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The neurotoxin 6-hydroxydopamine (6-OHDA), which causes transcriptional changes associated with oxidative and proteotoxic stress, has been widely used to generate an experimental model of Parkinson’s disease. The food-derived compound luteolin has multi-target actions including antioxidant, anti-inflammatory and neurotrophic activities. The aim of this study is to investigate how luteolin affects 6-OHDA-mediated stress response pathways. The results showed that when PC12 cells were pre-treated with luteolin (20 µM) 30 min prior to 6-OHDA (100 µM) exposure, 6-OHDA-induced ROS overproduction, cytotoxicity, caspase-3 activation, and mRNA expression of BIM, TRB3 and GADD34 were significantly attenuated. Moreover, 6-OHDA-mediated cell cycle arrest and transcription of p53 target genes, p21, GADD45α and PUMA, were reduced by luteolin. Luteolin also significantly down-regulated 6-OHDA-mediated unfolded protein response (UPR), leading to decreases in phospho-eIF2α, ATF4, GRP78 and CHOP. In addition, luteolin attenuated 6-OHDA-induced Nrf2-mediated HO-1 and GCLC. Taken together, these results suggest that diminishing intracellular ROS formation and down-regulation of p53, UPR and Nrf2-ARE pathways may be involved in the neuroprotective effect of luteolin. [ABSTRACT FROM AUTHOR]

Despite very different functions, studies increasingly report that there may be a potential central nervous anatomical connection between the heart and the small intestine. In this study, the central nervous anatomical relationship between the heart and small intestine was studied via a viral tracer. Pseudorabies virus (PRV) syngeneic strains with different fluorescent reporter genes (eGFP or mRFP) were microinjected into the heart walls and small intestinal walls of male C57BL/6J using glass microelectrode. The results showed that the co-labeled nuclei in the brain were lateral periaqueductal gray (LPAG) and ventrolateral periaqueductal gray (VLPAG) in the midbrain, mesencephalic trigeminal nucleus (Me5), and motor trigeminal nucleus anterior digastric Part (5Adi) in the pons. The co-labeled sites in the spinal cord were intermediolateral column (IML) in the second thoracic vertebra, IML and lamina 7 of the spinal gray (7SP) in the third thoracic vertebra, and IML in the fourth thoracic vertebra. Our data show that there is a neuroanatomical connection between the small intestine and the heart in the central nervous system (CNS). Neuroanatomical integration of the heart and small intestine may provide a basis for revealing the physiological and pathological interactions between the circulatory and digestive systems. The interactions may be mediated more effectively through sympathetic nerves. [ABSTRACT FROM AUTHOR]

Background: Lactate dehydrogenase (LDH) is associated with the prognosis of many diseases, but the relationship between LDH and the poor prognosis (recurrence and death) of acute ischemic stroke (AIS) has not been fully clarified. This study aimed to investigate the association between admission LDH level and poor prognosis in patients with AIS. Methods: This retrospective study enrolled AIS patients treated in Taizhou Hospital of Zhejiang Province from July 2019 to December 2019. Poor prognosis included AIS recurrence and all-cause death at 3, 6, and 18 months. The correction between LDH and poor prognosis or all-cause death was assessed. Lasso Cox expression and multivariate Cox expression analyses were used to evaluate the association of LDH with the risk of poor prognosis and all-cause death, respectively. A nomogram was constructed to evaluate the predictive Values of LDH for the poor prognosis and all-cause death of AIS. Results: 732 patients were included in the study. Multivariate analysis shows that admission LDH levels were significantly correlated with poor prognosis [odds ratio (OR),1.003; 95% confidence interval (95% CI), 1.001–1.005; P = 0.001] and all-cause death (OR, 1.005; 95% CI, 1.000–1.009; P = 0.031). The correlation analysis showed that admission LDH level was positively correlated with National Institutes of Health Stroke Scale (NIHSS) score and modified Rankin Scale (mRS) score. Time-dependent receiver operating characteristic (td-ROC) curves analysis showed that the AUC values of admission LDH level for predicting prognosis of AIS patients in 3-month, 6-month, 12-month and 18-month were 0.706 (95% CI, 0.604–0.810), 0.653 (95% CI, 0.583–0.723), 0.616 (95% CI, 0.556–60676) and 0.610 (95% CI, 0.552–0.680), respectively. And td-ROC also showed that the AUC values of admission LDH level for predicting all-cause death of AIS patients in 3-month, 6-month,12-month and 18-month were 0.861 (95% CI, 0.764–0.958), 0.824 (95% CI, 0.753–0.890), 0.726 (95% CI, 0.633–0.819) and 0.715 (95% CI, 0.622–0.807), respectively. The nomograms were constructed to create the predictive models of the poor prognosis and all-cause death of AIS. Conclusion: Higher LDH levels are independently associated with poor prognosis and all-cause death of AIS. [ABSTRACT FROM AUTHOR]

MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124) participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs). We then examined which DNA repair–related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair–related genes, encoding ATM interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1), were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is a chronic inflammatory disease with an increasing incidence in the world. Qingre-Chushi therapies (QC) can alleviate clinical symptoms. Therefore, a network meta-analysis was conducted to systematically evaluate the efficacy and safety of QC in the treatment of active UC patients. Methods: 7 databases were screened and relevant randomized controlled trials were selected. The tools of Cochrane Handbook and the GRADE system were conducted to assess the quality of outcomes. Pooled risk ratio or standard mean difference was calculated with 95% credible interval for outcomes measurement using the random-effects model. The surface under the cumulative ranking curve (SUCRA) was performed to rank the treatments. The larger SUCRA scores, the more effective interventions. Results: A total of 3560 articles were identified and 21 studies including 1829 participants were included for further analysis. Totally, 9 therapies regimens were compared: oral mesalazine, mesalazine enema, mesalazine suppository, oral mesalazine + mesalazine enema, oral QC, oral QC + oral mesalazine, QC enema, oral QC + QC enema, and oral mesalazine + QC enema. Based on the SUCRA plot, oral QC + oral mesalazine was the best treatment in inducing clinical response; oral QC + QC enema had the best efficacy in the improvement of Mayo scores and alleviating abdominal pain; oral mesalazine + mesalazine enema was the optimal therapy in the endoscopic improvement and reducing diarrhea; QC enema + oral mesalazine was the best option in preventing bloody stool. Conclusion: This study confirmed the efficacy and safety of QC in treating active UC and suggested that the combination of oral medications with topical can achieve more benefits. [ABSTRACT FROM AUTHOR]

Introduction: Plenty of clinical studies have suggested the value of Chinese herbal medicine (CHM) for patients with irritable bowel syndrome (IBS), but their efficacy and safety have not been systematically concluded yet. This article aimed to compare and rank the therapeutic effect and safety of CHM with routine pharmacotherapies and placebo in the treatment of IBS. Methods: Randomized controlled trials regarding CHM to treat IBS were searched in six databases from inception to Jan 31, 2020. A network meta-analysis was conducted to analyze the data of included publications. The quality assessment was assessed by Cochrane Handbook and GRADEpro software. The risk ratio was calculated for dichotomous outcomes while the standardized mean difference was used for continuous variables with 95% credible intervals. A Funnel plot was performed to evaluate publication bias. The surface under the cumulative ranking curve was conducted to rank the included interventions. Data were analyzed with STATA 15.0 and Review Manager 5.3. Result: 3194 records were searched, and 28 eligible trials involving 3323 patients ere identified. Compared with conventional therapies and placebo, Jianpi-Chushi therapy showed significant improvement in adequate relief and IBS symptom severity scale; Shugan-Jianpi therapy showed the best efficacy in relieving the abdominal pain and abdominal distension; Wenshen-Jianpi therapy had a better effect on avoiding adverse effects and improving stool character. Conclusion: This study confirmed that CHM could be beneficial for patients with IBS in relieving their clinical symptoms and should be recommended as alternative therapies. The quality of evidence in this study based on the GRADE system was "low". [ABSTRACT FROM AUTHOR]

Objective: China has a high cesarean delivery (CD) and low labor epidural analgesia (LEA) rate. This online survey was conducted to explore the reasons behind this phenomenon and potential solutions. Methods: A voluntary, anonymous survey was distributed via both WeChat and professional websites for 4 months amongst groups of Chinese perinatal professionals. Data was collected and analyzed using a Chi-square test and presented as percentages of respondents. Results: 1412 respondents were recorded (43% anesthesiologists, 35% obstetricians, 15.5% midwives or labor and delivery nurses, and 6.5% others), and 1320 respondents were care providers. It was found that 82.7% (1092/1320) of the provider respondents used CD per patient request in fear of lawsuits or yinao/yibao and 63.4% (837/1320) used CD for respecting superstitious culture. The number one reason (noted by 60.2% (795/1320) of all the three specialties) for low LEA use was lack of anesthesia manpower without statistical difference among specialties. The most recommended solution was increasing the anesthesia workforce, proposed by 79.8% (1053/1320) of the three specialties. However, the top solution provided by the two non-anesthesia specialties is different from the one proposed by anesthesiologists. The later (83%, 504/606) suggested increasing the incentive to provide the service is more effective. The answers to questions related to medical knowledge about CD and LEA, and unwillingness of anesthesiologists, parturients and their family members to LEA were similar for the most part, while the opinions regarding low LEA use related to poor experiences and unwillingness of obstetricians and hospital administrators were significantly divided among the three specialties. In the providers' point of view, the unwillingness to LEA from parturient's family members was the most salient (26.1%, 345/1320), which is more than all care providers, hospital administrators, and parturients themselves (16.8%, 222/1320). Conclusion: The reasons for high CD rate and low LEA use are multifactorial. The sociological issues (fear of yinao/yibao and superstitious culture) were the top two contributing factors for the high CD rate in China, while lack of anesthesia manpower was the top response for the low LEA use, which contributes to its being the most recommended solution overall from the three specialties. An incentive approach to providers is a short-term solution while training more perinatal care providers (especially among anesthesiologists and midwives), improving billing systems, and reforming legal systems are 3 systemic approaches to tackling this problem in the long-term. [ABSTRACT FROM AUTHOR]

Inhibitory glycinergic transmission in adult spinal cord is primarily mediated by glycine receptors (GlyRs) containing the α1 subunit. Here, we found that α1ins, a longer α1 variant with 8 amino acids inserted into the intracellular large loop (IL) between transmembrane (TM)3 and TM4 domains, was expressed in the dorsal horn of the spinal cord, distributed at inhibitory synapses, and engaged in negative control over nociceptive signal transduction. Activation of metabotropic glutamate receptor 5 (mGluR5) specifically suppressed α1ins-mediated glycinergic transmission and evoked pain sensitization. Extracellular signal-regulated kinase (ERK) was critical for mGluR5 to inhibit α1ins. By binding to a D-docking site created by the 8-amino–acid insert within the TM3–TM4 loop of α1ins, the active ERK catalyzed α1ins phosphorylation at Ser380, which favored α1ins ubiquitination at Lys379 and led to α1ins endocytosis. Disruption of ERK interaction with α1ins blocked Ser380 phosphorylation, potentiated glycinergic synaptic currents, and alleviated inflammatory and neuropathic pain. These data thus unraveled a novel, to our knowledge, mechanism for the activity-dependent regulation of glycinergic neurotransmission. [ABSTRACT FROM AUTHOR]

Objective: To systematically evaluate the efficacy and safety of Modified Tongxie Yaofang (M-TXYF) for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). Method: Electronic databases including PubMed, Springer Link, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature (CBM), Wanfang, and Chinese Scientific Journals Database (VIP) were conducted from their inception through May 11, 2017 without language restrictions. Primary and secondary outcomes were estimated by 95% confidence intervals (CI). RevMan 5.3 and the Cochrane Collaboration’s risk of bias tool were analyzed for this meta-analysis. Results: Twenty-three literatures with a total of 1972 patients were included for the meta-analysis. The overall risk of bias evaluation was low. The pooled odds ratio showed that M-TXYF was significantly superior to routine pharmacotherapies (RP) in clinical therapeutic efficacy (OR 4.04, 95% CI 3.09, 5.27, P < 0.00001, therapeutic gain = 17.6%, number needed to treat (NNT) = 5.7). Moreover, compared with RP, M-TXYF showed that it can significantly reduce the scores of abdominal pain (standardized mean difference (SMD) -1.27; 95% CI -1.99, -0.56; P = 0.0005), abdominal distention (SMD -0.37; 95% CI -0.73, -0.01; P = 0.09), diarrhea (SMD -1.10; 95% CI -1.95, -0.25; P = 0.01), and frequency of defecation (SMD -1.42; 95% CI -2.19, -0.65; P = 0.0003). The differences of the adverse events between experiment and control groups had no statistical significance. Conclusion: This meta-analysis indicated that M-TXYF could be a promising Chinese herbal formula in treating IBS-D. However, considering the lack of higher quality of randomized controlled trials (RCTs), highly believable evidences should be required. [ABSTRACT FROM AUTHOR]

Aim: This meta-analysis analyzed the efficacy and safety of traditional Chinese medicine (TCM) for the treatment of irritable bowel syndrome with constipation (IBS-C). Methods: We searched seven electronic databases for randomized controlled trials investigating the efficacy of TCM in the treatment of IBS-C. The search period was from inception to June 1, 2017. Eligible RCTs compared TCM with cisapride and mosapride. Article quality was evaluated with the Cochrane Risk Bias Tool in the Cochrane Handbook by two independent reviewers. Begg’s test was performed to evaluate publication bias. Review Manager 5.3 and Stata 12.0 were used for analyses. Results: Eleven eligible studies comprising a total of 906 participants were identified. In the primary outcome, TCM showed significant improvement in overall clinical efficacy compared with cisapride and mosapride (odds ratio [OR] = 4.00; 95% confidence interval [CI]: 2.74,5.84; P < 0.00001). In terms of secondary outcomes, TCM significantly alleviated abdominal pain (OR = 5.69; 95% CI: 2.35, 13.78; P = 0.0001), defecation frequency (OR = 4.38; 95% CI: 1.93, 9.93. P = 0.0004), and stool form (OR = 4.96; 95% CI: 2.11, 11.65; P = 0.0002) in the treatment group as compared to the control group. A lower recurrence rate was associated with TCM as compared to cisapride and mosapride (OR = 0.15; 95% CI: 0.08, 0.27; P < 0.00001). No adverse effects were observed during TCM treatment. Conclusions: TCM showed greater improvement in terms of clinical efficacy in the treatment of IBS-C than cisapride and mosapride, although it was not possible to draw a definitive conclusion due to the small sample size, high risk, and low quality of the studies. Large multi-center and long-term high-quality randomized control trials are needed. [ABSTRACT FROM AUTHOR]

Jianpi Yiqi therapy (JYT) is a classical therapy in treating chronic atrophic gastritis (CAG), but the clinical effects of it are still contentious. The purpose of this article is to evaluate the efficacy and safety of JYT for CAG. Seven electronic databases including PubMed, Embase, Springer Link, CNKI (China National Knowledge Infrastructure), VIP (Chinese Scientific Journals Database), Wan-fang database, and CBM (Chinese Biomedicine Database) were searched from their inception to November 1, 2016. 13 randomized controlled trials (RCTs) with a total of 1119 participants were identified for analysis. Meta-analyses demonstrated that both JYT (RR 1.41; 95% CI 1.27, 1.57; P < 0.00001) and JYT + western medicine (RR 1.27; 95% CI 1.17, 1.38; P < 0.00001) were more efficacious than only western medicine. Furthermore, JYT had potential improvement on traditional Chinese medicine (TCM) symptoms scores such as stomachache, stomach distention, belching, fatigue, et al. In addition, no serious adverse events were reported in the selected trials. The Cochrane Collaboration’s risk of bias tool was evaluated for the weaknesses of methodological quality, while the quality level of Grades of Recommendations Assessment Development and Evaluation (GRADE) evidence classification indicated “Very low”. This meta-analysis indicates that JYT may have potential effects on the treatment of patients with CAG. However, due to limitations of methodological quality and small sample size of the included studies, further standardized research of rigorous design should be needed. [ABSTRACT FROM AUTHOR]

This present study was designed to investigate the effects of alpha-1-antitrypsin (AAT) on oxidative stress in preeclampsia (PE) by regulating p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. HTR8/SVneo cells were randomly assigned into normal, hypoxia/reoxygenation (H/R), HR + AAT and HR + siRNA-AAT groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the mRNA and protein expressions of p-p38MAPK, AAT, signal transducer and activator of transcription 1 (STAT1) and activating transcription factor2 (ATF2). Flow cytometry, scratch test, cell counting kit-8 (CCK-8) assay and the 3-(4,5)-dimethylthiazol (-z-y1)-3,5-di- phenyltetrazolium bromide (MTT) assay were conducted to detect reactive oxygen species (ROS) and cell apoptosis, cell migration, proliferation and cytotoxicity, respectively. Mouse models in PE were established, which were divided into normal pregnancy (NP), PE and PE + AAT groups with blood pressure and urine protein measured. Chromatin immunoprecipitation (ChIP) and enzyme-linked immunosorbent assay (ELISA) were conducted to detect the activity of oxidative stress-related kinases and expressions of inflammatory cytokines and coagulation-related factors in cells and mice placenta. Immunohistochemistry, Western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect AAT and p38MAPK expressions, apoptosis-related protein expressions, and apoptosis rate in mice placenta. Compared with the normal group, the H/R group had decreased expression of AAT, activity of superoxide dismutase (SOD) and GSH-Px, cell proliferation and migration, but increased p38MAPK, STAT1, ATF2, MDA, H2O2, inflammatory cytokines, coagulation-related factors, cell cytotoxicity, ROS, apoptotic factors and apoptosis rate. Compared with the H/R group, the HR + ATT group had increased expressions of AAT, activity of SOD and GSH-Px, cell proliferation and migration but decreased p38MAPK, STAT1, ATF2, malonyldialdehyde (MDA), H2O2, inflammatory cytokines and coagulation-related factors, cell cytotoxicity, ROS, apoptotic factors and apoptosis rate, while opposite results were observed in the HR + siRNA-ATT group. Compared with the NP group, the PE group had decreased activity of SOD and GSH-Px but increased MDA, H2O2, AAT, p38MAPK, inflammatory cytokines, coagulation-related factors and apoptosis rate. The indexes in the PE + AAT group were between the NP and PE groups. Thus, we concluded that AAT suppressed oxidative stress in PE by inhibiting p38MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Aim: Glycyrrhizin (GL) has been reported to protect against ischemia and reperfusion (I/R)-induced injury by inhibiting the cytokine activity of high mobility group box 1 (HMGB1). In the present study, the protective effects of GL against I/R injury, as well as the related molecular mechanisms, were investigated in rat brains. Methods: Focal cerebral I/R injury was induced by intraluminal filamentous occlusion of the middle cerebral artery (MCA) in Male Sprague-Dawley rats. GL alone or GL and rHMGB1 were administered intravenously at the time of reperfusion. Serum levels of HMGB1 and inflammatory mediators were quantified via enzyme-linked immunosorbent assay (ELISA). Histopathological examination, immunofluorescence, RT-PCR and western blotting analyses were performed to investigate the protective and anti-apoptotic effects and related molecular mechanisms of GL against I/R injury in rat brains. Results: Pre-treatment with GL significantly reduced infarct volume and improved the accompanying neurological deficits in locomotor function. The release of HMGB1 from the cerebral cortex into the serum was inhibited by GL administration. Moreover, pre-treatment with GL alleviated apoptotic injury resulting from cerebral I/R through the inhibition of cytochrome C release and caspase 3 activity. The expression levels of inflammation- and oxidative stress-related molecules including TNF-α, iNOS, IL-1β, and IL-6, which were over-expressed in I/R, were decreased by GL. P38 and P-JNK signalling were involved in this process. All of the protective effects of GL could be reversed by rHMGB1 administration. Conclusions: GL has a protective effect on ischemia-reperfusion injury in rat brains through the inhibition of inflammation, oxidative stress and apoptotic injury by antagonising the cytokine activity of HMGB1. [ABSTRACT FROM AUTHOR]