[MtDNA haplogroup U4b is a genetic susceptibility factor for high altitude essential hypertension in the Chinese Tajik population].

Objective: To investigate the relationship between mitochondrial DNA (mtDNA) variation and high altitude essential hypertension(HAEH) in the Chinese Tajik population. Methods: Fifty-three patients with HAEH and 46 healthy subjects were enrolled from the Chinese Tajik population. The mtDNA fragments were amplificated by polymerase chain reaction, and products were sequenced to acquire full sequence of mtDNA. The mtDNA sequences of all subjects were compared to the Cambridge sequence to explore mtDNA variations and analyze difference between HAEH and healthy controls. Online softwares were applied to predict function changes caused by positive associated mtDNA variations. Results: Compared to the control group, the frequency of haplogroup U4b was significant higher in HAEH group(P=0.023,OR=7.062,CI(95%)=1.306-38.182), and the frequencies of 8 mutations from haplogroup U4b showed a significant difference between the HAEH group and control group (all with P values below 0.05). The mt DNA15693T＞C mutation was the only missense mutation, which affected amino acid 316 in mitochondrial cytochrome b (MTCYB) by changing it from methionine to threonine. Bioinformatics analysis indicated that the mutation in MTCYB may play a biological role through affecting the second structure of protein. Conclusion: MtDNA subhaplogroup U4b is a genetic factor for HAEH in the Chinese Tajik population, and mtDNA15693T＞C mutation may be an important molecular mechanism of HAEH.

[Changes of lncRNA-mRNA co-expression network induced by mtDNA3010A/G genotype mutation in hypoxia].

Objective: To analyze the long non-coding RNA (lncRNA) and messenger RNA (mRNA) co-expression network changes induced by mtDNA3010A/G mutation in acute hypoxia, and to investigate the role of key lncRNA and mRNA in the regulation of gene expression induced by hypoxia. Methods: The genotype combinations A-C-C and G-C-C of mitochondrial DNA 3010-5178-10400 were screened, and genotypes of mtDNA3010A and mtDNA3010G fusion cells were constructed by using osteosarcoma cell treated by ethidium bromide without mitochondrion (ρ0206 cell) as donors. After treatment with 1% O2 24 h, the lncRNA - mRNA expression chip was applied to detect the differently expressed lncRNA and mRNA in two kinds of fusing cells, and fluorescence quantitative polymerase chain method was used to verify differently expressed mRNA. Bioinformatics methods were applied to build co-expression network of lncRNA-mRNA, predict target genes of differently expressed lncRNA, and the functions of differently expressed mRNA and target genes predicted by lncRNA were also analyzed based on gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) forecast analysis. Results: After treatment with 1% O2 for 24 h, compared with mtDNA3010G fusion cells: 688 lncRNAs were up-regulated, 21 were more than 2 times; 1098 were down-regulated, and 4 were more than 2 times. There were 1151 mRNA expressions up-regulated, 14 were more than 2 times, 539 mRNA expressions were down-regulated, and 3 were more than 2 times. Conclusion: MtDNA3010A/G genotype mutation under hypoxia is able to affect the lncRNA-mRNA regulatory network, and the differentially expressed lncRNA and mRNA may play an important role in regulation network of gene expression induced by hypoxia, which is expected to be a target for the regulation of hypoxia reaction from the perspective of mitochondria.

Association between medical resources and the proportion of oldest-old in the Chinese population.

The potential association between medical resources and the proportion of oldest-old (90 years of age and above) in the Chinese population was examined, and we found that the higher proportion of oldest-old was associated with the higher number of beds in hospitals and health centers.

Sex-based differences in the prevalence of acute mountain sickness: a meta-analysis.

BACKGROUND: When lowlanders rapidly ascend to altitudes > 2500 m, they may develop acute mountain sickness (AMS). The individual susceptibility, ascending velocity, time spent at altitude, activity levels and altitude reached are considered risk factors for AMS. However, it is not clear whether sex is a risk factor. The results have been inconclusive. We conducted a meta-analysis to test whether there were sex-based differences in the prevalence of AMS using Lake Louise Scoring System. METHODS: Systematic searches were performed in August 2019 in EMBASE, PubMed, and Web of Science for prospective studies with AMS data for men and women. The titles and abstracts were independently checked in the primary screening step, and the selected full-text articles were independently assessed in the secondary screening step by the two authors (YPH and JLW) based on pre-defined inclusion criteria. The meta-analysis was performed using by the STATA 14.1 software program. A random-effects model was employed. RESULTS: Eighteen eligible prospective studies were included. A total of 7669 participants (2639 [34.4%] women) were tested. The results showed that there was a statistically significant higher prevalence rate of AMS in women than in men (RR = 1.24, 95%CI 1.09-1.41), regardless of age or race. Howerver, the heterogeneity was significant in the analysis (Tau2 = 0.0403, Chi2 = 50.15, df = 17; I2 = 66.1%, P = 0.000), it was main caused by different numbers of subjects among the studies (coefficient = - 2.17, P = 0.049). Besides, the results showed that there was no evidence of significant publication bias in the combined studies on the basis of Egger's test (bias coefficient = 1.48, P = 0.052) and Begg's test (P = 0.130). CONCLUSIONS: According to this study, the statistically significant finding emerging from this study was that women have a higher prevalence of AMS. However, the authors could not exclude studies where patients were on acetazolamide. Our analysis provided a direction for future studies of the relationship of sex and the risk of AMS, such as the pathological mechanism and prevention research.

GIT1 contributes to autophagy in osteoclast through disruption of the binding of Beclin1 and Bcl2 under starvation condition.

Approximately 10-15% of all bone fractures do not heal properly, causing patient morbidity and additional medical care expenses. Therefore, better mechanism-based fracture repair approaches are needed. In this study, a reduced number of osteoclasts (OCs) and autophagosomes/autolysosomes in OC can be observed in GPCR kinase 2-interacting protein 1 (GIT1) knockout (KO) mice on days 21 and 28 post-fracture, compared with GIT1 wild-type (GIT1 WT) mice. Furthermore, in vitro experiments revealed that GIT1 contributes to OC autophagy under starvation conditions. Mechanistically, GIT1 interacted with Beclin1 and promoted Beclin1 phosphorylation at Thr119, which induced the disruption of Beclin1 and Bcl2 binding under starvation conditions, thereby, positively regulating autophagy. Taken together, the findings suggest a previously unappreciated role of GIT1 in autophagy of OCs during fracture repair. Targeting GIT1 may be a potential therapeutic approach for bone fractures.

Mitochondrial division inhibitor 1 protects cortical neurons from excitotoxicity: a mechanistic pathway.

Mitochondrial division inhibitor 1 (Mdivi-1) is a selective cell-permeable inhibitor of dynamin-related protein-1 (Drp1) and mitochondrial division. To investigate the effect of Mdivi-1 on cells treated with glutamate, cerebral cortex neurons isolated from neonatal rats were treated with 10 mM glutamate for 24 hours. Normal cultured cells and dimethyl sulfoxide-cultured cells were considered as controls. Apoptotic cells were detected by flow cytometry. Changes in mitochondrial morphology were examined by electron microscopy. Drp1, Bax, and caspase-3 expression was evaluated by western blot assays and immunocytochemistry. Mitochondrial membrane potential was detected using the JC-1 probe. Twenty-four hours after 10 mM glutamate treatment, Drp1, Bax and caspase-3 expression was upregulated, Drp1 and Bax were translocated to mitochondria, mitochondrial membrane potential was decreased and the rate of apoptosis was increased. These effects were inhibited by treatment with 50 µM Mdivi-1 for 2 hours. This finding indicates that Mdivi-1 is a candidate neuroprotective drug that can potentially mitigate against neuronal injury caused by glutamate-induced excitotoxicity.

Association between acute mountain sickness (AMS) and age: a meta-analysis.

BACKGROUND: Acute mountain sickness (AMS) is a potentially lethal condition caused by acute hypoxia after ascending to altitudes higher than 2500 m in a short time. The main symptom of AMS is headache. Numerous risk factors of AMS have been examined, including gender, obesity, ascent rate, age and individual susceptibility. In previous studies, age was considered a predisposing factor for AMS. However, different opinions have been raised in recent years. To clarify the association between AMS and age, we conducted this meta-analysis. METHODS: We obtained observational studies that explored risk factors for AMS by searching PubMed, Embase, China National Knowledge Internet (CNKI), the Wanfang database and CQVIP for articles published before March 2017. The studies included were required to provide the mean age and its standard deviation for subjects with and without AMS, the maximum altitude attained and the mode of ascent. The Lake Louse Score (LLS) or the Chinese AMS score (CAS) was used to judge the severity of AMS symptoms and incidence. Studies were pooled for the analysis by using a random effects model in RevMan 5.0. Meta-regression and subgroup analyses were conducted to identify sources of heterogeneity using Stata 14.2 and RevMan 5.0. RESULTS: In total, 17 studies were included, and the overall number of subjects with and without AMS was 1810 and 3014, respectively. The age ranged from 10 to 76 years. Analysis of the 17 included studies showed that age was not associated with AMS (mean difference (MD) = 0.10; 95% CI: -0.38-0.58; P = 0.69). CONCLUSION: This meta-analysis suggests that there is no association between age and the risk of AMS. Race, age, and ascent mode are common sources of heterogeneity, which may provide an analytical orientation for future heterogeneity analyses.

Bioinformatics analysis of the molecular mechanisms underlying traumatic spinal cord injury.

Spinal cord injury (SCI) is a cause of disability. The present study aimed to investigate the molecular mechanisms involved in traumatic SCI. Transcriptome data under accession no. GSE5296, including 96 chips, were downloaded from the Gene Expression Omnibus database. The raw data were normalized and differentially expressed genes (DEGs) were identified. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology enrichment analysis of up­ and downregulated DEGs was performed. Additionally, a protein­protein interaction network was constructed and the expression patterns of different genes were determined. Compared with sham samples, there were 374, 707, 1,322, 1,475, 1,724 and 1,342 DEGs identified at 0.5, 4, 24 and 72 h, and 7 and 28 days post­injury, respectively. At 24 and 72 h, and 7 days following injury, the upregulated DEGs were markedly enriched in 'inflammatory response' and 'immune process'. Downregulated DEGs were predominantly enriched in neuronal function­associated pathways and 'steroid biosynthesis' process. Protein­protein interaction network analysis demonstrated similar results. Trend charts further demonstrated that the inflammatory and neuronal functions were altered in a temporal and site­specific manner. The present study provided an insight into the molecular mechanisms underlying traumatic SCI, which may benefit future SCI research and aid in therapy development.

Role of medical resource level in iodine deficiency disorder.

BACKGROUND: Iodine deficiency disorders (IDDs) refer to a series of diseases caused by the human body's insufficient iodine intake. Edible salt became iodized in China in 1996, which yielded remarkable results. We have known that IDDs is associated with iodine in the human body, but it is not clear whether IDDs is related to medical resource level. METHODS: We collected the number of IDDs cases and an index for the level of medical resource from 31 provinces, autonomous regions and municipalities directly under the central government in China. All data came from the China Statistical Yearbook of Health and Family Planning issued in 2013 by the Peking Union Medical College Publishing House. Data standardization and linear regression analysis were used. RESULTS: The results showed that IDDs correlated with the number of beds in medical and health institutions, number of medical health personnel, number of medical and health institutions, total health expenditure, average health expenditure per capita, medical insurance for urban resident and new rural cooperative medical rural residents (P < 0.01). In a multiple linear regression, IDDs was most significantly associated with the number of beds in hospitals, the number of rural health personnel, the number of basic medical and health institutions and government health expenditure for these institutions. CONCLUSION: Based on the experimental data, we concluded that IDDs had a positive connection with the medical resource level, and basic and rural areas had a more significant association with IDDs. This analysis provides new and explicit ideas for iodine prevention and control work in China.

Association of iodized salt with goiter prevalence in Chinese populations: a continuity analysis over time.

BACKGROUND: Iodine deficiency disorders (IDD) refer to diseases that are caused by insufficient iodine intake, and the best strategy to prevent IDD is the addition of iodine to dietary salt. Because iodine deficiency is a common cause of goiter, the prevalence as effectively controlled after the implementation of universal salt iodization (USI) in China. However, there is substantial controversy as to whether the incidence of thyroid disorders is related to iodized salt intake. Therefore, we aimed to clarify whether the risk of goiter can be promoted by USI. METHODS: A longitudinal continuous study based on the national monitoring results of IDD in China was performed for 3 consecutive years. We recorded the following indicators of IDD from 31 provinces: goiter number, two degrees of goiter (the degree of goiter severity) and cretinism (three endemic diseases), iodized salt intake, median urinary iodine concentration (UIC), soil iodine content and coverage rates of iodized salt. One-way Analysis of Variance (ANOVA) and linear regression analyses examined the differences between the three groups and correlations, respectively. Data were collected from the Chinese national IDD surveillance data in 2011-2013, and the background values of Chinese soil elements were published in 1990. RESULTS: A reference male's daily intake of maximum iodine was 378.9 µg, 379.2 µg and 366.9 µg in 2011, 2012, and 2013, respectively. No statistical association between daily iodized salt intake and the three endemic diseases was observed in 2011-2013 (P > 0.05). No association was observed between daily iodized salt intake and the UIC of children in 2011 (P > 0.05). Linear regression revealed no significant correlation between the soil iodine content and three endemic diseases. The present study indicated no difference in the daily iodized salt intake in each province during three years (F = 0.886, P = 0.647). The coverage rate of iodized salt remained above 98.7%, and goiter rates were stable in 2011-2013. CONCLUSION: There was no significant association between iodized salt intake and the three endemic diseases, suggesting that the current nutrition level of iodized salt did not cause the high goiter prevalence.

Association between smoking and the risk of acute mountain sickness: a meta-analysis of observational studies.

BACKGROUND: People rapidly ascending to high altitudes (>2500 m) may suffer from acute mountain sickness (AMS). The association between smoking and AMS risk remains unclear. Therefore, we performed a meta-analysis to evaluate the association between smoking and AMS risk. METHODS: The association between smoking and AMS risk was determined according to predefined criteria established by our team. Meta-analysis was conducted according to the PRISMA guidelines. We included all relevant studies listed in the PubMed and Embase databases as of September 2015 in this meta-analysis and performed systemic searches using the terms "smoking", "acute mountain sickness" and "risk factor". The included studies were required to provide clear explanations regarding their definitions of smoking, the final altitudes reached by their participants and the diagnostic criteria used to diagnose AMS. Odds ratios (ORs) were used to evaluate the association between smoking and AMS risk across the studies, and the Q statistic was used to test OR heterogeneity, which was considered significant when P < 0.05. We also computed 95% confidence intervals (CIs). Data extracted from the articles were analyzed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). RESULTS: We used seven case-control studies including 694 smoking patients and 1986 non-smoking controls to analyze the association between smoking and AMS risk. We observed a significant association between AMS and smoking (OR = 0.71, 95% CI 0.52-0.96, P = 0.03). CONCLUSIONS: We determined that smoking may protect against AMS development. However, we do not advise smoking to prevent AMS. More studies are necessary to confirm the role of smoking in AMS risk.

The associations between MDM4 gene polymorphisms and cancer risk.

Considerable studies have investigated the associations between MDM4 gene polymorphisms and cancer risk recently, but with contradictory results. The aim of this meta-analysis was to evaluate the associations between MDM4 gene polymorphisms and cancer risk. Relevant studies were identified by a systematic search of PubMed, Embase, and CNKI databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to describe the strength of the associations. Fifty-six studies published in 11 publications involving 18,910 cases and 51,609 controls were included in this meta-analysis. Five MDM4 gene polymorphisms were evaluated: rs4245739, rs1563828, rs11801299, rs10900598, and rs1380576. Our analyses suggested that the rs4245739 polymorphism was significantly associated with overall cancer risk. Furthermore, stratification analyses of ethnicity indicated that rs4245739 decreased the risk of cancer among the Asian population, and stratification analyses of smoking status indicated that rs4245739 decreased the risk of cancer among nonsmokers. However, stratification analyses of cancer type and sex suggested that rs4245739 was not related to cancer risk. There were no associations of rs1563828, rs11801299, rs10900598, or rs1380576 with overall cancer risk. In conclusion, our analyses indicated that rs4245739 polymorphism in the MDM4 gene may play an important role in the etiology of cancer.

Association between endothelial nitric oxide synthase (ENOS) G894T polymorphism and high altitude (HA) adaptation: a meta-analysis.

OBJECTIVE: Highland natives adapt well to the hypoxic environment at high altitude (HA). Several genes have been reported to be linked to HA adaptation. Previous studies showed that the endothelial ni- tric oxide synthase (ENOS) G894T polymorphism contributed to the physiology and pathophysiology of hu- mans at HA by regulating the production of NO. In this meta-analysis, we evaluate the association between the ENOS G894T polymorphism and HA adaptation through analyzing the published data. METHODS: We searched all relevant literature about the ENOS G894T polymorphism and HA adaptation in PubMed, Med- line, and Embase before Step 2015. A random-effects model was applied (Revman 5.0), and study quality was assessed in duplicate. Six studies with 634 HA native cases and 621 low-altitude controls were included in this meta-analysis. RESULTS: From the results, we observed that the wild-type allele G was significantly overrepresented in the HA groups (OR = 1.85; 95% Cl, 1.47-2.33; P < 0.0001). In addition, the GG genotype was significantly associated with HA adaptation (OR = 1.99; 95% Cl, 1.54-2.57; P < 0.0001). CONCLUSION: Our results showed that in 894 G allele carriers, the GG genotype might be a beneficial factor for HA adaptation through enhancing the level of NO. However, more studies were needed to confirm our findings due to the limited sample size.

Over-starvation aggravates intestinal injury and promotes bacterial and endotoxin translocation under high-altitude hypoxic environment.

AIM: To study whether over-starvation aggravates intestinal mucosal injury and promotes bacterial and endotoxin translocation in a high-altitude hypoxic environment. METHODS: Sprague-Dawley rats were exposed to hypobaric hypoxia at a simulated altitude of 7000 m for 72 h. Lanthanum nitrate was used as a tracer to detect intestinal injury. Epithelial apoptosis was observed with terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Serum levels of diamino oxidase (DAO), malondialdehyde (MDA), glutamine (Gln), superoxide dismutase (SOD) and endotoxin were measured in intestinal mucosa. Bacterial translocation was detected in blood culture and intestinal homogenates. In addition, rats were given Gln intragastrically to observe its protective effect on intestinal injury. RESULTS: Apoptotic epithelial cells, exfoliated villi and inflammatory cells in intestine were increased with edema in the lamina propria accompanying effusion of red blood cells. Lanthanum particles were found in the intercellular space and intracellular compartment. Bacterial translocation to mesenteric lymph nodes (MLN) and spleen was evident. The serum endotoxin, DAO and MDA levels were significantly higher while the serum SOD, DAO and Gln levels were lower in intestine (P < 0.05). The bacterial translocation number was lower in the high altitude hypoxic group than in the high altitude starvation group (0.47 ± 0.83 vs 2.38 ± 1.45, P < 0.05). The bacterial translocation was found in each organ, especially in MLN and spleen but not in peripheral blood. The bacterial and endotoxin translocations were both markedly improved in rats after treatment with Gln. CONCLUSION: High-altitude hypoxia and starvation cause severe intestinal mucosal injury and increase bacterial and endotoxin translocation, which can be treated with Gln.

CoCl2-induced expression of p300 promotes neuronal-like PC12 cell damage.

Hypoxia inducible factor-1 (HIF-1) is an important transcription activator involved in cell responses to hypoxic stress. Previous studies demonstrated that HIF-1 exerts both pro- and anti-survival effects under hypoxia. The mechanisms underlying these contrary effects of HIF-1 remain unclear. Transcription co-activator p300 is necessary for HIF-1-induced transcriptional activation. Many factors inhibit HIF-1 activity by competitively binding to p300, which suggests that p300 is a key player in the modulation of HIF-1 function. To examine the alteration of p300 expression under hypoxia and its role in hypoxia-induced neuronal damage, neuronal-like PC12 cells were cultured with cobalt chloride (CoCl2), a hypoxia mimic reagent. The results showed that CoCl2 treatment-induced p300 expression along with an increase in cell damage. Furthermore, CoCl2-induced cell damage was attenuated by suppression of p300 expression with short hairpin RNA (shRNA). The data suggests that CoCl2-induced up-regulation of p300 expression promotes neuronal-like PC12 cell damage.