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

Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.
Humans ; Tumor Microenvironment/immunology* ; Neoplasms/therapy* ; Lactic Acid/immunology* ; Mitochondria/metabolism* ; Animals ; Signal Transduction

Objective To investigate the expression and clinical significance of microRNA-93-5p (miR-93-5p) in patients with type 2 diabetes mellitus (T2DM) complicated with coronary heart disease (CHD). Methods A total of 60 patients with T2DM (T2DM group), 57 patients with T2DM complicated with CHD (T2DM with CHD group), and 60 healthy individuals (control group) were enrolled in this study from August 2019 to May 2021. The general information, serum miR-93-5p, and interleukin-6 (IL-6) levels were compared among the T2DM with CHD group, control group and T2DM group; the relationships of serum miR-93-5p and IL-6 levels with low-density lipoprotein cholesterol (LDL-C), fasting insulin (FINS), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), triglyceride (TG), glycated hemoglobin (HbA1c), and total cholesterol (TC) were analyzed in T2DM with CHD patients; the influencing factors of T2DM complicated with CHD were analyzed; the predictive value of serum miR-93-5p and IL-6 for T2DM complicated with CHD was evaluated. Results The levels of LDL-C, FINS, TG, FPG, TC, HbA1c, serum miR-93-5p, and IL-6 in the T2DM with CHD group and T2DM group were significantly higher than those in the control group, while the HDL-C level was significantly lower (P < 0.01); the levels of LDL-C, FINS, TG, FPG, TC, HbA1c, serum miR-93-5p, and IL-6 in the T2DM with CHD group were significantly higher than those in the T2DM group, while the HDL-C level was significantly lower (P < 0.01). The serum miR-93-5p and IL-6 levels in T2DM with CHD patients were positively correlated with LDL-C, FINS, HbA1c, TC and FPG (P < 0.01), and negatively correlated with HDL-C (P < 0.01); the expression level of miR-93-5p in serum was positively correlated with IL-6 (P < 0.05). LDL-C, FINS, FPG, HbA1c, TC, miR-93-5p, and IL-6 were the influencing factors of T2DM complicated with CHD (P < 0.05); the area under the curve (AUC) of serum miR-93-5p and IL-6 for predicting T2DM complicated with CHD was 0.888 and 0.898 respectively, with cut-off values of 2.59 and 77.98 ng/L respectively, sensitivity of 75.4% for both serum miR-93-5p and IL-6, and the specificity was 89.2% for miR-93-5p and 85.8% for IL-6; the AUC of the combined prediction of miR-93-5p and IL-6 for T2DM complicated with CHD was 0.939, with sensitivity and specificity of 91.2% and 83.3% respectively. Conclusion The serum miR-93-5p level is elevated in patients with T2DM complicated with CHD, and miR-93-5p together with IL-6 may participate in the process of T2DM complicated with CHD. The combined detection of IL-6 and miR-93-5p is expected to serve as an auxiliary method for prediction of T2DM complicated with CHD.

Objective:To investigate the application value of a multi-dimensional digital moni-toring platform for perioperative period in gastric cancer patients.Methods:The retrospective cohort study was conducted. The clinical data of 50 patients who underwent laparoscopic radical gastrec-tomy in The Affiliated Hospital of Nanjing University of Chinese Medicine from July 2022 to January 2024 were collected. There were 35 males and 15 females, aged (64±12)years. All patients followed the concept of enhanced recovery after surgery, and the multi-dimensional digital monitoring platform based on wearable monitoring equipment was used to implement perioperative management measures. Observation indicators: (1) results of heart rate variability (HRV) monitoring; (2) results of blood glucose and blood oxygen monitoring; (3) results of exercise and sleep monitoring; (4) results of body composition monitoring. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(IQR). Repeated measurement data were analyzed using the repeated ANOVA. Measurement data with skewed distri-bution were transformed to normal distribution by SPSS transformation function before testing. For comparison between pre- and postoperation, paired sample t test was used for measurement data with normal distribution, and nonparametric Wilcoxon signed rank sum test was used for measure-ment data with skewed distribution. Results:(1) Results of HRV monitoring. From preoperation to the third day after surgery, the standard deviation normal to normal heart beat of 50 patients was changed from(103±26)ms to(101±36)ms, the mean of the standard deviations of normal to normal heart beat calculated per 5 min segment was changed from (45±16)ms to(33±12)ms, the number of pairs of adjacent NN intervals differing by more than 50 ms in the entire recording was changed from 6.02%(4.96%) to 5.79%(4.20%), the low frequency power was changed from 376.78(468.96)ms 2 to 742.79(525.20)ms 2, the high frequency power was changed from 273.61(273.58)ms 2 to 397.48(164.87)ms 2, the ratio of low frequency power to high frequency power was changed from 1.6±0.5 to 1.6±0.6, showing significant differences in above indicators before and after operation ( F=34.43, 26.15, 24.58, 5.51, 6.11, 6.02, P<0.05). (2) Results of blood glucose and blood oxygen monitoring. From preoperation to the third day after surgery, the blood glucose of 50 patients was changed from 6.75(2.05)mmol/L to 6.90(2.63)mmol/L, showng a significant difference before and after operation ( F=45.84, P<0.05). The blood oxygen was changed from 97.00%(5.00%) to 97.50%(3.00%), showing no significant difference before and after operation ( F=2.25, P>0.05). (3) Results of exercise and sleep monitoring. From preoperation to the third day after surgery, the number of steps fo 50 pati-ents was changed from 3 043(1 224) to 1 473(767), sleep duration was changed from(8.2±1.1)hours to(7.3±0.8)hours, sleep score was changed from 80±10 to 78±5,showing significant differences in above indicators before and after operation ( F=716.46, 29.02, 47.32, P<0.05).(4) Results of body composition monitoring. The body weight of 50 patients was changed from (63±8)kg to(61±8)kg before and after operation, body fat rate was changed from 24%±8% to 22%±9%, muscle mass was changed from 43 (12)kg to 41(17)kg, body mass index was changed from (23.0±2.6)kg/m 2 to(22.1±2.5)kg/m 2, showing significant differences in above indicators before and after operation ( t=8.19, 3.00, Z=-2.78, t=7.34, P<0.05), while there was no significant difference in basal metabolic indicators from (1 390±134)kcal to (1 379±139)kcal before and after operation ( t=1.02, P>0.05). Conclusion:The multi-dimensional digital monitoring platform for preoperative period can accurately monitor the perioperative stress level and evaluate the postoperative recovery of gastric cancer patients, which can present the visual results.

Objective:To establish a method for simultaneous determination of 7 elemental impurities(V,Co,Ni,As,Cd,Hg Pb)in amlodipine besylate tablets based on inductively coupled plasma mass spectrometry(ICP-MS).Methods:After the samples were treated by microwave digestion,the solution was analyzed by ICP-MS.Ge,In,Bi were selected as the internal standards.The established method was validated.The contents of 7 elemental impurities in amlodipine besylate tablets from 54 enterprises were determined by this method.Results:The content of(V,Co,Ni,As,Cd,Hg,Pb had good linear relationship in the ranges of 1-100,1-100,1-100,1-100,1-100,0.5-4,1-100 ng·mL-1,respectively.The correlation coefficients(r)all above 0.999 4.The detec-tion limits and quantification limits were in the range of 0.000 4-0.018 4 ng·mL-1 and 0.001 4-0.061 2 ng·mL-1.The RSD of precision was less then 1.8％.The RSD of repeatability was less then 6.1％.The average re-coveries(n=9)were between 85.4％-106.5％,while their RSD was less then 4.7％.The content of 7 elemental impurities in 54 sample batches were in accordance with the limit value.Conclusion:The method is simple,rapid,accurate,reliable and highly sensitive,and can be used for the quality control of elemental impurities in amlodipine besylate tablets.

With the aging of the population, the number of patients with degenerative scoliosis continues to increase. Surgical treatment of degenerative scoliosis is challenging. Patients with degenerative scoliosis often present with multiple comorbidities, osteoporosis, and sarcopenia. Traditional open surgeries are associated with high risks and multiple complications, whereas minimally invasive surgeries have increasingly gained acceptance among patients and physicians. Lateral Lumbar Interbody Fusion (LLIF) offers advantages such as minimal trauma, less blood loss, rapid postoperative recovery, reduced risk of neural complications, and larger interbody cages with more grafting capacity. Mini-open lateral-anterior lumbar interbody fusion is a new standardized LLIF technique with smaller incisions, which does not require splitting the psoas muscle, thereby reducing the risk of muscle and nerve injuries, and involves vertical implantation of the fusion device. Posterior instrumentation via the Wiltse approach is characterized by shorter operational times, minimal radiation exposure, reduced muscular damage, increased graft fusion capabilities, and the ability to perform de-rotation maneuvers. Therefore, the Wiltse approach is particularly suitable for patients with degenerative scoliosis. Staged surgery significantly reduces the duration of each surgery and anesthesia, lowering surgical risks and enhancing postoperative recovery. Staged mini-open lateral-anterior lumbar interbody fusion and posterior instrumentation via the Wiltse approach maximizes the reduction of surgical trauma, significantly decreases surgical complications, and offers marked clinical outcomes, providing an alternative minimally invasive treatment for degenerative scoliosis.

Objective To investigate the effect of MALAT1 expressions on cell proliferation and apoptosis in astrocytes by regulating mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK1,2)pathway.Methods The MALAT1 gene was knocked down and over-expressed in C8-D1A cells by lentiviral and plasmid vectors,respectively.The expressions of MALAT1,cell proliferation-related markers(Ki67,MCM2,PCNA)and apoptosis-related proteins(Caspase-3,Bax,Bcl-2)were detected by quantitative real-time polymerase chain reaction(qPCR).CCK-8 assay and flow cytometry were used for cell proliferation and apoptosis in C8-D1A cells.Immunofluorescence was adopted to detect the protein expressions of Caspase-3 and Ki67.Western blotting was used to detect the protein expressions of Caspase-3,Bax,Bcl-2,ERK1/2,p-ERK1/2,p38MAPK and p-p38MAPK.Results Compared with the control group,over-expressed MALAT1 inhibited cell proliferation and induced cell apoptosis in C8-D1A cells while the knockdown of MALAT1 significantly enhanced cell proliferation and anti-apoptotic ability in C8-D1A cells.The proportion of C8-D1A cells in G0/G1-phase and G2/M-phase was higher than in the control group as evidenced by flow cytometry,but was lower in S-phase.Meanwhile,data showed that Caspase-3 was increased while p-ERK1/2 was decreased in terms of protein levels.The mRNA expressions of Ki67 and PCNA were decreased.After knockdown of MALAT1,the proportion of C8-D1A cells in S-phase was higher,but was lower in G2/M-phase.The protein expressions of Caspase-3 and Bax decreased while those of p-ERK1/2 and p-p38MAPK increased.The mRNA expressions of Ki67,MCM2 and PCNA were increased.The differences were all statistically significant(P＜0.05).Conclusion MALAT1 promotes astrocyte apoptosis and inhibits proliferation by regulating the MAPK/ERK1,2 signaling pathway.

Objective:To explore the role of metagenomic next-generation sequencing (mNGS) in the diagnosis of pathogens in primary infectious diseases of the spine (IDS) and to reveal its pathogen spectrum.Methods:This is a retrospective multi-center case series study. Clinical data of 380 patients with primary IDS who were treated at four medical centers in China from December 2019 to April 2024 were retrospectively analyzed. Among them, 82 cases were from the Department of Spine Surgery at the Affiliated Hospital of Qingdao University, 129 cases were from the Orthopedics Section Ⅱ (Bone Infection), Public Health Clinical Center Affiliated to Shandong University, 112 cases were from the Department of Spine Surgery, Fuzhou Second General Hospital, and 57 cases were from the Department of Orthopedic Surgery, Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. There were 238 males and 242 females, with an age of (61.4±13.1) years (range: 10 to 91 years). Specimens from the site of spinal infection were obtained for pathogen culture, pathological examination, and mNGS detection preoperatively or intraoperatively in all patients. The number, types, and positive rates of pathogens detected by the two methods were analyzed and compared using the Chi-square test.Results:Among the 380 patients, 320 had confirmed pathogenic bacteria, with the highest proportion being pyogenic bacterial infections, accounting for 76.9% (246/320). The most common pathogen was Staphylococcus aureus, accounting for 22.8% (73/320). Brucella accounted for 13.8% (44/320); Mycobacterium tuberculosis accounted for 6.3% (20/320). Fungal infections accounted for 3.4% (11/320), mainly Aspergillus and Candida. In addition, Mycoplasma was detected in 3 cases (0.9%) and Benacox body in 4 cases (1.2%). The pathogen spectrum constructed by mNGS covered 46 types of pathogens, higher than the 22 types detected by traditional methods. The positive rate of mNGS was 80.8% (308/381), significantly higher than the 27.9% (106/381) of traditional methods ( χ2=182.53, P<0.01). Conclusions:mNGS improves the positive rate of pathogen diagnosis in IDS, detecting a broader spectrum of pathogens, and serves as a valuable complement to traditional diagnostic methods. Combining both methods in the diagnosis of IDS can maximize detection rates, providing robust evidence for precise anti-infective treatment.

Doxorubicin(DOX)is a commonly administered chemotherapy drug for treating hematological malignancies and solid tumors;however,its clinical application is limited by significant cardiotoxicity.Cynaroside(Cyn)is a flavonoid glycoside distributed in honeysuckle,with confirmed potential biological functions in regulating inflammation,pyroptosis,and oxidative stress.Herein,the effects of Cyn were evaluated in a DOX-induced cardiotoxicity(DIC)mouse model,which was established by intraperitoneal injections of DOX(5 mg/kg)once a week for three weeks.The mice in the treatment group received dexrazoxane,MCC950,and Cyn every two days.Blood biochemistry,histopathology,immunohistochemistry,reverse transcription-quantitative polymerase chain reaction(RT-qPCR),and western blotting were conducted to investigate the cardioprotective effects and potential mechanisms of Cyn treatment.The results demonstrated the significant benefits of Cyn treatment in mitigating DIC;it could effectively alleviate oxidative stress to a certain extent,maintain the equilibrium of cell apoptosis,and enhance the cardiac function of mice.These effects were realized via regulating the transcription levels of pyroptosis-related genes,such as nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),caspase-1,and gasdermin D(GSDMD).Mechanistically,for DOX-induced myocardial injury,Cyn could significantly modulate the expression of pivotal genes,including adenosine monophosphate-activated protein kinase(AMPK),peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α),sirtuin 3(SIRT3),and nuclear factor erythroid 2-related factor 2(Nrf2).We attribute it to the mediation of AMPK/SIRT3/Nrf2 pathway,which plays a central role in preventing DOX-induced cardiomyocyte injury.In conclusion,the present study confirms the therapeutic potential of Cyn in DIC by regulating the AMPK/SIRT3/Nrf2 pathway.

Objective To investigate the serum levels of microRNA-146a(miR-146a)and soluble pro-grammed death ligand 2(sPD-L2)in children with Mycoplasma pneumoniae pneumonia(MPP)and to ana-lyze their relationship with disease severity and their predictive value for prognosis.Methods A total of 89 MPP patients diagnosed and treated in Linfen People's Hospital from February 2019 to June 2021 were includ-ed,and they were divided into severe group(50 cases)and mild group(39 cases)based on disease severity.Based on the prognosis of MMP patients,they were categorized into good prognosis group(70 cases)and poor prognosis group(19 cases).Moreover,50 healthy children who underwent physical examination at the same time were setected as the control group.Real-time fluorescence quantitative PCR was performed to assess the serum miR-146a levels in each group,while serum sPD-L2 levels were measured using the enzyme-linked im-munosorbent assay.Pearson correlation analysis was conducted to evaluate the relationship between serum miR-146a and sPD-L2 levels in children with MPP.Logistic regression analysis was performed to identify fac-tors influencing poor prognosis in children with MPP.The predictive efficacy of serum miR-146a and sPD-L2 for predicting the poor prognosis in children with MPP was assessed by receiver operating characteristic curve.Results The serum miR-146a levels decreased sequentially from the control group to the mild group and the severe group(P<0.05),while the sPD-L2 levels increased sequentially(P<0.05).Serum miR-146a was negatively correlated with sPD-L2 levels in children with MPP(r=-0.735,P<0.001).Duration of fe-ver,proportion of pleural effusion,C-reactive protein(CRP)levels,proportion of severe MPP patients and ser-um sPD-L2 levels in the poor prognosis group were higher than those in the good prognosis group,while ser-um miR-146a level was lower than that in the good prognosis group(P<0.05).Severe MMP and serum sPD-L2 were identified as independent risk factors for poor prognosis in children with MPP(P<0.05),whereas miR-146a was found to be a protective factor(P<0.05).The area under the curve of the combination of ser-um miR-146a and sPD-L2 levels in predicting the poor prognosis in children with MPP was 0.915(95%CI:0.861-0.949),which was higher than 0.844 of miR-146a(95%CI:0.801-0.886)and 0.859 of sPD-L2(95%CI:0.814-0.897)alone(Z=4.780,4.023,P<0.05).Conclusion In children with MPP,serum miR-146a level decreases,while sPD-L2 level increases,and the two are associated with the disease severity of MPP.The combination of these two demonstrates high predictive value for the poor prognosis in MPP.