was induced by quercetin, [Ca2+]i was significantly increased. And after being incubated with calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N-tetraacetic acid-AM, autophagy was suppressed, which implied that [Ca2+]i elevation appeared to be the cause for autophagy induction. These results suggested that calcium from intracellular calcium storage may play an important role in quercetin-induced autophagy.
Abstract Necroptosis is crucially involved in severe cardiac pathological conditions. However, whether necroptosis contributes to age‐related intolerance to ischemia/reperfusion (I/R) injury remains elusive. In addition, metformin as a potential anti‐aging related injury drug, how it interacts with myocardial necroptosis is not yet clear. Male C57BL/6 mice at 3–4‐ (young) and 22–24 months of age (aged) and RIPK3‐deficient ( Ripk 3 −/− ) mice were used to investigate aging‐related I/R injury in vivo. Metformin (125 μg/kg, i.p.), necrostatin‐1 (3.5 mg/kg), and adenovirus vector encoding p62‐shRNAs (Ad‐sh‐p62) were used to treat aging mice. I/R‐induced myocardial necroptosis was exaggerated in aged mice, which correlated with autophagy defects characterized by p62 accumulation in aged hearts or aged human myocardium. Functionally, blocking autophagic flux promoted H/R‐evoked cardiomyocyte necroptosis in vitro. We further revealed that p62 forms a complex with RIP1‐RIP3 (necrosome) and promotes the binding of RIP1 and RIP3. In mice, necrostatin‐1 treatment (a RIP1 inhibitor), RIP3 deficiency, and cardiac p62 knockdown in vivo demonstrated that p62‐RIP1‐RIP3‐dependent myocardial necroptosis contributes to aging‐related myocardial vulnerability to I/R injury. Notably, metformin treatment disrupted p62‐RIP1‐RIP3 complexes and effectively repressed I/R‐induced necroptosis in aged hearts, ultimately reducing mortality in this model. These findings highlight previously unknown mechanisms of aging‐related myocardial ischemic vulnerability: p62‐necrosome‐dependent necroptosis. Metformin acts as a cardioprotective agent that inhibits this unfavorable chain mechanism of aging‐related I/R susceptibility.
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