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CONTEXT: Taohong Siwu decoction (THSWD) has been shown to promote heart repair in myocardial infarction. OBJECTIVE: To determine the effects of modified THSWD (THSWD plus four ingredients) on myocardial ischaemia and reperfusion (I/R) injury. MATERIALS AND METHODS: Sixty Sprague-Dawley rats were randomly divided into the I/R group and three different modified THSWD dose groups (gavage administration, 1.215, 2.43, and 4.86 g, respectively). 2,3,5-Triphenyltetrazolium chloride and Evans blue staining were used to detect the infarct area at 24 h after treatment. The serum biochemical indexes and cell apoptosis were examined to determine myocardial injury. The number of endogenous stem cells, expression of stromal dell derived factor-1 (SDF-1) and stem cell factor (SCF), and cardiac function were measured at 4 weeks. The serum was collected for metabolomic analysis. RESULTS: The high-dose modified THSWD group presented a reduced infarction area (decreased by 21.3%), decreased levels of lactate dehydrogenase and creatinine kinase, attenuated cell apoptosis, and enhanced superoxide dismutase activity in early stage I/R compared with other groups. The serum SCF and SDF-1 levels were higher in the high-dose group than in the I/R group. At 4 weeks, the infarct size and collagen content were the lowest, and the ejection fraction and fractional shortening values were the highest in the high-dose group. Moreover, high-dose modified THSWD affected the metabolism of phosphonate and phosphonate, taurine, and hypotaurine. CONCLUSIONS: Endogenous stem cell mobilization and metabolic regulation were related to the cardioprotection of modified THSWD. We provided a new strategy and direction for the treatment of cardiovascular diseases with traditional Chinese medicine.

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BACKGROUND: Overexposure to manganese (Mn) can lead to neurodegenerative damage, resulting in manganism with similar syndromes to Parkinson's disease (PD). However, little is known about changes in transcriptomics induced by the toxicological level of Mn. In this study, we conducted RNA-seq to explore the candidate genes and signaling pathways included by Mn in human SH-SY5Y neuroblastoma cells. METHODS: The differentially expressed genes (DEGs) between the Mn-treated group and the control group were screened, and weighted gene co-expression network analysis (WGCNA) was employed to identify hub genes. Then, pathway enrichment analyses for those candidate genes were performed in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We further validated the concentration- and time-response effects of Mn exposure (0-500 µM, 3-12 h) on mitochondrial unfolded protein response (UPRMT) by real-time quantitative reverse transcription PCR (qRT-PCR). RESULTS: The results showed 179 up-regulated differentially expressed genes (DEGs) and 681 down-regulated DEGs after Mn exposure. Based on the intersection of DEGs genes and hub genes, 73 DEGs were related to neurotoxicity. The comprehensive pathway analysis showed Mn had widespread effects on the mitogen-activated protein kinase (MAPK) signaling pathway, unfolded protein response, longevity regulating pathway, inflammatory bowel disease, and mitophagy signaling pathway. After Mn exposure, the expressions of activating transcription factor 3 (ATF3) and C-C motif chemokine ligand 2 (CCL2) increased, while the expressions of C/EBP homologous protein (CHOP), caseinolytic protease P (CLPP), and Lon protease 1 (LONP1) decreased in a concentration- and time-dependent manner. CONCLUSIONS: Overall, our study suggests that UPRMT is a new sight in understanding the mechanism of Mn-induced neurotoxicity.

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BACKGROUND: Exposure to heavy metals has been related to decreased lung function in workers. However, due to limitations in statistical methods for mixtures, previous studies mainly focused on single or several toxic metals, with few studies involving metal exposome and lung function. OBJECTIVES: The study aimed to evaluate the effects of co-exposure to the metal mixtures on multiple parameters of pulmonary function tests and to identify the elements that play an essential role in elastic-net regression (ENET), multivariate linear regression, bayesian kernel machine regression (BKMR), and quantile g-computation (QG-C) models. METHODS: We have recruited 186 welders from Anhui (China) in 2019. And their end-of-shift urine and lung function measure data were collected with informed consent. The urinary concentrations of 23 metals were measured by inductively coupled urinary mass spectrometry. The lung function measures including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF) were also detected as outcome indicators. Four statistical methods, ENET, multivariate linear regression, BKMR, and QG-C models were used to evaluate the associations of element mixtures on lung function comprehensively. RESULTS: Lead and cadmium were negatively associated with FVC and FEV1, nickel and chromium were inversely associated with PEF, and strontium showed significant positive effects in linear regression models, which were consistent with the results in BKMR and QG-C models. Both BKMR and QG-C models showed a significantly negative overall effect of metal mixtures on lung function parameters (FVC, FEV1, and PEF). Meanwhile, BKMR showed the non-linear relationships of cadmium with FVC. CONCLUSION: Multi-pollutant mixtures of metals were negatively associated with lung function. Lead, cadmium, nickel, and strontium might be crucial elements. Our findings highlight a need to prioritize workers' environmental health, and guide future research into the toxic mechanisms of metal-mediated lung function injury.

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To verify the role of PI3K-AKT-GSK3ß pathway during manganese (Mn)-induced cell death, apoptosis, related indicators were investigated. SH-SY5Y cells were directly exposed to different concentrations of MnCl2. Then, cell viability, apoptosis, necrosis rate, and cell cycle were detected by MTT, FITC Annexin V Apoptosis Detection Kit with PI and PI staining. Then, in two intervention groups, cells were preconditioned with agonist (PQQ) and suppressant (LY294002). The cell viability decreased with a dose-response relationship (p < 0.05), while apoptosis and necrosis increased (p < 0.05). The ratio of G0/G1 and G2/M also decreased, but the percentage of S phase increased (p < 0.05). During above process, PI3K-AKT-GSK3ß pathway was involved by regulating the expression of PI3K, AKT, p-AKT, and GSK3ß (p < 0.05). For further research, cell cycle and apoptosis were detected pretreatment with PQQ and LY294002 before Mn exposure. The result showed cell ability, apoptosis, and necrosis rate changed obviously compared with non-pretreated group (p < 0.05). The variance of G0/G1 and G2/M ratio and percentage of S phase were also different, especially in 2.0 mM (p < 0.05). Mn can cause apoptosis and necrosis, varying cell cycle of SH-SY5Y cells, which could be changed by PQQ and LY294002 by regulating PI3K-AKT-GSK3ß pathway.

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OBJECTIVE: To evaluate the effects of electroacupuncture (EA) combined with exercise training on motor function and microtubule-associated protein (MAP)-2 in the hippocampal CA3 region of rats in the middle and late stages of cerebral infarction, and explore potential underlying mechanisms of action. METHODS: A total of 80 Wistar rats were randomly divided into model, EA, training and EA + training groups (n = 20 per group) after establishing the middle cerebral artery occlusion (MCAO) model of cerebral infarction. Rats were treated with EA and/or training in the sixth week post-MCAO. After receiving 2 weeks of treatment, motor function was assessed and MAP-2 expression in the CA3 region was measured using an immunohistochemical method. RESULTS: Compared to the model group, significant differences in walking stick, balance beam and screen capture ability were detected in the EA, training and EA + training groups (p < 0.05). The EA + training group showed greater improvements than the EA and training groups (p < 0.05 each). Significant differences in MAP-2 expression were detected in the EA, training and EA + training groups compared to the model group (p < 0.05). MAP-2 expression was higher in the EA + training group than in the EA and training groups (p < 0.05 each). CONCLUSION: MAP-2 expression and motor functional recovery were higher in the combined therapy (EA + training) group compared to the monotherapy (EA or training) groups. EA combined with exercise training appeared to significantly promote the recovery of motor function in the middle and late stages of cerebral infarction in this rat model.

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Two currently used brominated flame retardants (BFRs), α, ß, γ-hexabromocyclododecane (HBCDD) and tetrabromobisphenol A (TBBPA), were measured in 111 breast milk samples from 37 Beijing mothers. Each mother provided one milk sample per month for 3 months. HBCDD was detected in almost all samples, and the median level reached 5.67 ng g-1 lipid weight (lw). α- HBCDD was the most abundant isomer (median: 4.23 ng g-1 lw), followed by γ- and ß-HBCDD. For TBBPA, a relatively lower detecting frequency (64%) and contamination level (median: 1.57 ng g-1 lw) were obtained. A comparison to our previous study revealed that the occurrence of TBBPA and HBCDD in Beijing human milk significantly rose from 2011 to 2014, whereas another commonly used class of BFRs, polybrominated diphenyl ethers (PBDEs), showed significantly decreased during this period. However, a comparison among currently used BFRs showed that levels of some BFRs, such as HBCDD, surpassed those of PBDEs, which indicated that PBDEs were no longer the primarily used BFR in China. However, no significant temporal trends for BFR levels were observed over the 3 months of lactation. Daily intakes of TBBPA and HBCDD were calculated for nursing infants and the median TBBPA and HBCDD intakes via breastfeeding were 6.62 and 26.4 ng kg-1 bw day-1, respectively. These values were several times higher than those for adults via food consumption. However, risk assessment using the margin of exposure approach indicated that intakes of TBBPA and HBCDD via breastfeeding can scarcely cause significant health risks to infants.

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Cardiovascular disease has been established as a major cause of morbidity and mortality worldwide, resulting in a huge burden to patients, families, and society. Traditional Chinese Medicine (TCM) presents several advantages for the prevention and treatment of cardiovascular diseases including multitargets, multi-ingredients, fewer side effects, and low cost. In this study, a rat model of myocardial infarction (MI) was established by ligating the anterior descending branch of the left coronary artery, and the effect of the Taohong Siwu decoction (THSWD) on cardiac function was evaluated in MI rats. Following the intragastric administration of THSWD, the cardiac function was examined using echocardiography. The infarct size and collagen deposition in the infarct area were measured using Masson's trichrome staining, and the number of CD31- and α-SMA-positive blood vessels in the peri-infarct and infarct area was evaluated by immunofluorescent staining. The mRNA expression of bFGF, IGF-1, and HGF was detected using RT-PCR assay. Cell apoptosis in the infarcted area was assessed by TUNEL staining, and the p-Akt level was detected using the western blot assay. The mitochondrial ROS production was measured using MitoSOX staining, and mitochondrial dynamics and mitophagy were evaluated with western blotting 7 days after THSWD treatment. THSWD increased the ejection fraction (EF) and fractional shortening (FS) values in the rat hearts; however, no statistical difference was found between the THSWD and MI groups 4 weeks after treatment. Furthermore, THSWD significantly decreased the value of the left ventricular end-systolic volume (LVESV). Compared with the model group, THSWD significantly increased the expression of IGF-1 and bFGF, reduced collagen deposition, promoted angiogenesis, reduced cell apoptosis, and activated the PI3K/Akt signaling pathway. Notably, THSWD significantly decreased mitochondrial ROS production and Fis1 expression. No statistical differences were observed in the expression of mitochondrial LC3B and Mfn1 between the THSWD and control groups. In summary, THSWD may possess a beneficial effect on cardiac function by improving the local ischemic microenvironment and by decreasing mitochondrial fission after MI. Hence, this may present a promising auxiliary strategy in the treatment of ischemic cardiomyopathy such as MI.

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Since the KCNB1 encoding Kv2.1 channel accounts for the majority of Kv currents modulating insulin secretion by pancreatic islet beta-cells, we postulated that KCNB1 is a plausible candidate gene for genetic variation contributing to the variable compensatory secretory function of beta-cells in type-2 diabetes (T2D). We conducted two studies, a case-control study and a cross-section study, to investigate the association of common single-nucleotide polymorphisms (SNPs) in KCNB1 with T2D and its linking traits. In the case-control study, we first examined the association of 20 tag SNPs of KCNB1 with T2D in a population with 226 T2D patients and non-diabetic subjects (screening study). We then identified the association in an enlarged population of 412 T2D patients and non-diabetic subjects (replication study). In the cross-sectional study, we investigated the linkage between the candidate SNP rs1051295 and T2D by comparing beta-cell function and insulin sensitivity among rs1051295 genotypes in a general population of 1051 subjects at fasting and after glucose loading (oral glucose tolerance tests, OGTT) in 84 fasting glucose impaired subjects, and several T2D-related traits. We found that among the 19 available tag SNPs, only the KCNB1 rs1051295 was associated with T2D (P = 0.027), with the rs1051295 TT genotype associated with an increased risk of T2D compared with genotypes CC (P = 0.009). At fasting, rs1051295 genotype TT was associated with a 9.8% reduction in insulin sensitivity compared to CC (P = 0.008); along with increased plasma triglycerides (TG) levels (TT/CC: P = 0.046) and increased waist/hip (W/H) ratio (TT/CC: P = 0.013; TT/TC: P = 0.002). OGTT confirmed that genotype TT exhibited reduced insulin sensitivity by 16.3% (P = 0.030) compared with genotype TC+CC in a fasting glucose impaired population. The KCNB1 rs1051295 genotype TT in the Chinese Han population is associated with decreased insulin sensitivity and increased plasma TG and W/H ratio, which together contribute to an increased risk for T2D.

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It is reported that consumption of antioxidant-rich foods significantly increased plasma total antioxidant capacity (T-AOC) in humans. Also, it is proved that the antioxidants from plant foods improve the body's antioxidant defence by acting additively and synergistically. As a result, rational combination of antioxidant-rich foods is recommended to population in the prevention of oxidative stress-related diseases. Both apple and grape are antioxidant-rich fruits. In this study, 2 weeks dietary intervention study was carried out in 25 healthy subjects to investigate the influences of apple and grape juices consumption on body antioxidant status. Our results indicated that 2 weeks of apple and grape juice consumption increased the plasma T-AOC and decreased the concentration of malondialdehyde. However, no change was found in the content of plasma carbonyl. Erythrocyte glutathione peroxidase and catalase activities were enhanced by 2 weeks of fruit juice consumption; however, no change was found in the activity of erythrocyte superoxide dismutase. The in vitro comet assay results indicated that apple and grape juice consumption did not influence lymphocyte damage upon hydrogen peroxide treatment. Urinary 8-hydroxy-2-deoxyguanosine content was not affected by 2 weeks of fruit juice intervention. These findings indicated that concomitant intake of apple and grape juice was efficient in enhancing the body's antioxidant status.

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Preeclampsia (PE) is a severe hypertensive disorder associated with pregnancy; despite substantial research effort in the past several years, the etiology of PE is still unclear. The role of epigenetic factors in the etiology of PE, including DNA methylation, has been poorly characterized. In the present study, we investigated global DNA methylation as well as DNA methylation of the paternally imprinted H19 gene in preeclamptic placentas. Using 5-methylcytosine immunohistochemistry and Alu and LINE-1 repeat pyrosequencing, we found that the global DNA methylation level and the DNA (cytosine-5) methyltransferase 1 mRNA level were significantly higher in the early-onset preeclamptic placentas when compared with the normal controls. Data from methylation-sensitive high resolution melting demonstrated hypermethylation of the promoter region of the H19 gene, and results of real-time PCR showed decreased mRNA expression of H19 gene in the early-onset preeclamptic placentas as compared with the normal controls. Our results suggest that abnormal DNA methylation during placentation might be involved in the pathophysiology of PE, especially early-onset preeclampsia.

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A solid-phase extraction (SPE) method for the simultaneous extraction of hexabromocyclododecanes (HBCDs)/tetrabromobisphenol A (TBBPA) and polybrominated diphenyl ethers (PBDEs) in human serum was developed. The extracts of HBCDs/TBBPA and PBDEs were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and gas chromatography-negative chemical ionization/mass spectrometry (GC-NCI/MS), respectively. The samples with the spiked internal standards, 13C(12)-HBCD, 13C(12)-TBBPA, 3, 3', 4, 4'-tetrabromodiphenyl ether (BDE-77) and 13C(12)-decabromodiphenyl ether (BDE-209), were extracted using the mixture of methyl tert-butyl ether (MTBE) and hexane (1:1, v/v). Then the co-extracted lipid was removed by sulfuric acid treatment. The newly obtained extract was purified using SPE with an LC-Si column and two fractions of HBCDs/TBBPA and PBDEs were finally got. The determination of HBCDs/TBBPA was performed on a 50 mm BEH C18 column in the multi-reaction monitoring (MRM) mode and the determination of PBDEs was on a 15 m capillary column in the selected ion-monitoring (SIM) mode. The limits of detection (LODs, S/N = 3) ranged from 1.81 to 42.16 pg/g. The average recoveries were from 80.3% to 108.8% at two spiked levels of 0.5 and 5 ng/g for HBCDs, 0.05 and 0.5 ng/g for TBBPA and BDE-209 with the relative standard deviations between 1.02% and 11.42% (n = 5). The developed method has been successfully applied to the determination of the 12 analytes in 42 pooled human serum samples. The levels of TBBPA in the samples ranged from < LOD to 6.58 ng/g, that of alpha-HBCD diastereoisomer ranged from < LOD to 7.22 ng/g, which was the most abundant isomer comparing with beta- and gamma-HBCD. The total PBDEs found ranged from 2.90 to 89.69 ng/g. This method was validated to be accurate and sensitive for the analysis of HBCDs, TBBPA and PBDEs in serum samples.

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OBJECTIVE: To examine the effects and mechanism of exercise on resisting brain aging from the aspect of synaptic plasticity. METHODS: Forty male ICR mice were randomly divided into 4 groups: the D-galactose-induced brain aging, brain aging plus exercise, exercise only and normal controls. Mice were subjected to treadmill running at intensity (25 m/min for 20 min daily, 6 days a week) level of exercise and were given 100 mg x kg(-1) x d(-1) subcutaneous injection of D-galactose to prepare brain aging model for 9 weeks. The Morris water maze (MWM) test was employed to determine their spatial learning and memory ability. Flow cytometry (FCM) was used to analyze the amount of hippocampal synaptosomes. Membrane fluidity of synaptosomes was measured by fluorescence polarization technique. Acetylcholinesterase (AChE) activity in brain was determined by hydroxylamine colorimetric assay. RESULTS: (1) In Morris water maze test, brain aging mice showed a significant longer escape latency (EL) than the normal control mice (P < 0.05). Brain aging mice plus exercise exhibited a significant shorter EL than brain aging mice (P < 0.05), but no difference was found when compared with normal control mice (P > 0.05). There were no statistical difference in EL between the controls and exercise group (P > 0.05). (2) The number of synaptosomes in brain aging mice and brain aging mice plus exercise were less than those in non-brain aging mice (the exercise and the control mice) (P < 0.05). The number of synaptosomes in brain aging mice plus exercise was more than brain aging mice (P < 0.05). There were no statistical difference in the number of synaptosomes between the controls and exercise group (P > 0.05). (3) Membrane fluidity of synaptosomes: the viscosity of membrane in brain aging group was higher than in non-brain aging group, and higher than brain aging plus exercise group (P < 0.05). There were no statistical difference in viscosity of membrane between brain aging group and non-brain aging group, and between the controls and exercise group (P > 0.05). (4) The AChE activity in brain aging and brain aging plus exercise group were higher than those in control and exercise group (P < 0.05). There were no statistical difference in AChE activity between the controls and exercise group (P > 0.05). CONCLUSION: Exercise can effectively protect against decline in the capacity of learning and memory in brain aging mice.

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Voltage-gated outward K(+) currents from pancreatic islet beta-cells are known to repolarize the action potential during a glucose stimulus, and consequently to modulate Ca(2+) entry and insulin secretion. The voltage gated K(+) (Kv) channel, Kv2.1, which is expressed in rat islet beta-cells, mediates over 60% of the Kv outward K(+) currents. A novel peptidyl inhibitor of Kv2.1/Kv2.2 channels, guangxitoxin (GxTX)-1, has been shown to enhance glucose-stimulated insulin secretion. Here, we show that SNAP-25(1-180) (S180), an N-terminal SNAP-25 domain, but not SNAP-25(1-206) (S206), inhibits Kv current and enhances glucose-dependent insulin secretion from rat pancreatic islet beta-cells, and furthermore, this enhancement was induced by the blockade of the Kv2.1 current. This study indicates that the Kv2.1 channel is a potential target for novel therapeutic agent design for the treatment of type 2 diabetes. This target may possess advantages over currently-used therapies, which modulate insulin secretion in a glucose-independent manner.

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PURPOSE: To explore the needs for basic community-based rehabilitation services for disabled persons in Xuanwu District, Beijing, China, and to identify factors which influence disabled persons to accept rehabilitation services. METHOD: One hundred and eight disabled persons were selected by systematic sampling and simple random sampling to assess their needs for community-based rehabilitation services. RESULTS: Of the interviewees, 57.4% needed the community-based rehabilitation services, but only 13.9% took advantage of it. The main factors influencing the interviewees to accept these services were cost (P < 0.05), knowledge about rehabilitation medicine (P < 0.05); and the belief in the therapeutic benefit of the community-based rehabilitation service (P < 0.05). CONCLUSION: A considerable gap exists between the supply of community-based rehabilitation services in Beijing and the needs for these services by disabled residents underscoring the need for improved availability, and for additional research.

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