Biphasic Dose-Response of Mn-Induced Mitochondrial Damage, PINK1/Parkin Expression, and Mitophagy in SK-N-SH Cells.

Excessive manganese (Mn) exposure produces neurotoxicity with mitochondrial damage. Mitophagy is a protective mechanism to eliminate damaged mitochondria to protect cells. The aim of this study was to determine the dose-response of Mn-induced mitochondria damage, the expression of mitophagy-mediated protein PINK1/Parkin and mitophagy in dopamine-producing SK-N-SH cells. Cells were exposed to 0, 300, 900, and 1500 µM Mn2+ for 24 h, and ROS production, mitochondrial damage and mitophagy were examined. The levels of dopamine were detected by ELISA and neurotoxicity and mitophagy-related proteins (α-synuclein, PINK1, Parkin, Optineurin, and LC3II/I) were detected by western blot. Mn increased intracellular ROS and apoptosis and decreased mitochondrial membrane potential in a concentration-dependent manner. However, at the low dose of 300 µM Mn, autophagosome was increased 11-fold, but at the high dose of 1500 µM, autophagosome was attenuated to 4-fold, together with decreased mitophagy-mediated protein PINK1/Parkin and LC3II/I ratio and increased Optineurin expression, resulting in increased α-synuclein accumulation and decreased dopamine production. Thus, Mn-induced mitophagy exhibited a novel biphasic regulation: at the low dose, mitophagy is activated to eliminate damaged mitochondria, however, at the high dose, cells gradually loss the adaptive machinery, the PINK1/Parkin-mediated mitophagy weakened, resulting in neurotoxicity.

Amylin receptor insensitivity impairs hypothalamic POMC neuron differentiation in the male offspring of maternal high-fat diet-fed mice.

OBJECTIVE: Amylin was found to regulate glucose and lipid metabolism by acting on the arcuate nucleus of the hypothalamus (ARC). Maternal high-fat diet (HFD) induces sex-specific metabolic diseases mediated by the ARC in offspring. This study was performed to explore 1) the effect of maternal HFD-induced alterations in amylin on the differentiation of hypothalamic neurons and metabolic disorders in male offspring and 2) the specific molecular mechanism underlying the regulation of amylin and its receptor in response to maternal HFD. METHODS: Maternal HFD and gestational hyper-amylin mice models were established to explore the role of hypothalamic amylin and receptor activity-modifying protein 3 (Ramp3) in regulating offspring metabolism. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and RNA decay assays were performed to investigate the mechanism underlying the influence of maternal HFD on Ramp3 deficiency in the fetal hypothalamus. RESULTS: Male offspring with maternal HFD grew heavier and developed metabolic disorders, whereas female offspring with maternal HFD showed a slight increase in body weight and did not develop metabolic disorders compared to those exposed to maternal normal chow diet (NCD). Male offspring exposed to a maternal HFD had hyperamylinemia from birth until adulthood, which was inconsistent with offspring exposed to maternal NCD. Hyperamylinemia in the maternal HFD-exposed male offspring might be attributed to amylin accumulation following Ramp3 deficiency in the fetal hypothalamus. After Ramp3 knockdown in hypothalamic neural stem cells (htNSCs), amylin was found to fail to promote the differentiation of anorexigenic alpha-melanocyte-stimulating hormone-proopiomelanocortin (α-MSH-POMC) neurons but not orexigenic agouti-related protein-neuropeptide Y (AgRP-Npy) neurons. An investigation of the mechanism involved showed that IGF2BP1 could specifically bind to Ramp3 in htNSCs and maintain its mRNA stability. Downregulation of IGF2BP1 in htNSCs in the HFD group could decrease Ramp3 expression and lead to an impairment of α-MSH-POMC neuron differentiation. CONCLUSIONS: These findings suggest that gestational exposure to HFD decreases the expression of IGF2BP1 in the hypothalami of male offspring and destabilizes Ramp3 mRNA, which leads to amylin resistance. The subsequent impairment of POMC neuron differentiation induces sex-specific metabolic disorders in adulthood.

Dietary vitamin B intake and the risk of esophageal cancer: a meta-analysis.

BACKGROUND: Several epidemiology studies have explored the association between dietary B vitamins' intake and the risk of esophageal cancer (EC). However, the results remain inconclusive. Thus, we conducted a systematic review with meta-analysis to evaluate such association. METHODS: Literature retrieval was performed using PubMed (Medline), ScienceDirect, and Cochrane Library electronic databases for all studies published from database inception to December 2017. RESULTS: The meta-analysis included 19 studies and showed an overall decreased risk of EC (OR=0.77, 95% CI: 0.68-0.87) in association with multivitamin B (ie, B1, B2, B3, B5, B6, B9, and B12) dietary intake. In a subgroup analysis based on vitamin B subclass, B1, B3, B6, and B9 vitamins were associated with decreased EC risk (vitamin B1: OR=0.68, 95% CI: 0.56-0.82; vitamin B3: OR=0.70, 95% CI: 0.53-0.94; vitamin B6: OR=0.64, 95% CI: 0.49-0.83; and vitamin B9: OR=0.69, 95% CI: 0.55-0.86). By contrast, no association was detected between dietary vitamin B2 and vitamin B5 intake and EC risk (vitamin B2: OR=0.86, 95% CI: 0.64-1.16; vitamin B5: OR=0.49, 95% CI: 0.20-1.20), whereas a potential non-linear dose-response association was found between dietary vitamin B12 intake and EC risk. A statistically significant, inverse association was observed for an increase of 100 µg/day in supplemental vitamin B6 and B9 and EC risk (vitamin B6: OR=0.98, 95% CI: 0.98-0.99; vitamin B9: OR= 0.89; 95% CI: 0.86-0.94). CONCLUSION: These findings support that vitamin B may have an influence on carcinogenesis of the esophagus. Vitamin B1, B3, B6, B9 showed a decreased risk of EC, and vitamin B12 showed an increased risk of EC.

Tumor vascularity and lipiodol deposition as early radiological markers for predicting risk of disease progression in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization.

This study evaluated the factors impacting overall survival (OS) and time to progression (TTP) in patients with unresectable hepatocellular carcinoma (HCC) who received transarterial chemoembolization (TACE). HCC patients were grouped based on tumor vascularity and lipidiol deposition after TACE. Tumor vascularity was classified based on contrast enhancement on arterial phase baseline CT scans. Lipiodol deposition was evaluated using CT scans. The progression-free rate was significantly higher in patients with good blood supply + good lipiodol deposition compared to those with good blood supply + poor lipiodol deposition. In patients with poor lipidiol deposition, risk of death was significantly positively correlated with stage, and negatively correlated with number of TACE procedures and degree of lipidiol deposition after the first TACE. Risk of disease progression in these patients was positively correlated with tumor size, and negatively correlated with number of TACE procedures and degree of lipidiol deposition after the first TACE. Our data showed that tumor vascularity and lipiodol deposition can be used as early radiological markers to identify patients who do not respond to TACE, and who can be considered earlier for alternative combination treatment strategies. Our data also indicated that poor lipiodol retention may predict a poor TTP and OS despite the blood supply status.

[Acupuncture for post-stroke depression: a randomized controlled trial].

OBJECTIVE: To explore the efficacy and safety of acupuncture for post-stroke depression (PSD). METHODS: The randomized, double-blind control study was designed. 43 post-stroke patients with current major depression episode (DSM-IV) were randomly assigned to an observation group (23 cases) and a control group (20 cases). The conventional symptomatic, supportive and anti-infection treatment in neurological internal medicine was applied to all of the cases in two groups. In observation group, acupuncture was applied to Baihui (GV 20), Yintang (EX-HN 3), Sishencong (EX-HN 1), Taichong (LR 3), etc. Additionally, the placebo was taken orally. In control group, acupuncture was applied to non-acupoint spots (5 mm lateral to the acupoints selected in observation group) with shallow needling technique. Moreover, Fluoxetine was taken orally. The treatment lasted for 6 weeks. Hamilton Depression Scale (HAMD), Asberg antidepressant side effect scale (ASES), adverse response of acupuncture and efficacy were compared between two groups. RESULTS: The total effective rate was 73.9% (17/23) in observation group and was 80.0% (16/20) in control group, indicating equivalent efficacy between two groups. After treatment, HAMD score was reduced remarkably as compared with that before treatment in two groups (P < 0.05). ASES scores in 4 weeks of treatment and after treatment in observation group and ASES score after treatment in control group were reduced remarkably as compared with those before treatment (all P < 0.05). ASES scores in 4 weeks of treatment and after treatment in observation group were reduced much more remarkably as compared with those in control group (both P < 0.05). The incidences of adverse response of acupuncture were 13.0% (3/23) and 15.0% (3/20) respectively in observation group and control group, indicating that the adverse response was transient and had not recurred after symptomatic measures. CONCLUSION: Acupuncture for PSD is as effective as fluoxetine, without obvious drug-induced adverse reaction involved.

[Clinical study of method of strengthening body resistance and disintoxication disintoxication in patients with HCC of post-TACE].

OBJECTIVE: To research the effect of a complex prescription of Chinese crude drug with the function of strengthening body resistance and disintoxication disintoxication in patients with HCC of post-TACE. METHOD: 45 patients with HCC of post-TACE, as the treatment group, were treated by a complex prescription of Chinese crude drug with the function of strengthening body resistance and disintoxication disintoxication and routine methods of protecting liver. Other 37 patients, as the control group, with the same clinical feature were treated by routine methods of protecting liver only. In the later 1 month, accumulated points of clinical symptom, hepatic function and AFP were observed in all of the patients. And the clinical effect of the two groups was compared. RESULT: One week later, in the treatment group, there is no improvement in anorexia but nausea, abdominal distention and lassitude were improved more obviously than pretherapy in both a week and one month later (P < 0.01 or P <0.05). In the control group, anorexia were improved a week later (P <0.05), but there is no improvement in nausea, abdominal distention and lassitude at the same time, and one month later all of the indexes above improved (P <0.01 or P <0.05). Accumulated points of clinical symptom was decreased more obviously in the treatment group than in the control group in both a week and one month later (P <0.05). At the end of the therapy, in the both groups, ALT, TBIL and AFP all improved except ALB, (P <0.01 or P <0.05). And TBIL improved more obviously in the treatment group than in the control one month later (P <0.05). CONCLUSION: This complex prescription of Chinese crude drug can lighten the adverse reaction of post-TACE. And also it can promote the recovery of liver function and evaluate the quality of lives of such patients.

He Jie Tang in the treatment of chronic hepatitis B patients.

AIM: To explore the effect of He Jie Tang (decoction for medication) on serum levels of T lymphocyte subsets, NK cell activity and cytokines in chronic hepatitis B patients. METHODS: Eighty-five patients with chronic hepatitis B were divided randomly into two groups. Fifty patients in group I were treated with He Jie Tang (HJT) and 35 patients in group II were treated with combined medication. The levels of T-lymphocyte subsets (CD(3)(+), CD(4)(+), CD(8)(+)), NK cell activity, cytokines (TNF-alpha, IL-8, sIL-2R) were observed before and after the treatment. Another 20 normal persons served as group 3. RESULTS: The level of CD(4)(+) cells and NK cell activity were lower, whereas the level of CD(8)(+) cells in patients was higher than that in normal persons (t = 2.685, 3.172, and 2.754 respectively; P<0.01). The levels of TNF-alpha, IL-8, and sIL-2R in chronic hepatitis B patients were higher than those in normal persons (t = 3.526, 3.170, and 2.876 respectively; P<0.01). After 6 months of treatment, ALT, AST, and TB levels in the two groups were obviously decreased (t = 3.421, 3.106, and 2.857 respectively; P<0.01). The level of CD(4)(+) cells and NK cell activity were increased whereas the level of CD(8)(+) cells decreased (t = 2.179, 2.423, and 2.677 respectively; P<0.05) in group I. The levels of TNF-alpha, IL-8, and sIL-2R in group I were decreased significantly after the treatment (t = 2.611, 2.275, and 2.480 respectively; P<0.05) but had no significant difference in group II after the treatment (t = 1.906, 1.833, and 2.029 respectively; P>0.05). The total effective rate had no significant difference between the two groups (c2 = 2.882, P>0.05) but the markedly effective rate was significantly different between the two groups (c2 = 5.340, P<0.05). CONCLUSION: HJT is effective in treating chronic hepatitis B. HJT seems to exert its effect by improving the cellular immune function and decreasing inflammatory cytokines in chronic hepatitis B patients. The function of HJT in protecting liver function in the process of eliminating virus needs to be further studied.