Down-regulated miR-374c and Hsp70 promote Th17 cell differentiation by inducing Fas expression in experimental autoimmune encephalomyelitis.

OBJECTIVE: Fas is a positive regulator of Th17 cells differentiation in experimental autoimmune encephalomyelitis (EAE). However, its upstream regulators are still not fully determined. This study was designed to explore the upstream regulators of Fas in regulating Th17 cells differentiation in EAE. METHODS: The mouse model of EAE was established by myelin oligodendrocyte glycoprotein injection. Th17 cells differentiation was induced by IL-23, IL-6 and TGF-ß. RESULTS: Down-regulated Hsp70 and miR-374c and up-regulated Fas were observed in the spleen and brain of EAE mice. Hsp70 overexpression evidently reduced Fas protein level, but not mRNA level. The luciferase reporter assay indicated that miR-374c targets Fas. Overexpression of miR-374c down-regulated the mRNA and protein level of Fas. The concentration of IL-17A in CD4+ T-cells was reduced by miR-374c or Hsp70 overexpression, and Fas overexpression altered this trend. Hsp70 did not regulate the expression of miR-374c, and likewise, miR-374c did not regulate the expression of Hsp70. Further results suggested that Hsp70 and miR-374c regulated Fas expression through different ways to affect Th17 cells differentiation in EAE. CONCLUSIONS: This study suggested that down-regulated miR-374c and Hsp70 promote Th17 cell differentiation by inducing Fas expression in EAE.

Interaction between GDF5 gene polymorphisms and environment factors increased the risk of knee osteoarthritis: a case-control study.

Using a case-control design, we assessed the association between single nucleotide polymorphisms (SNPs) of growth and differentiation factor 5 (GDF5)/rs143383 gene and interaction with environments and knee osteoarthritis (KOA). We recruited 288 KOA patients from the First Clinical College, Henan University of Chinese Medicine between June 2017 and May 2018. There was significant difference in genotype distribution between case group and control group (χ2 = 22.661, P=0.000). The minor C allele was significantly higher in the case group than that in the control group (20.5 vs 8.1%, P=0.000, odds ratio (OR) = 1.62, 95% confidence interval (CI): 1.29-2.03). Significant differences were also observed in other gene models. For age, all models show significant differences (P<0.05) for those whose age was more than 60 years, and no significant difference was observed for those under 60 years. For non-smoking group, there were significant differences between case group and control group, and for smoker, significance level was found in TT compared with CC and allele gene models. Patients with drinking and Bbody mass index (MI )≥ 24 also showed significant relationship between rs143383 and osteoarthritis (OA) under the following models: TT vs CC (P=0.000, P=0.018), TT/CT vs CC (P=0.043), TT vs CT/CC (P=0.000, P=0.009), and T vs C (P=0.024, P=0.000). Other gene models indicated no significance (P>0.05). Our results revealed a possible genetic association between GDF5 and KOA, and the TT genotype of rs143383 increased the risk of KOA in Chinese Han population. The interaction between GDF5 gene and drinking, smoking, and obesity further increased the risk of KOA.

A Multicenter Clinical Study on Treating Post-Dural Puncture Headache with an Intravenous Injection of Aminophylline.

BACKGROUND: Post-dural puncture headache (PDPH) is the most common complication of lumbar puncture. Aminophylline has been reported to be effective in the prevention of PDPH in some clinical studies, but its efficacy for the treatment of PDPH has been unproven. OBJECTIVE: To evaluate the efficacy and safety of an intravenous (IV) injection of aminophylline on PDPH. STUDY DESIGN: The study was a multicenter, open-label study to assess the effectiveness and safety of aminophylline on PDPH. SETTING: The First Affiliated Hospital of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, and Henan Province Hospital of Traditional Chinese Medicine. METHODS: Thirty-two PDPH patients received an IV injection of aminophylline. The primary and secondary endpoints were the degree of headache and the patient's overall response to the treatment, respectively. Treatment safety was evaluated based on the occurrence of adverse reactions. RESULTS: Thirty-one patients completed the study. Before the initial aminophylline administration, the visual analog scale (VAS) score was 7.72 ± 1.65. The VAS scores at 30 minutes, one hour, 8 hours, one day, and 2 days post-treatment were 4.84 ± 2.53, 3.53 ± 2.06, 2.38 ± 1.96, 1.44 ± 1.87, and 0.81 ± 1.79, respectively, and were statistically significantly different (P < 0.05) compared with those before treatment. More than 50% (17/32) of the patients reported that they were "very much improved" or "much improved" 30 minutes after the initial treatment, increasing to 93.8% (30/32) at 2 days post-treatment. One patient experienced mild allergic reaction after treatment. LIMITATIONS: Although this study had the largest sample size among current studies on treating PDPH with theophylline drugs, the sample size was still relatively small and the method employed was not compared with a placebo or other current clinical treatments for PDPH. CONCLUSION: An IV injection of aminophylline may be an effective and safe early-stage treatment for PDPH.

Tetramethylpyrazine inhibits CoCl2 -induced neurotoxicity through enhancement of Nrf2/GCLc/GSH and suppression of HIF1α/NOX2/ROS pathways.

Hypoxia-mediated neurotoxicity contributes to various neurodegenerative disorders, including Alzheimer's disease and multiple sclerosis. Tetramethylpyrazine (TMP), a major bioactive component purified from Ligusticum wallichii Franchat, exhibited potent neuroprotective effect. However, the mechanism of TMP-exerted neuroprotective effect against hypoxia was not clear. In the study, we investigated the mechanism of the neuroprotective effect of TMP against hypoxia induced by CoCl2 in vitro and in vivo. The results showed that TMP could protect against CoCl2 -induced neurotoxicity in PC12 cells and in rats, as evidenced by enhancement of cell viability in PC12 cells and improvement of learning and memory ability in rats treated with CoCl2 . TMP could inhibit mitochondrial dysfunction, mitochondrial apoptotic molecular events, and thus apoptosis induced by CoCl2 . TMP inhibited CoCl2 -increased reactive oxygen species (ROS) level, which may contribute to hypoxia-related neurotoxicity induced by CoCl2 . The antioxidant and neuroprotective activities of TMP involved two pathways: one was the enhancement of nuclear factor erythroid 2-related factor 2 (Nrf2)/catalytic subunit of γ-glutamylcysteine ligase-mediated regulation of GSH and the other was the inhibition of hypoxia-inducible factor 1 α/NADPH oxidase 2 (NOX2)-mediated ROS generation. These two pathways contributed to improvement of oxidative stress and thus the amelioration of apoptosis under hypoxic conditions. These results have appointed a new path toward the understanding of pathogenesis and TMP-related therapy of hypoxia-related neurodegenerative diseases. We proposed two cascades for tetramethylpyrazine-exhibited protective effects against CoCl2 -induced neurotoxicity: One is enhancement of nuclear factor erythroid 2-related factor 2-catalytic subunit of γ-glutamylcysteine ligase-mediated regulation of glutathone and the other was the inhibition of hypoxia-inducible factor 1 α-NADPH oxidase-2-mediated ROS generation. We think these findings should provide a new understanding of pathogenesis and tetramethylpyrazine-related therapy of hypoxia-related neurodegenerative diseases.