Autophagy dysfunctions are involved in the pathogenesis of Parkinson disease (PD). In the present study, we aimed to evaluate the involvement of G-protein coupled estrogen receptor (GPER) in the inhibitory effect of insulin-like growth factor-1 (IGF-1) against excessive autophagy in PD animal and cellular models. 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treatment significantly induced mice movement disorder and decreased the protein level of tyrosine hydroxylase (TH) in the substantia nigra (SN) and dopamine (DA) content in striatum. Along with the dopamine neuron injury, we observed significant up-regulations of microtubule associated light chain-3 II (LC3-Ⅱ) and α-synuclein as well as a down-regulation of P62 in MPTP-treated mice. These changes could be restored by IGF-1 pretreatment. Co-treatment with IGF-1R antagonist JB-1 or GPER antagonist G15 could block the neuroprotective effects of IGF-1. 1-methy-4-phenylpyridinium (MPP+) treatment could also excessively activate autophagy along with the reduction of cell viability in SH-SY5Y cells. IGF-1 could inhibit the neurotoxicity through promoting the phosphorylation of Akt and mTOR, which could also be antagonized by JB-1 or G15. These data suggest that IGF-1 inhibits MPTP/MPP+-induced autophagy on dopaminergic neurons through the IGF-1R/PI3k-Akt-mTOR pathway and GPER.

Abstract. Sepsis is one of the leading causes of mortality in severe systemic inflammatory syndrome. The endotoxin-induced inflammatory response has been linked to the development of sepsis. Rhein is a lipophilic anthraquinone isolated from Rheum rhabarbarum (rhubarb), which has a protective effect on intestinal damage in vivo. However, the underlying mechanism responsible for the protective effects of rhein remains to be elucidated. In the present study, mice were exposed to 20 mg/kg lipopolysaccharide (LPS), prior to being treated with either 100 mg/kg rhein or 0.3 mg/kg toll-like receptor 4 (TLR4) signaling inhibitor TAK-242. In the rhein-treated mice, the colon length (cm) was extended and colon injury was attenuated. In addition, treatment with rhein significantly decreased the expression levels of the LPS-induced inflammatory cytokines interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α, in both the plasma and colon tissue. However, mice treated with TAK-242 exhibited increased expression levels of IL-10, as determined by ELISA and western blot analysis. In addition, immunohistochemistry and western blot analyses demonstrated that treatment with rhein was able to reduce TLR4 expression and inhibit nuclear factor-κB (NF-κB) phosphorylation in colon tissue. Furthermore, LPS induction was blocked by TAK-242. These results demonstrate that the observed rhein-attenuated inflammatory response during sepsis may be achieved via the TLR4 NF-κB signaling pathway. In conclusion, the results of the present study provide a novel insight into the protective effects of rhein on LPS-induced intestinal inflammation, and demonstrate that rhein may act as a beneficial therapeutic agent in the treatment of sepsis-induced intestinal damage.

BackgroundIn China, most patients with nasopharyngeal carcinoma (NPC) are diagnosed at a late stage and consequently have a poor prognosis. This study aimed to investigate potential factors associated with the clinical stage of NPC at diagnosis.MethodsData were obtained from 118 patients with early-stage NPC and 274 with late-stage NPC who were treated at Sun Yat-sen University Cancer Center between August 2014 and July 2015. Patients were individually matched by age, sex, and residence, and a conditional logistic regression model was applied to assess the associations of clinical stage at diagnosis with socioeconomic status indicators, knowledge of NPC, physical examinations, patient interval, and risk factors for NPC.ResultsAlthough knowledge of early NPC symptoms, smoking cessation, and patient interval were important factors, the number of cigarettes smoked per day, motorbike ownership, and physical examination exhibited the strongest associations with the clinical stage of NPC at diagnosis. Compared with smoking fewer than ten cigarettes a day, smoking 10–30 cigarettes [odds ratio (OR) 4.03; 95% confidence interval (CI) 1.11–14.68] or more than 30 cigarettes (OR 11.46; 95% CI 1.26–103.91) was associated with an increased risk of late diagnosis. Compared with not owning a motorbike, owning a motorbike (OR 0.38; 95% CI 0.23–0.64) was associated with early diagnosis. Subjects who underwent physical examinations were less likely to receive a late diagnosis than those who did not undergo examinations (OR 0.50; 95% CI 0.28–0.89). However, indicators of wealth were not significant factors.ConclusionsInitiatives to improve NPC patient prognosis should aim to promote knowledge about early symptoms and detection, health awareness, and accessibility to health facilities among all patients, regardless of socioeconomic status.

The long‐term failure of vein grafts due to neointimal hyperplasia remains a difficult problem in cardiovascular surgery. Exploring novel approaches to prevent neointimal hyperplasia is important. MicroRNA‐146a (miR‐146a) plays an essential role in promoting vascular smooth muscle cell (VSMC) proliferation. Thus, the aim of the present study is to investigate whether adenovirus‐mediated miR‐146a sponge (Ad‐miR‐146a‐SP) gene therapy could attenuate neointimal formation in rat vein grafts. (Ad‐miR‐146a‐SP) was constructed to transfect cultured VSMCs and grafted veins. To improve the efficiency of transferring the miR‐146a sponge gene into the grafted veins, 20% poloxamer F‐127 gel incorporated with 0.25% trypsin was used to increase adenovirus contact time and penetration. miR‐146a‐SP transduction significantly reduced the expression of miR‐146a both in cultured VSMCs and vein grafts. miR‐146a sponge markedly attenuated VSMC proliferation and migration. Consistent with this, miR‐146a sponge gene therapy significantly attenuated neointimal formation and also improved blood flow in the vein grafts. Mechanistically, we identified the Krüppel‐like factor 4(KLF4) as a potential downstream target gene of miR‐146a in vein grafts. Our data show that miR‐146a sponge gene therapy could effectively reduce miR‐146a activity and attenuate neointimal formation in vein grafts, suggesting its potential therapeutic application for prevention of vein graft failure. © 2018 IUBMB Life, 71(1):125–133, 2019

Background Germline mutations in PALB2 gene make a small contribution to heritable breast cancer susceptibility. A recent report has revealed that women with mutations in the PALB2 gene were more than nine times as likely to develop breast cancer compared to those without. The aim of this study is to understand the status of PALB2 mutations among Chinese high-risk breast cancer patients in a multi-ethnic region in China.Methods152 patients with hereditary predisposition to breast cancer from the Xinjing region of China were enrolled in the study, and 100 control samples from healthy women were collected in the same locality. We sequenced the coding sequences and flanking intronic regions of PALB2 gene from DNA samples obtained from all subjects by direct sequencing.ResultsA total of 4 deleterious PALB2 mutations were identified in 152 breast cancer patients with a prevalence of about 2.6 % (4/152). The PALB2 mutation prevalence was 3.2 % (3/95) in cases with family history of breast cancer. In addition to the four deleterious mutations, we identified nine missense variants in 12 patients, using the prediction Softwares SIFT and PolyPhen, four of which might be disease associated (in 5 patients). Two of the 4 patients with deleterious mutations and 2 of the 5 patients presenting putative deleterious missense mutations had triple-negative breast cancer. No PALB2 mutation carriers were identified in 100 healthy controls.ConclusionPALB2 mutations account for a small, but not negligible, proportion of patients with hereditary predisposition to breast cancer in the Xinjing region of China.