The activation of microglial NADPH oxidase (NOX2) induced by α-synuclein has been implicated in Parkinson's disease (PD) and other synucleinopathies. However, how α-synuclein activates NOX2 remains unclear. Previous study revealed that both toll-like receptor 2 (TLR2) and integrin play important roles in α-synuclein-induced microglial activation. In this study, we found that blocking CD11b, the α chain of integrin αMβ2, but not TLR2 attenuated α-synuclein-induced NOX2 activation in microglia. The involvement of CD11b in α-synuclein-induced activation of NOX2 was further confirmed in CD11b-/- microglia by showing reduced membrane translocation of NOX2 cytosolic subunit p47phox and superoxide production. Mechanistically, α-synuclein bound to CD11b and subsequently activated Rho signaling pathway. α-Synuclein induced activation of RhoA and downstream ROCK but not Rac1 in a CD11b-dependent manner. Moreover, siRNA-mediated knockdown of RhoA impeded NOX2 activation in response to α-synuclein. Furthermore, we found that inhibition of NOX2 failed to interfere with the activation of RhoA signaling and interactions between α-synuclein and CD11b, further confirming that NOX2 was the downstream target of CD11b. Finally, we found that genetic deletion of CD11b abrogated α-synuclein-induced NOX2 activatoin in vivo. Taken together, our results indicated that integrin CD11b mediates α-synuclein-induced NOX2 activation through a RhoA-dependent pathway, providing not only a novel mechanistic insight but also a new potential therapeutic target for synucleinopathies.

Tubeless VATS approach for SPNs is feasible in carefully selected patients. Intubation, chest drainage, and/or urinary catheterization may not be necessary in all patients.

Atorvastatin is a substrate of cytochrome P450 3a (CYP3a), organic anion-transporting polypeptides (OATPs), breast cancer-resistance protein (BCRP), and P-glycoprotein (P-gp). We aimed to develop a semiphysiologically based pharmacokinetic (semi-PBPK) model involving both enzyme and transporters for predicting the contributions of altered function and expression of CYP3a and transporters to atorvastatin transport in diabetic rats by combining high-fat diet feeding and low-dose streptozotocin injection. Atorvastatin metabolism and transport parameters comes from in situ intestinal perfusion, primary hepatocytes, and intestinal or hepatic microsomes. We estimated the expressions and functions of these proteins and their contributions. Diabetes increased the expression of hepatic CYP3a, OATP1b2, and P-gp but decreased the expression of intestinal CYP3a, OATP1a5, and P-gp. The expression and function of intestinal BCRP were significantly decreased in 10-day diabetic rats but increased in 22-day diabetic rats. Based on alterations in CYP3a and transporters by diabetes, the developed semi-PBPK model was successfully used to predict atorvastatin pharmacokinetics after oral and intravenous doses to rats. Contributions to oral atorvastatin PK were intestinal OATP1a5 < intestinal P-gp < intestinal CYP3a < hepatic CYP3a < hepatic OATP1b2 < intestinal BRCP. Contributions of decreased expression and function of intestinal CYP3a and P-gp by diabetes to oral atorvastatin plasma exposure were almost attenuated by increased expression and function of hepatic CYP3a and OATP1b2. Opposite alterations in oral plasma atorvastatin exposure in 10-and 22-day diabetic rats may be explained by altered intestinal BCRP. In conclusion, the altered atorvastatin pharmacokinetics by diabetes was the synergistic effects of altered intestinal or hepatic CYP3a and transporters and could be predicted using the developed semi-PBPK.

Sorafenib resistance is one of the main obstacles to the treatment of advanced/recurrent hepatocellular carcinoma (HCC). Here, sorafenib-resistant HCC cells and xenografts in nude mice were used as experimental models. A cohort of patients with advanced recurrent HCC who were receiving sorafenib therapy was used to assess the clinical significance of this therapy. Our data showed that 14-3-3η maintained sorafenib resistance in HCC. An analysis of the underlying molecular mechanisms revealed that 14-3-3η stabilizes hypoxia-inducible factor 1α (HIF-1α) through the inhibition of ubiquitin-dependent proteasome protein degradation, which leads to the maintenance of cancer stem cell (CSC) properties. We further found that microRNA-16 (miR-16) is a competent miRNA that reverses sorafenib resistance by targeting the 3′-UTR of 14-3-3η and thereby inhibits 14-3-3η/HIF-1α/CSC properties. In HCC patients, significant negative correlations were found between the expression of miR-16 and 14-3-3η, HIF-1α, or CSC properties. Further analysis showed that low miR-16 expression but high 14-3-3η expression can prognosticate sorafenib resistance and poor survival. Collectively, our present study indicated that miR-16/14-3-3η is involved in sorafenib resistance in HCC and that these two factors could be potential therapeutic targets and biomarkers for predicting the response to sorafenib treatment.