Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
Humans ; Acetylation ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Pyruvate Dehydrogenase Complex/genetics* ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Cell Line, Tumor ; Protein Processing, Post-Translational ; Histones/metabolism* ; Disease Progression

Objective To conduct a retrospective cohort study on the influencing factors of poor prognosis of young and middle-aged patients with pulmonary tuberculosis. Methods Selecting 426 young and middle-aged patients who were diagnosed with pulmonary tuberculosis in our hospital from January to December 2018 as the research subjects. Collecting the social demography information of all patients and the information of potential factors affecting the prognosis (allergy history, smoking history, drinking history, BMI level, disease information, treatment information, etc.) and discussing the factors affecting the prognosis of young and middle-aged pulmonary tuberculosis patients and their effects. Results The average age of 426 patients was (41.93±5.17) years old, the average BMI of them was (21.97±3.15) kg/m2, and an average course of disease of them was (2.76±0.99) years. There was no significant difference in the basic sexual information between men and women. In this study, a total of 128 patients with poor prognosis were retrospectively followed up, including 90 males and 38 females. The detection rate of males was significantly higher than that of females (χ²=16.976, P<0.05). The detection rate of poor prognosis was lower in patients with lower BMI levels (F=12.774, P<0.001) and longer disease course (F=3.704, P<0.001). In addition, the proportion of patients with poor prognosis who had a history of smoking (χ²=18.850, P<0.001) and had comorbidities was higher (χ²=38.924, P<0.001), and the proportion of patients with ≥ 3 lung field lesions (χ²=127.207, P<0.001) and those with pulmonary cavities (χ²=32.566, P<0.001) were also higher, with statistically significant differences compared to those with good prognosis. Among those with poor prognosis, the proportion of regular treatment was lower (χ²=16.715, P<0.001), and the proportion of adverse reactions was higher (χ²=17.315, P<0.001). At the same time, a total of 128 cases with poor prognosis were retrospectively followed up in this study, and the incidence of poor prognosis was higher in males than in females (χ²=16.976，P<0.05) . At the same time , research has shown that the detection rate of poor prognosis has a potential positive correlation with lower BMI, longer disease duration, smoking history, comorbidities, ≥ 3 lung field lesions, and the presence of pulmonary cavities, while there is a potential negative correlation with regular treatment, both P<0.05. In the study, univariate regression equations were used to discuss the impact of potential factors on adverse prognosis. It can be seen that male, emaciated body type, disease course ≥ 5 years, smoking history, number of lung field lesions ≥ 3, pulmonary cavities, and comorbidities are potential risk factors, with HR>1 and P<0.05; Regular treatment suggests a potential protective factor, with an HR of 0.341 and P<0.05. Multivariate regression analysis further suggests that male, emaciated body type, smoking history, pulmonary cavities, and comorbidities are potential risk factors, with HR>1 and P<0.05; Regular treatment still showed potential protective factors, with an HR of 0.408, P<0.05. Conclusion: Male, emaciated body type, disease course ≥ 5 years, smoking history, number of lung field lesions ≥ 3, presence of pulmonary cavities and comorbidities are potential risk factors, while regular treatment suggests potential protective factors. Conclusion More targeted disease control and management should be implemented for middle-aged and young patients with pulmonary tuberculosis based on the aforementioned influencing factors to improve their prognosis.

Objective:To identify early diagnostic biomarkers for preeclampsia by analyzing the placental and peripheral circulatory transcriptomic data of patients.Methods:Clinical information and microarray expression profiles of preeclampsia patients were sourced from high-throughput gene expression databases. Multi-omics approaches, including differential gene expression analysis, enrichment analysis, and weighted gene co-expression network analysis (WGCNA), were utilized to identify candidate diagnostic markers and explore potential mechanisms of preeclampsia. Subsequently, a combination of machine learning techniques, including random forest, support vector machine, and least absolute shrinkage and selection operator (LASSO), were employed for further screening of these candidates. Finally, the selected diagnostic markers were validated using a peripheral circulation dataset.Results:Differential gene expression analysis revealed 71 upregulated and 21 downregulated genes in preeclampsia. WGCNA linked the onset of preeclampsia with blue and teal modules. Enrichment analysis of candidate biomarkers suggested changes in cell cycle, cellular senescence, and immune-related pathways as primary drivers of preeclampsia. Further refinement through machine learning identified significant upregulation of COL17A1 and DIO2 genes in the peripheral blood of patients, demonstrating robust diagnostic potential. Conclusions:COL17A1 and DIO2 genes can be used as peripheral circulating diagnostic markers for the early diagnosis of eclampsia.

Objective:To investigate the effect and mechanism of glycine on rat cardiomyocytes pretreated with serum from burned rats (hereinafter referred to as burn serum).Methods:Experimental research methods were adopted. Thirty gender equally balanced Wistar rats aged 7 to 8 weeks were collected, 10 of which were used to prepare normal rat serum (hereinafter referred to as normal serum), and the other 20 were inflicted with full-thickness burn of 30% total body surface area to prepare burn serum. Primary cardiomyocytes were isolated and cultured from the apical tissue of 180 Wistar rats aged 1 to 3 days by either gender for follow-up experiments. Cells were divided into normal serum group and burn serum group treated with corresponding serum according to the random number table (the same grouping method below). Trypanosoma blue staining was performed at post treatment hour (PTH) 1, 3, 6, 9, and 12 to detect the cell survival rate. Cells were divided into burn serum alone group treated with burn serum for 6 h followed by routine culture of 30 min and 0.4 mmol/L glycine group, 0.8 mmol/L glycine group, 1.2 mmol/L glycine group, 1.6 mmol/L glycine group, and 2.0 mmol/L glycine group treated with burn serum for 6 h followed by culture of 30 min with corresponding final molarity of glycine, i.e., at post intervention hour (PIH) 6.5, the cell survival rate was detected as before. Cells were divided into normal serum group, burn serum alone group, 0.8 mmol/L glycine group, 1.2 mmol/L glycine group, and 1.6 mmol/L glycine group, with the same intervention of 6.5 h as before, respectively. The content of adenosine monophosphate (AMP) and adenosine triphosphate (ATP) was detected by high performance liquid chromatography, and the AMP/ATP ratio was calculated. The protein expressions of phosphorylated mammalian target of rapamycin complex 1 (p-mTORC1), phosphorylated p70 ribosomal protein S6 kinase (p-p70 S6K), phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4E-BP1), and phosphorylated AMP-activated protein kinase (p-AMPK) were detected by Western blotting. Cells were divided into normal serum group, burn serum alone group, 0.8 mmol/L glycine group intervened as before and 0.8 mmol/L glycine+25 ng/mL rapamycin group treated with burn serum followed by culture with two reagents. The expressions of heat shock protein 70 (HSP70), metallothionein (MT), and tubulin were detected by immunofluorescence method after 30 min of corresponding culture at PTH 1, 3, and 6, i.e., at PIH 1.5, 3.5, and 6.5, and the microtubule morphology was observed at PIH 6.5. The sample number at each time point was 10. Data were statistically analyzed with analysis of variance for factorial design, one-way analysis of variance, least significant difference (LSD)- t test, LSD test, and Bonferroni correction. Results:At PTH 1, 3, 6, 9, and 12, the cell survival rates in burn serum group were significantly lower than those in normal serum group (with t values of 4.96, 16.83, 35.51, 34.33, and 27.88, P<0.05). In burn serum group, the cell survival rate at PTH 3, 6, 9, or 12 was significantly lower than that at PTH 1 ( P<0.05), the cell survival rate at PTH 6, 9, or 12 was significantly lower than that at PTH 3 ( P<0.05), and the cell survival rate at PTH 6 was similar to that at PTH 9 ( P>0.05) but significantly higher than that at PTH 12 ( P<0.05). Treatment of 6 h was selected as the follow-up intervention time of burn serum. At PIH 6.5, compared with that in burn serum alone group, the cell survival rate in each glycine group was significantly increased ( P<0.05). The cell survival rate in 0.8 mmol/L glycine group was the highest, and 0.8, 1.2, and 1.6 mmol/L were selected as subsequent glycine intervention concentrations. At PIH 6.5, the AMP/ATP ratio of cells in burn serum alone group was significantly higher than that in normal serum group, 1.2 mmol/L glycine group, or 1.6 mmol/L glycine group ( P values all <0.05), and the AMP/ATP ratio of cells in 1.6 mmol/L glycine group was significantly lower than that in 0.8 mmol/L glycine group ( P<0.05). At PIH 6.5, the protein expressions of p-mTORC1, p-p70 S6K, and p-4E-BP1 of cells in normal serum group, burn serum alone group, 0.8 mmol/L glycine group, 1.2 mmol/L glycine group, and 1.6 mmol/L glycine group were 1.001±0.037, 0.368±0.020, 1.153±0.019, 1.128±0.062, 1.028±0.037, 0.96±0.07, 0.63±0.12, 1.17±0.13, 1.13±0.16, 1.11±0.11, and 0.98±0.06, 0.45±0.08, 1.13±0.05, 0.77±0.12, 0.51±0.13. Compared with those in burn serum alone group, the protein expressions of p-mTORC1, p-p70 S6K, and p-4E-BP1 of cells in normal serum group and each glycine group were significantly increased ( P<0.05), while the protein expressions of p-AMPK were significantly decreased ( P<0.05). Compared with those in 0.8 mmol/L glycine group, the protein expression of p-4E-BP1 of cells in 1.2 mmol/L glycine group and the protein expressions of p-mTORC1 and p-4E-BP1 of cells in 1.6 mmol/L glycine group were significantly decreased ( P<0.05). Compared with those in 1.2 mmol/L glycine group, the protein expressions of p-mTORC1 and p-4E-BP1 of cells in 1.6 mmol/L glycine group were significantly decreased ( P<0.05), while the protein expression of p-AMPK was significantly increased ( P<0.05). Compared with those in normal serum group, the expression of tubulin of cells in burn serum alone group was significantly decreased at PIH 1.5, 3.5, and 6.5 ( P<0.05), while the expression of HSP70 of cells at PIH 1.5 and 3.5 and the expression of MT at PIH 3.5 and 6.5 were significantly increased ( P<0.05). The expressions of HSP70 and MT of cells at PIH 1.5, 3.5, and 6.5 and the expression of tubulin at PIH 1.5 and 3.5 in burn serum alone group and 0.8 mmol/L glycine+25 ng/mL rapamycin group were significantly lower than those in 0.8 mmol/L glycine group ( P<0.05). At PIH 6.5, compared with that in normal serum group, the cell microtubule structure in burn serum alone group was disordered; the cell boundary in 0.8 mmol/L glycine group was clearer than that in burn serum alone group, and the microtubule structure arranged neatly near the nucleus. Compared with that in 0.8 mmol/L glycine group, 0.8 mmol/L glycine+25 ng/mL rapamycin group had unclear cell boundaries and disordered microtubule structure. Conclusions:Burn serum can cause cardiomyocytes damage in rats. Glycine can significantly up-regulate mammalian target of rapamycin/p70 ribosomal protein S6 kinase/eukaryotic translation initiation factor 4E-binding protein 1 signaling pathway through AMP-activated protein kinase, promote the synthesis of protective proteins HSP70, MT, and tubulin, stabilize the microtubule structure, and exert cardiomyocytes protection function.

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Objective To investigate the clinical value of bone metabolism biochemical marker N-MID,TP1NP and beta-CTx combined with whole body bone scintigraphy in early diagnosis of bone metastasis of tumor.Methods The concentration of the 3 markers were measured by the electrochemical luminescence analysis method in 30 cases of healthy control group and 210 cases of patients with malignant tumor,which were divided into non bone metastasis group(45 cases) and bone metastasis group(165 cases).The bone metastasis group were divided into 4 grades(0-grade Ⅲ) by Soloway classification according to whole body bone imaging.Results The levels of serum N-MID,TP1NP and beta-CTx in 165 malignant tumor patients with bone metastasis were significantly higher than in 45 malignant tumor patients with bone metastasis and in 30 healthy control group,the difference was statistically significant(P<0.05).With the increase of the number of metastatic lesions in the bone metastasis group,the serum levels of N-MID,TP1NP,and beta-CTx were increased gradually,and they were positively correlated with the progression of the disease.According to the analysis of ROC curve,the cut-off value,sensitivity and specificity in the diagnosis of tumor bone metastasis were 17.59 ng/mL,70.3％,88.9％ for serum N-MID,43.04 ng/mL,78.2％,95.6％ for TP1NP,and 0.48 ng/mL,73.9％,93.3％ for beta-CTx.Under the ROC curve(AUC) was 0.831 for serum N-MID,0.890 for TP1NP,and 0.869 for beta-CTx.The sensitivity and specificity of three bone metabolic markers in the diagnosis of bone metastasis of malignant tumor were significantly higher.Conclusion Bone metabolism biochemical markers:Serum N-MID,TP1NP and beta-CTx for diagnosis of bone metastasis of malignant tumor are sensitive,accurate and simple,which can significantly improve the efficiency of diagnosis of bone metastasis,and can be combined with whole-body bone scintigraphy in early diagnosis of bone metastasis with malignant tumor.

Objective To investigate the gender differences of coronary heart disease secondary prevention status in patients post percutaneous coronary intervention (PCI). Methods Patients diagnosed with coronary heart disease from 31 tertiary hospitals were enrolled for a baseline survey. Medical history and laboratory tests were taken. Analysis was done for outpatient or inpatient with the history of at least one PCI treatment. Status of smoking cessation, weight management, blood pressure < 140/90 mm Hg, low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL (2.6 mmol/L), and use of antiplatlet drugs, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) and statins were collected and compared. Results Women (n=1151) accounted for 25.4% of all PCI patients (n=4532). Proportion of female with history of smoking was signiifcantly lower than male, but the proportion of quitting was similar between female and male, 53%(n=98) vs. 53.7%(n=1344), P=0.849. The average body mass index, mean waist circumference and proportion of overweight were higher in man than women, P=0.000. However, the proportion of abdominal obesity in women is higher than men, 75.2%vs. 52.8%, P=0.000. More female were comorbid with hypertension, hyperlipidemia and diabetes than male and the differences were signiifcant, P=0.000. Control rate of blood pressure, LDL-C and fasting glucose were lower in women than in man, the differences were 66.2% vs 73.4% for blood pressure, 47.8%vs. 57.0%for LDL-C and 57.5%vs. 62.7%for fasting glucose, P=0.000. There was no signiifcant difference in medication usage between different genders. Conclusions In patients post pecutaneous coronary intervention, female patients had more risk factors than male while risk factor control rate was lower comparing with male. Medication usage for coronary heart disease secondary prevention was similar between different genders.

BACKGROUNDNeutrophil/lymphocyte ratio (NLR) has been proposed as a novel marker of systemic inflammation and oxidative stress. The objective of this study was to ascertain the relationship between levels of NLR and recurrence of lone atrial fibrillation (AF) after catheter ablation.

METHODSA total of 379 lone AF patients who underwent catheter ablation were enrolled in the study. The NLR before and after catheter ablation was determined. Cox regression analyses were used to estimate the relationship between NLR and the recurrence of lone AF.

RESULTSAfter a mean follow-up of (30.5 ± 5.3) months, 124 (32.7%) patients had AF recurrences. The patients who developed AF recurrence had a higher postablation NLR (post-NLR) than patients with no recurrence (5.74 ± 1.55 vs. 4.66 ± 1.27, P < 0.001). Multivariate Cox regression analysis revealed that post-NLR (hazard ratio (HR) 1.514, 95% confidence interval (CI) 1.364-1.680, P < 0.001), left atrium diameter (HR 1.035, 95% CI 1.001-1.071, P = 0.04) and body mass index (HR 1.028, 95% CI 1.002-1.054, P = 0.03) were independent predictors of AF recurrence. Using a cut-off level of 5.15, post-NLR predicted AF recurrence with a sensitivity of 73% and specificity of 67%.

CONCLUSIONSOur results indicate that an elevated post-NLR is associated with a high rate of lone AF recurrence. A simple measurement of NLR may help us to identify high-risk patients who need pharmacologic intervention to prevent recurrence.

Adult ; Atrial Fibrillation ; surgery ; Catheter Ablation ; Female ; Humans ; Lymphocytes ; immunology ; Male ; Middle Aged ; Neutrophils ; immunology ; Proportional Hazards Models

Objective To study the correlation between the cytochrome P450 3A5 gene polymorphism and essential hypertension (EH) in Chinese population .Methods The real-time PCR genotyping at CYP3A5*3(6986A>G) position was established using Taqman minor groove binding (MGB) probes .Total 170 EH patients and 193 matched controls of Chinese Han population were genotyped at CYP3A5*3(6986A>G) position using this method .Results The GG ,GA ,AA genotyped frequencies were 51 .2% , 42 .4% and 6 .5% for the EH patients and 39 .9% ,50 .8% and 9 .3% for the control group respectively .The risk of EH for person carrying GG genotype was 1 .579 fold of the persons carrying at least one A allele(95% CI:1 .041-2 .395) .Conclusion CYP3A5*3(6986A>G) polymorphism may be associated with EH in Chinese population .The risk of EH is decreased in the persons carrying allele A ,slightly lower levels of systolic blood pressure exists .

10.3969/j.issn.2095-4344.2013.26.013