Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Although its pathogenesis remains unclear, growing evidencce suggests that microglia-mediated neuroinflammation contributes greatly to the progression of PD. P7C3, an aminopropyl carbazole, possesses significant neuroprotective effects in several neurodegenerative disease animal models, including PD. In this study, we designed to investigate the effects of P7C3 on neuroinflammation. We showed that P7C3 specially suppressed the expression of lipopolysaccharide (LPS)-induced pro-inflammatory factors but not influenced the anti-inflammatory factors in microglia. The inhibition of the nuclear factor κB (NF-κB) signaling pathway was involved in the mechanisms of the anti-inflammatory effects by P7C3. LPS-induced activation of IκB kinase (IKK), degradation of the inhibitory κB alpha (IκBα) and nuclear translocation of NF-κB can be attenuated by the pretreatment of P7C3 in microglia. Furthermore, in LPS-treated microglia, P7C3-pretreatment decreased the toxicity of conditioned media to MES23.5 cells (a dopaminergic (DA) cell line). Most importantly, the anti-inflammatory effects of P7C3 were observed in LPS-stimulated mouse model. In general, our study demonstrates that P7C3 inhibits LPS-induced microglial activation through repressing the NF-κB pathway both in vivo and in vitro, providing a theoretical basis for P7C3 in anti-inflammation.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. Although its pathogenesis remains unclear, mitochondrial dysfunction plays a vital role in the pathology of PD. P7C3, an aminopropyl carbazole, possesses a significant neuroprotective ability in several neurodegenerative disorders, including PD. Here, we showed that P7C3 stabilized mitochondrial membrane potential, reduced reactive oxygen species production, and inhibited cytochrome c release in MES23.5 cells (a dopaminergic (DA) cell line) exposed to 1-methyl-4-phenylpyridinium (MPP+). In MES23.5 cells, P7C3 inhibited glycogen synthase kinase-3 beta (GSK3β) activation induced by MPP+. P7C3 also inhibited p53 activity and repressed Bax upregulation to protect cells from MPP+ toxicity. In addition, the activation of p53 was significantly attenuated with the inhibition of GSK3β activity by P7C3. Furthermore, P7C3 blocked GSK3β and p53 activation in the midbrain, and prevented DA neuronal loss in the substantia nigra in 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine mice. Thus, our study demonstrates that P7C3 protects DA neurons from neurotoxin-induced cell death by repressing the GSK3β-p53-Bax pathway both in vitro and in vivo, thus providing a theoretical basis for P7C3 in the potential clinical treatment of PD.
Aim: In the penumbra after focal cerebral ischemia, an increase of protease Omi is linked to a decrease of Hs1-associated protein X-1 (Hax-1), a protein belonging to the Bcl-2 family. In this study we investigated the mechanisms underlying the regulation of Hax-1 by protease Omi in cerebral ischemia/reperfusion (I/R) injury. Methods: Mouse neuroblastoma N2a cells were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R); cell viability was assessed with MTT assay. Mice underwent 2-h middle cerebral artery occlusion (MCAO) and reperfusion, and the infarct volume was determined with TTC staining. The expression of Omi and Hax-1 was detected using immunoblot and immunofluorescence assays. The mitochondrial membrane potential was measured using TMRM staining. Results: In the brains of MCAO mice, the protein level of Omi was significantly increased, while the protein level of Hax-1 was decreased. Similar changes were observed in OGD/R-treated N2a cells, but the mRNA level of Hax-1 was not changed. Furthermore, in OGD/R-treated N2a cells, knockdown of Omi significantly increased Hax-1 protein level. Immunofluorescence assay showed that Omi and Hax-1 were co-localized in mitochondria of N2a cells. OGD/R caused marked mitochondrial damage and apoptosis in N2a cells, while inhibition of Omi protease activity with UCF-101 (10 μmol/L) or overexpression of Hax-1 could restore the mitochondrial membrane potential and attenuate cell apoptosis. Moreover, pretreatment of MCAO mice with UCF-101 (7.15 mg/kg, ip) could restore Hax-1 expression, inhibit caspase activation, and significantly reduce the infarct volume. Conclusion: Protease Omi impairs mitochondrial function by cleaving Hax-1, which induces apoptosis in OGD/R-treated N2a cells and causes I/R injury in MCAO mice.
MitoTEMPO, a mitochondrial antioxidant, has protective effects on liver-related diseases. However, the role of MitoTEMPO on nonalcoholic fatty liver disease (NAFLD) and its possible mechanisms are largely unknown. Here, we investigated the effects of MitoTEMPO on NAFLD using high fat diet- (HFD-) induced obese mice as animal models. MitoTEMPO was intraperitoneally injected into HFD mice. Liver morphological changes were observed by H&E and Oil Red O staining, and the frequency of MDSCs in peripheral blood was analyzed by flow cytometry. Moreover, real-time quantitative PCR, western blot, and immunohistochemistry were conducted to detect the mRNA and protein expressions in the liver tissues. The results showed that the hepatic steatosis in liver tissues of HFD mice injected with MitoTEMPO was significantly ameliorated. Additionally, MitoTEMPO reduced the frequency of CD11b+Gr-1+ MDSCs in peripheral circulation and decreased Gr-1+ cell accumulation in the livers. Further studies demonstrated that MitoTEMPO administration suppressed the mRNA and protein expressions of MDSC-associated proinflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9). Our results suggest that MitoTEMPO appears to be a potential chemical compound affecting certain immune cells and further ameliorates inflammation in obese-associated NAFLD.
Polydatin (PD), an active component of Chinese herbs, is reported to have many biological functions, such as cardioprotective actions, anti-inflammatory activities, and antitumor effects. In this study, we investigated the effects of PD on body weight control, glucose and lipid metabolic regulation, and anti-inflammation in a high-fat-diet- (HFD-) induced obese mice model. After treatment of PD (100 mg/kg/d for 4 weeks), HFD mice reduced body weight, retroperitoneal fat mass, and adipose cell sizes; significantly lowered serum total cholesterol triglyceride (TG) and low-density lipoprotein (LDL) levels; and increased high-density lipoprotein (HDL) levels compared with the HFD control mice. Further studies showed that PD downregulated the mRNA and protein expressions of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor involving in the regulation of adipocyte differentiation, in the retroperitoneal fat of HFD mice. Additionally, PD significantly upregulated the mRNA and protein expressions of leptin, an adipocyte-derived anorexic hormone that regulates food intake and energy expenditure, in the adipose tissues of HFD mice. Moreover, PD reduced the expression levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) in the retroperitoneal and epididymal tissues of HFD mice, suggesting that PD prevented adipose tissue inflammation. In conclusion, PD may serve as a pharmaceutic candidate for obesity-related lipid metabolism, anti-inflammation, and body weight loss.
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