Background/Aims: Acetyl coenzyme A (acetyl-CoA) is one of the most essential metabolites in cell metabolism but its function and concentration in hepatocellular carcinoma (HCC) remain elusive and controversial. Methods: A comprehensive analysis of acetyl-CoA levels and acetyl-CoA synthetase 2 (ACSS2) expression across a range of samples, including patient specimens from both hepatitis B virus (HBV) positive and HBV negative HCC individuals, HBV-transgenic mouse HCC models, and multiple cell lines. Furthermore, to evaluate the functional significance of ACSS2 in HBV-related HCC, we implemented both genetic and pharmacological inhibition strategies targeting ACSS2. Molecular mechanism and mitophagy assessment were revealed by cleavage under target and tagmentation sequencing, RNA sequencing, bioinformatic analyses, transmission electron microscopy and JC-1 staining. Results: Our study revealed a distinct metabolic signature of HBV-related HCC, marked by elevated acetyl-CoA, which was driven by ACSS2. ACSS2 was upregulated by the carbohydrate response element-binding protein in HBV-related HCC. Furthermore, ACSS2 improved tumor cell proliferation, an effect that was dependent on its enzymatic activity. Mechanistically, ACSS2-induced acetyl-CoA accumulation activated voltage-dependent anion channels 1 transcription through increased H3K27ac occupancy, which subsequently promoted mitophagy and HBV-related HCC tumorigenesis. Notably, targeting ACSS2 by depletion or inhibition with a catalytic inhibitor significantly suppressed tumor growth. Conclusions These findings not only illustrate the interplay between metabolic reprogramming, epigenetic modification, and tumorigenesis in the context of HBV infection, but also highlight ACSS2 as a novel metabolic vulnerability in HBV-related HCC. Therefore, targeting ACSS2 could be a novel strategy against HBV-related HCC.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

OBJECTIVE: Pneumoconiosis, a lung disease caused by irreversible fibrosis, represents a significant public health burden. This study investigates the causal relationships between gut microbiota, gene methylation, gene expression, protein levels, and pneumoconiosis using a multi-omics approach and Mendelian randomization (MR). METHODS: We analyzed gut microbiota data from MiBioGen and Esteban et al. to assess their potential causal effects on pneumoconiosis subtypes (asbestosis, silicosis, and inorganic pneumoconiosis) using conventional and summary-data-based MR (SMR). Gene methylation and expression data from Genotype-Tissue Expression and eQTLGen, along with protein level data from deCODE and UK Biobank Pharma Proteomics Project, were examined in relation to pneumoconiosis data from FinnGen. To validate our findings, we assessed self-measured gut flora from a pneumoconiosis cohort and performed fine mapping, drug prediction, molecular docking, and Phenome-Wide Association Studies to explore relevant phenotypes of key genes. RESULTS: Three core gut microorganisms were identified: Romboutsia ( OR = 0.249) as a protective factor against silicosis, Pasteurellaceae ( OR = 3.207) and Haemophilus parainfluenzae ( OR = 2.343) as risk factors for inorganic pneumoconiosis. Additionally, mapping and quantitative trait loci analyses revealed that the genes VIM, STX8, and MIF were significantly associated with pneumoconiosis risk. CONCLUSIONS This multi-omics study highlights the associations between gut microbiota and key genes ( VIM, STX8, MIF) with pneumoconiosis, offering insights into potential therapeutic targets and personalized treatment strategies.
Humans ; Male ; East Asian People/genetics* ; Europe ; Gastrointestinal Microbiome ; Lung ; Macrophage Migration-Inhibitory Factors/metabolism* ; Mendelian Randomization Analysis ; Multiomics ; Pneumoconiosis/microbiology* ; Intramolecular Oxidoreductases

BACKGROUND: Medical informatics accumulated vast amounts of data for clinical diagnosis and treatment. However, limited access to follow-up data and the difficulty in integrating data across diverse platforms continue to pose significant barriers to clinical research progress. In response, our research team has embarked on the development of a specialized clinical research database for cardiology, thereby establishing a comprehensive digital platform that facilitates both clinical decision-making and research endeavors. METHODS: The database incorporated actual clinical data from patients who received treatment at the Cardiovascular Medicine Department of Chinese PLA General Hospital from 2012 to 2021. It included comprehensive data on patients' basic information, medical history, non-invasive imaging studies, laboratory test results, as well as peri-procedural information related to interventional surgeries, extracted from the Hospital Information System. Additionally, an innovative artificial intelligence (AI)-powered interactive follow-up system had been developed, ensuring that nearly all myocardial infarction patients received at least one post-discharge follow-up, thereby achieving comprehensive data management throughout the entire care continuum for high-risk patients. RESULTS: This database integrates extensive cross-sectional and longitudinal patient data, with a focus on higher-risk acute coronary syndrome patients. It achieves the integration of structured and unstructured clinical data, while innovatively incorporating AI and automatic speech recognition technologies to enhance data integration and workflow efficiency. It creates a comprehensive patient view, thereby improving diagnostic and follow-up quality, and provides high-quality data to support clinical research. Despite limitations in unstructured data standardization and biological sample integrity, the database's development is accompanied by ongoing optimization efforts. CONCLUSION The cardiovascular specialty clinical database is a comprehensive digital archive integrating clinical treatment and research, which facilitates the digital and intelligent transformation of clinical diagnosis and treatment processes. It supports clinical decision-making and offers data support and potential research directions for the specialized management of cardiovascular diseases.

Objective To investigate the regulatory effect and possible mechanism of lactic acid on the fibrotic phenotype of cardiac fibroblasts.Methods Mouse cardiac fibroblasts(mCFs)were divided into control group(conventional culture),experimental-L group(4 mmol·L-1 L-lactic acid),experimental-M group(8 mmol·L-1 L-lactic acid),experimental-H group(12 mmol·L-1 L-lactic acid),transforming growth factor-β1(TGF-β1)group(10 ng·mL-1 TGF-β1),combined group(10 ng·mL-1 TGF-β1+12 mmol·L-1 L-lactic acid)and monocarboxylate transporter inhibitor(CHC)group(3 mmol·L-1 CHC).Western blot was used to detect the expression of fibrosis-related proteins and pan-lactate modification(Pan Kla)and H3 histone K18 lactate modification;cell scratch assay was used to detect cell migration ability.Results The cell migration rates of the control group,TGF-β1 group,experimental-H group and combined group were(40.56±0.03)％,(61.61±0.04)％,(26.59±0.05)％and(38.33±0.06)％,respectively.Compared with the control group,TGF-β1 group and experimental-H group,TGF-β1 group and combined group,the differences were statistically significant(all P＜0.01).The relative expression levels of collagen type Ⅰ alpha 1(COL1A1)protein in the control group,TGF-β1 group,experimental-H group and TGF-β1+experimental-H group were 0.76±0.09,1.10±0.07,0.40±0.04 and 0.68±0.10,respectively;the relative expression levels of COL3A1 protein were 0.87±0.05,1.15±0.07,0.32±0.07 and 0.73±0.06,respectively;the relative expression levels of α-smooth muscle actin(α-SMA)protein were 0.86±0.04,1.24±0.09,0.30±0.05 and 0.74±0.08,respectively.Compared with the control group,the above indexes of the TGF-β1 group and the experimental-H group were significantly different from those of the control group,and the above indexes of the TGF-β1 group were significantly different from those of the combined group(all P＜0.01).The cell migration rates of mCFs in the control group,experimental-H group and CHC group were(62.60±6.50)％,(28.00±8.15)％and(39.40±4.50)％,respectively;the relative expression levels of COL1A1 protein were 1.10±0.07,0.49±0.04 and 0.34±0.06,respectively;the relative expression levels of COL3A1 protein were 1.04±0.10,0.60±0.20 and 0.37±0.03,respectively;the relative expression levels of α-SMA protein were 1.20±0.11,0.67±0.20 and 0.48±0.18,respectively;the modification levels of Pan Kla were 1.06±0.07,1.54±0.09 and 1.53±0.12,respectively;the modification levels of H3K18la protein were 0.67±0.06,1.23±0.06 and 1.14±0.08,respectively.The above indexes of CHC group and experimental-H group were significantly different from those of control group(all P＜0.01).Conclusion L-lactic acid may play a role in inhibiting the fibrosis phenotype of mCFs by increasing non-histone lactic acid modification and H3K18la modification.

Objective To investigate the regulatory effect and possible mechanism of lactic acid on the fibrotic phenotype of cardiac fibroblasts.Methods Mouse cardiac fibroblasts(mCFs)were divided into control group(conventional culture),experimental-L group(4 mmol·L-1 L-lactic acid),experimental-M group(8 mmol·L-1 L-lactic acid),experimental-H group(12 mmol·L-1 L-lactic acid),transforming growth factor-β1(TGF-β1)group(10 ng·mL-1 TGF-β1),combined group(10 ng·mL-1 TGF-β1+12 mmol·L-1 L-lactic acid)and monocarboxylate transporter inhibitor(CHC)group(3 mmol·L-1 CHC).Western blot was used to detect the expression of fibrosis-related proteins and pan-lactate modification(Pan Kla)and H3 histone K18 lactate modification;cell scratch assay was used to detect cell migration ability.Results The cell migration rates of the control group,TGF-β1 group,experimental-H group and combined group were(40.56±0.03)％,(61.61±0.04)％,(26.59±0.05)％and(38.33±0.06)％,respectively.Compared with the control group,TGF-β1 group and experimental-H group,TGF-β1 group and combined group,the differences were statistically significant(all P＜0.01).The relative expression levels of collagen type Ⅰ alpha 1(COL1A1)protein in the control group,TGF-β1 group,experimental-H group and TGF-β1+experimental-H group were 0.76±0.09,1.10±0.07,0.40±0.04 and 0.68±0.10,respectively;the relative expression levels of COL3A1 protein were 0.87±0.05,1.15±0.07,0.32±0.07 and 0.73±0.06,respectively;the relative expression levels of α-smooth muscle actin(α-SMA)protein were 0.86±0.04,1.24±0.09,0.30±0.05 and 0.74±0.08,respectively.Compared with the control group,the above indexes of the TGF-β1 group and the experimental-H group were significantly different from those of the control group,and the above indexes of the TGF-β1 group were significantly different from those of the combined group(all P＜0.01).The cell migration rates of mCFs in the control group,experimental-H group and CHC group were(62.60±6.50)％,(28.00±8.15)％and(39.40±4.50)％,respectively;the relative expression levels of COL1A1 protein were 1.10±0.07,0.49±0.04 and 0.34±0.06,respectively;the relative expression levels of COL3A1 protein were 1.04±0.10,0.60±0.20 and 0.37±0.03,respectively;the relative expression levels of α-SMA protein were 1.20±0.11,0.67±0.20 and 0.48±0.18,respectively;the modification levels of Pan Kla were 1.06±0.07,1.54±0.09 and 1.53±0.12,respectively;the modification levels of H3K18la protein were 0.67±0.06,1.23±0.06 and 1.14±0.08,respectively.The above indexes of CHC group and experimental-H group were significantly different from those of control group(all P＜0.01).Conclusion L-lactic acid may play a role in inhibiting the fibrosis phenotype of mCFs by increasing non-histone lactic acid modification and H3K18la modification.

Objective: To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. Methods: The clinical data of 656 ENKTL patients diagnosed at 11 medical centers in the Huaihai Lymphoma Working Group from March 2014 to April 2021 were retrospectively analyzed. The patients were randomly divided into two groups: a training set (460 cases) and a validation set (196 cases) at 7∶3, and the prognostic factors of the patients were analyzed. A prognostic scoring system was established, and the predictive performance of different models was compared. Results: Patients' median age was 46 (34, 57) years, with 456 males (69.5% ) and 561 nasal involvement (85.5% ). 203 patients (30.9% ) received a chemotherapy regimen based on L-asparaginase combined with anthracyclines, and the 5-year overall survival rate of patients treated with P-GEMOX regimen (pegaspargase+gemcitabine+oxaliplatin) was better than those treated with SMILE regimen (methotrexate+dexamethasone+cyclophosphamide+L-asparaginase+etoposide) (85.9% vs 63.8% ; P=0.004). The results of multivariate analysis showed that gender, CA stage, the Eastern Cooperative Oncology Group performance status (ECOG PS) score, HGB, and EB virus DNA were independent influencing factors for the prognosis of ENKTL patients (P<0.05). In this study, the predictive performance of the prognostic factors is superior to the international prognostic index, Korean prognostic index, and prognostic index of natural killer lymphoma. Conclusion: Gender, CA stage, ECOG PS score, HGB, and EB virus DNA are prognostic factors for ENKTL patients treated with pegaspargase/L-asparaginase.
Male ; Humans ; Middle Aged ; Asparaginase/therapeutic use* ; Prognosis ; Retrospective Studies ; Lymphoma, Extranodal NK-T-Cell/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Etoposide ; Cyclophosphamide ; Methotrexate/therapeutic use* ; DNA/therapeutic use* ; Treatment Outcome

Aim To study the role of diosmetin ( Dio) in liver ischemia/reperfusion and its possible mecha-nism.Methods Thirty-two mice were randomly di¬vided into sham group, I/R group, low-dose Dio group and high-dose Dio group, with 8 mice in each group.The I/R group received liver I/R surgery, and the sham group performed sham surgery.The low- and high-dose Dio groups received intraperitoneal injection of 10 mg • kg ~1 and 40 mg • kg ~1 Dio at 30 min before liver I/R, respectively.Blood and liver samples were collected at 24 h after reperfusion.ELISA was used to detect the levels of interleukin ( IL)-ip, 1L-6, lactic dehydrogenase ( LDH ) and aspartate transaminase ( AST) in serum.Hie levels of malondialdehyde ( MDA ) , reactive oxygen species ( ROS) , reduced glutathione (GSH) and total bilirubin (TBIL) in liver homogenate were measured.HE staining was used to observe liver injury.Immunohistochemical staining was used to observe the expression of IL-ip in liver tis¬sues.Western blot was used to detect the expression of cleaved-c a spa se-3 , p-NF-kb p65 and p-p38 proteins in liver tissues.Results Compared with sham group, the degree of liver injury in I/R group significantly in¬creased , and the levels of 1L-1 (3, 1L-6, LDH and AST in serum, MDA, ROS and cleaved-caspase-3, p-NF- kb p65 and p-p38 proteins in liver tissues markedly in¬creased ; however, the levels of GSH and TB1L signifi¬cantly decreased, and the differences in the above in¬dexes were statistically significant.Compared with I/R group, the above indexes in low- and high-dose Dio groups were significantly improved, and the effect of high-dose group was better than that of low-dose group.Conclusions Dio pretreatment can reduce liver I/R injury, which may be related to the reduction of oxida¬tive stress and inflammation-related pathways induced by liver I/R.

Objective:The investigation and research on the application status of Hepatic Venous Pressure Gradient (HVPG) is very important to understand the real situation and future development of this technology in China.Methods:This study comprehensively investigated the basic situation of HVPG technology in China, including hospital distribution, hospital level, annual number of cases, catheters used, average cost, indications and existing problems.Results:According to the survey, there were 70 hospitals in China carrying out HVPG technology in 2021, distributed in 28 provinces (autonomous regions and municipalities directly under the central Government). A total of 4 398 cases of HVPG were performed in all the surveyed hospitals in 2021, of which 2 291 cases (52.1%) were tested by HVPG alone. The average cost of HVPG detection was (5 617.2±2 079.4) yuan. 96.3% of the teams completed HVPG detection with balloon method, and most of the teams used thrombectomy balloon catheter (80.3%).Conclusion:Through this investigation, the status of domestic clinical application of HVPG has been clarified, and it has been confirmed that many domestic medical institutions have mastered this technology, but it still needs to continue to promote and popularize HVPG technology in the future.

OBJECTIVE: To assess the efficacy and safety of Bushen Huoxue Formula (BSHXF) for the treatment of discogenic low-back pain (DLBP). METHODS: This was a parallel, double-blind, randomized, clinical trial performed between May 2019 and June 2020. Seventy patients were assigned by computerized random number table to the treatment group (lumbar traction and BSHXF, 35 cases) or the control group (lumbar traction and placebo, 35 cases). The patients received intervention for 3 weeks. Assessment was conducted before treatment and at week 1, 2, 3 during treatment. Primary outcome was the self-reported score of Oswestry Disability Index (ODI). Secondary outcomes included Visual Analog Scale (VAS), clinical efficacy rate by minimal clinically important difference (MCID) as well as lumbar tenderness, muscle tone and lumbar spine mobility. Adverse reactions were recorded. Follow-up was performed at 1 and 3 months after the end of treatment. RESULTS: In the treatment group, ODI score was significantly decreased compared with baseline (P<0.05) and the control group at 2- and 3- week treatment. Similarly, VAS score decreased compared with the baseline (P<0.05) and was lower than that in the control group at 2- and 3- week treatment (P<0.05). The clinical efficacy rate of the treatment group was higher than that of the control group after treatment [32.35% (11/34) vs. 3.13% (1/32), P<0.05). Moreover, the tenderness, and muscle tone, as well as the back extension and left flexion in lumbar spine mobility in the treatment group at 3-week treatment were significantly improved compared with the control group (P<0.05). Follow-up showed that at 1-month after treatment, the treatment group had better outcomes than the control group with regard to a total score of ODI and VAS scores, as well as clinical efficacy rate (all P<0.05). Moreover, VAS score was still significantly lower than the control group at 3-month follow-up (P<0.05). No adverse reactions were reported during the study. CONCLUSION BSXHF combined with lumbar traction can significantly improve the clinical symptoms including pain intensity, functionality, muscle tone, and lumbar spine mobility in DLBP patients. (Registration No. ChiCTR1900027777).
Humans ; Intervertebral Disc Degeneration/therapy* ; Low Back Pain/drug therapy* ; Lumbar Vertebrae ; Pain Measurement ; Treatment Outcome