Objective To investigate the correlation between the level of N-terminal pro-Brain natriuretic peptide(NT-proBNP)and cardiorespiratory fitness following acute exposure to high altitude.Methods Forty-six subjects were recruited from the Second Affiliated Hospital of Army Medical University in June 2022,including 19 males and 27 females.After completing cardiopulmonary exercise test(CPET),serological detection of myocardial cell-related markers,and multiple metabolites at a plain altitude(300 meters above sea level),all subjects flew to a high-altitude location(3900 meters above sea level).Biomarker testing and CPET were repeated on the second and third days after arrival at high altitude.Changes in serum biomarker and key CPET indicators before and after rapid ascent to high altitude were compared,and the correlation between serum levels of various myocardial cell-related markers and metabolites and high altitude cardiorespiratory fitness was analyzed.Results Compared with the plain altitude,there was a significant decrease in maximal oxygen uptake after rapid ascent to high altitude[(25.41±6.20)ml/(kg.min)vs.(30.17±5.01)ml/(kg.min),P<0.001].Serum levels of NT-proBNP,Epinephrine(E),plasma renin activity(PRA),angiotensin Ⅱ(Ang Ⅱ),angiotensin-converting enzyme 2(ACE2)and leptin(LEP)significantly increased,with all differences being statistically significant(P<0.05)after acute high altitude exposure.In contrast,no statistically significant differences were observed for creatine kinase MB(CK-MB),cardiac troponin I(cTnI),myoglobin(Myo)and norepinephrine(NE)(P>0.05).Correlation analysis showed a significant negative correlation between NT-proBNP at plain altitude(r=-0.768,P<0.001)and at high altitude(r=-0.791,P<0.001)with maximal oxygen uptake at high altitude.Multivariate linear regression analysis indicated that maximal oxygen uptake at plain altitude(t=2.069,P=0.045),NT-proBNP at plain altitude(t=-2.436,P=0.020)and at high altitude(t=-3.578,P=0.001)were independent influencing factors of cardiorespiratory fitness at high altitude.Conclusion Cardiorespiratory fitness significantly decreases after rapid ascent to high altitude,and the baseline NT-proBNP level at plain altitude is closely related to cardiorespiratory fitness at high altitude,making it a potential predictor indicator for high altitude cardiorespiratory fitness.

A small proportion of mononuclear diploid cardiomyocytes (MNDCMs), with regeneration potential, could persist in adult mammalian heart. However, the heterogeneity of MNDCMs and changes during development remains to be illuminated. To this end, 12 645 cardiac cells were generated from embryonic day 17.5 and postnatal days 2 and 8 mice by single-cell RNA sequencing. Three cardiac developmental paths were identified: two switching to cardiomyocytes (CM) maturation with close CM-fibroblast (FB) communications and one maintaining MNDCM status with least CM-FB communications. Proliferative MNDCMs having interactions with macrophages and non-proliferative MNDCMs (non-pMNDCMs) with minimal cell-cell communications were identified in the third path. The non-pMNDCMs possessed distinct properties: the lowest mitochondrial metabolisms, the highest glycolysis, and high expression of Myl4 and Tnni1. Single-nucleus RNA sequencing and immunohistochemical staining further proved that the Myl4⁺Tnni1⁺ MNDCMs persisted in embryonic and adult hearts. These MNDCMs were mapped to the heart by integrating the spatial and single-cell transcriptomic data. In conclusion, a novel non-pMNDCM subpopulation with minimal cell-cell communications was unveiled, highlighting the importance of microenvironment contribution to CM fate during maturation. These findings could improve the understanding of MNDCM heterogeneity and cardiac development, thus providing new clues for approaches to effective cardiac regeneration.
Animals ; Mice ; Diploidy ; Heart ; Myocytes, Cardiac/metabolism* ; Cell Communication ; Gene Expression Profiling ; Mitochondria ; Regeneration ; Mammals/genetics*

OBJECTIVE: To evaluate the implications of the prognostic nutrition index (PNI) in non-metastatic renal cell carcinoma (RCC) patients treated with surgery and to compare it with other hematological biomarkers, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune inflammation index (SII). METHODS: A cohort of 328 non-metastatic RCC patients who received surgical treatment between 2010 and 2012 at Peking University First Hospital was analyzed retrospectively. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values of the hematological biomarkers. The Youden index was maximum for PNI was value of 47.3. So we divided the patients into two groups (PNI≤ 47. 3 and >47. 3) for further analysis. Categorical variables [age, gender, body mass index (BMI), surgery type, histological subtype, necrosis, pathological T stage and tumor grade] were compared using the Chi-square test and Student' s t test. The association of the biomarkers with overall survival (OS) and disease-free survival (DFS) was analyzed using Kaplan-Meier methods with log-rank test, followed by multivariate Cox proportional hazards model. RESULTS: According to the maximum Youden index of ROC curve, the best cut-off value of PNI is 47. 3. Low level of PNI was significantly associated with older age, lower BMI and higher tumor pathological T stage (P < 0.05). Kaplan-Meier univariate analysis showed that lower PNI was significantly correlated with poor OS and DFS (P < 0.05). In addition, older age, lower BMI, tumor necrosis, higher tumor pathological T stage and Fuhrman grade were significantly correlated with poor OS (P < 0.05). Cox multivariate analysis showed that among the four hematological indexes, only PNI was an independent factor significantly associated with OS, whether as a continuous variable (HR=0.9, 95%CI=0.828-0.978, P=0.013) or a classified variable (HR=2.397, 95%CI=1.061-5.418, P=0.036). CONCLUSION Low PNI was a significant predictor for advanced pathological T stage, decreased OS, or DFS in non-metastatic RCC patients treated with surgery. In addition, PNI was superior to the other hematological biomar-kers as a useful tool for predicting prognosis of RCC in our study. It should be externally validated in future research before the PNI can be used widely as a predictor of RCC patients undergoing nephrectomy.
Humans ; Prognosis ; Nutrition Assessment ; Carcinoma, Renal Cell/surgery* ; Retrospective Studies ; Biomarkers ; Kidney Neoplasms/pathology*

OBJECTIVE: The study explores the effects of electroacupuncture (EA) at the governing vessel (GV) on proteomic changes in the hippocampus of rats with cognitive impairment. METHODS: Healthy male rats were randomly divided into 3 groups: sham, model and EA. Cognitive impairment was induced by left middle cerebral artery occlusion in the model and EA groups. Rats in the EA group were treated with EA at Shenting (GV24) and Baihui (GV20) for 7 d. Neurological deficit was scored using the Longa scale, the learning and memory ability was detected using the Morris water maze (MWM) test, and the proteomic profiling in the hippocampus was analyzed using protein-labeling technology based on the isobaric tag for relative and absolute quantitation (iTRAQ). The Western blot (WB) analysis was used to detect the proteins and validate the results of iTRAQ. RESULTS: Compared with the model group, the neurological deficit score was significantly reduced, and the escape latency in the MWM test was significantly shortened, while the number of platform crossings increased in the EA group. A total of 2872 proteins were identified by iTRAQ. Differentially expressed proteins (DEPs) were identified between different groups: 92 proteins were upregulated and 103 were downregulated in the model group compared with the sham group, while 142 proteins were upregulated and 126 were downregulated in the EA group compared with the model group. Most of the DEPs were involved in oxidative phosphorylation, glycolipid metabolism and synaptic transmission. Furthermore, we also verified 4 DEPs using WB technology. Although the WB results were not exactly the same as the iTRAQ results, the expression trends of the DEPs were consistent. The upregulation of heat-shock protein β1 (Hspb1) was the highest in the EA group compared to the model group. CONCLUSION EA can effect proteomic changes in the hippocampus of rats with cognitive impairment. Hspb1 may be involved in the molecular mechanism by which acupuncture improves cognitive impairment.
Rats ; Male ; Animals ; Rats, Sprague-Dawley ; Electroacupuncture ; Proteomics ; Cognitive Dysfunction/therapy* ; Hippocampus

Background: Recent studies showed that the clinical outcome of moderately severe acute pancreatitis (MSAP) are different among different subgroups. Aims: To further subdivide MSAP, and explore the heterogeneity of MSAP subgroups. Methods: A retrospective analysis was performed on patients with acute pancreatitis (AP) from January 2016 to December 2020 at Northern Jiangsu People’s Hospital, including 538 patients with mild acute pancreatitis (MAP) and 461 patients with MSAP. MSAP patients were divided into four groups according to local complication and transient organ failure (TOF), including single acute peripancreatic fluid collection (APFC) without TOF group (group A), multiple APFC without TOF group (group B), other local complication without TOF group (group C) and TOF group (group D). The baseline data and the severity of AP among the four subgroups were compared. Meanwhile, the severity of disease between group A and MAP patients was also compared. Logistic regression analysis was used to evaluate the risk factors of MSAP. Results: Patients in group D were older than those in group A (P<0.05). There were statistically significant differences in different scoring systems among the four subgroups (P<0.05). The proportions of APACHE Ⅱ≥8, Glasgow≥3 and BISAP≥3 in group D were significantly higher than those in the other three groups (P<0.05). There were significant differences in levels of Ca

Mutations of the X-linked methyl-CpG-binding protein 2 (MECP2) gene in humans are responsible for most cases of Rett syndrome (RTT), an X-linked progressive neurological disorder. While genome-wide screens in clinical trials have revealed several putative RTT-associated mutations in MECP2, their causal relevance regarding the functional regulation of MeCP2 at the etiologic sites at the protein level requires more evidence. In this study, we demonstrated that MeCP2 was dynamically modified by O-linked-β-N-acetylglucosamine (O-GlcNAc) at threonine 203 (T203), an etiologic site in RTT patients. Disruption of the O-GlcNAcylation of MeCP2 specifically at T203 impaired dendrite development and spine maturation in cultured hippocampal neurons, and disrupted neuronal migration, dendritic spine morphogenesis, and caused dysfunction of synaptic transmission in the developing and juvenile mouse cerebral cortex. Mechanistically, genetic disruption of O-GlcNAcylation at T203 on MeCP2 decreased the neuronal activity-induced induction of Bdnf transcription. Our study highlights the critical role of MeCP2 T203 O-GlcNAcylation in neural development and synaptic transmission potentially via brain-derived neurotrophic factor.
Animals ; Humans ; Methyl-CpG-Binding Protein 2/metabolism* ; Mice ; Neurodevelopmental Disorders/genetics* ; Rett Syndrome/genetics* ; Synaptic Transmission ; Threonine

Objective To determine the purine adenylate [adenosine triphosphate （ATP）, adenosine diphosphate （ADP）, adenosine monophosphate （AMP）] content in the muscles of both hind limbs of rats at different postmortem interval （PMI）, calculate the changes in the total adenine nucleotide （TAN） content and the adenylic-acid energy charge （AEC）, and explore their relationship with PMI. Methods Healthy rats were sacrificed by cervical dislocation and kept at 20 ℃. The muscles of their hind limbs were extracted at 0, 24, 48, 72, 96, 120, 144, and 168 h after death. Reversed-phase high performance liquid chromatography was used to determine the content of purine adenylates, the TAN and AEC of the muscles of the both hind limbs were calculated, and the related regression equations of their relationship with PMI were established. Results Within 168 h of death of rats, the trend of ATP change was different from ADP, and the content of AMP continuously increased. The TAN value gradually increased with the extension of PMI, and the AEC showed a downward trend within 168 h after death. Among them, the patterns of AEC changes with PMI were obvious, the correlation coefficient was high （ R²=0.903）, and the curve fitting relationship was good; the fitting relationship between ATP, ADP, AMP, TAN and PMI was poor （ R²=0.198-0.754）. Conclusion The postmortem change patterns of AEC provide new research ideas for PMI estimation in the forensic field.
Adenine Nucleotides ; Adenosine Monophosphate ; Animals ; Forensic Pathology ; Muscles ; Rats ; Rats, Sprague-Dawley ; Time Factors

OBJECTIVE: To explore the effect of regulating A20 expression on NF-κB and biological characteristics of Jurkat cells with glucocorticoid (GC) resistance. METHODS: CCRF CEM and Jurkat cells were treated with dexamethasone (DEX) at concentrations of 100、10、1、0.1、0.01 and 0.001 μmol/L, and cultured for 24、48 and 72 h. The proliferation inhibition rate of Jurkat cell was detected by CCK-8. A20 plasmid was constructed, A20-siRNA was designed and synthesized, and transfected into Jurkat cells by liposome. CCK-8 was used to detect the proliferation rates of Jurkat cells in different concentrations of DEX group, DEX combined with A20 plasmid group and A20-siRNA group. The mRNA expression level of NF-κB was detected by RT-qPCR, the protein expression level of NF-κB was detected by Western blot, and the apoptosis of Jurkat cells was examined by flow cytometry. RESULTS: The inhibitory effects of DEX at different concentrations on the growth of CCRF CEM cells were time-dependent (r=0.984, P＜0.05) and concentration-dependent (r=0.966, P＜0.05). At the point of 24 hour, the IC approached 1 μmol/L in CCRF CEM cells. Great large differences began to appear between 1 and 10 μmol/L, the proliferation rate of Jurkat cells treated with 1 μmol/L DEX did not show a significant change. Therefore, 1 μmol/L was selected as control group. The cell proliferation rate of A20 plasmid transfection combined with different concentrations of DEX group was lower than that of DEX group and A20-siRNA combined with DEX group. After transfection of A20 plasmid, the expression level of NF-κB was significantly lower than that of control group (P＜0.05), and the apoptotic rate was significantly higher than that of control group (P＜0.05). After transfection of Jurkat cells with A20-siRNA, the expression level of NF-κB was significantly higher than that of control group (P＜0.05). The apoptotic rate of cells in A20-siRNA group was not significantly changed (P＞0.05). CONCLUSION Jurkat cells are resistant to DEX. A20 overexpression combined with DEX can increase sensitivity of Jurkat cells with GC resistance and decrease the proliferation rate of Jurkat cells, down-regulate the expression level of NF-κB and promote the apoptosis of Jurkat cells.
Apoptosis ; Cell Proliferation ; Humans ; Jurkat Cells ; NF-kappa B ; RNA, Small Interfering ; Transfection ; Tumor Necrosis Factor alpha-Induced Protein 3

OBJECTIVE: To investigate the relation of blood arsenic concentration (BAC) with clinical effect and safety of arsenic-containing Qinghuang Powder (, QHP) in patients with myelodysplastic syndrome (MDS). METHODS: Totally 163 patients with MDS were orally treated with QHP for 2 courses of treatment, 3 months as 1 course. The BACs of patients were detected by atomic fluorescence spectrophotometry at 1, 3, and 6 months during the treatment, and the effective rate, hematological improvement and safety in patients after treatment with QHP were analyzed. RESULTS: After 2 courses of treatment, the total effective rate was 89.6% (146/163), with 31.3% (51/163) of hematological improvement and 58.3% (95/163) of stable disease. The hemoglobin increased from 73.48 ± 19.30 g/L to 80.39 ± 26.56 g/L (P<0.05), the absolute neutrophil count increased from 0.81 ± 0.48 × 10/L to 1.08 ± 0.62 × 10/L (P<0.05), and no significant changes were observed in platelet counts (P>0.05). Among 46 patients previously depended on blood transfusion, 28.3% (13/46) completely got rid of blood transfusion and 21.7% (10/46) reduced the volume of blood transfusion by more than 50% after treatment. The BACs were significantly increased in patients treated for 1 month with 32.17 ± 18.04 μ g/L (P<0.05), 3 months with 33.56 ± 15.28 μ g/L (P<0.05), and 6 months with 36.78 ± 11.92 μ g/L (P<0.05), respectively, as compared with those before treatment (4.08 ± 2.11 μ g/L). There were no significant differences of BACs among the patients treated for 1, 3 and 6 months (P>0.05). The adverse reactions of digestive tract during the treatment were mild abdominal pain and diarrhea in 14 cases (8.6%), and no patients discontinued the treatment. The BACs of patients with gastrointestinal adverse reactions were significantly lower than those without gastrointestinal adverse reactions (22.39 ± 10.38 vs. 37.89 ± 11.84, μ g/L, P<0.05). The BACs of patients with clinical effect were significantly higher than those failed to treatment (40.41 ± 11.69 vs. 23.84 ± 12.03, μ g/L, P<0.05). CONCLUSION QHP was effective and safe in the treatment of patients with MDS and the effect was associated with BACs of patients.