Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

Objective To investigate the effects of total flavones from Oxytropis falcata Bunge on hepatic fibrosis(HF)induced by carbon tetrachloride and liver transforming growth factor(TGF-β)/Smad signaling pathway.Methods Forty-eight male rats were randomly divided into normal group(intraperitoneal injection of peanut oil,intragastric administration of 0.9％NaCl),model group(intraperitoneal injection of 40％CC14 peanut oil solution induced HF model,intragastric administration of 0.9％NaCl),positive control group(modeling,intragastric administration of 0.2 mg·kg-1 of colchicine),experimental-L,-M,-H groups(modeling,intragastric administration of 100,200 and 400 mg·kg-1 of total flavonoid extract of Oxytropis falcata Bunge),8 individuals in each group,for 4 consecutive weeks.The histopathological changes were observed by hematoxylin-eosin and Masson staining.Serum liver function and liver fibrosis were measured;erum inflammatory factors were detected;fluorescence quantitative polymerase chain reaction(RT-qPCR)was used to determine gene expression in liver.Results The pathological injury of liver tissue in the model group was serious,and a large number of inflammatory factors and collagen fibers were accumulated,while the rest of the treatment groups had different degrees of remission.In normal group,model group,positive control group,experimental-L,-M,-H groups,glutamic-pyruvic transaminase levels were(49.28±12.44),(5 885.42±948.37),(4 454.60±489.27),(4 650.47±843.53),(3 761.75±887.30)and(3 544.90±1 066.75)μg·L-1;glutamic-oxaloacetic transaminase levels were(186.90±46.89),(5 936.23±793.81),(3 971.37±780.28),(4 360.30±863.35),(3 943.10±439.47)and(3 971.38±631.08)μg·L-1;hyaluronic acid levels were(45.08±17.16),(104.32±36.06),(66.83±20.09),(70.30±21.07),(60.00±9.68)and(59.02±10.73)μg·L-1;laminin levels were(23.13±3.89),(60.85±13.66),(35.67±9.92),(39.98±9.39),(36.55±12.21)and(34.68±24.83)μg·L-1;type Ⅲ procollagen level were(24.98±5.34),(82.58±30.14),(40.70±16.14),(51.08±23.21),(43.60±12.48)and(44.20±11.66)p±g·L-1;interleukin(IL)-1β levels were(37.63±1.24),(46.10±3.23),(39.22±2.36),(41.33±0.93),(40.25±2.04)and(39.18±2.23)pg·mL-1;tumor necrosis factor-α levels were(314.58±20.56),(383.71±16.97),(349.00±7.93),(348.88±25.11),(325.75±27.84)and(335.07±21.33)pg·mL-1;TGF-β1 mRNA expression of relative quantity respectively were 1.00±0.00,60.99±15.70,9.61±1.59,7.37±1.09,6.41±0.64,6.87±1.09;Smad7 mRNA relative expression were 1.00±0.00,0.34±0.05,0.21±0.03,0.35±0.02,0.38±0.02,0.42±0.03.The above indexes in the model group were compared with the normal group,and the above indexes in the experimental-M,-H groups were compared with the model group,and the differences were statistically significant(P＜0.05,P＜0.01,P＜0.001).Conclusion Total flavonoids of Oxytropis falcata Bunge have protective effects on CC14-induced liver fibrosis in rats,and the mechanism may be related to the regulation of TGF-β/Smad pathway.

Objective To evaluate the characteristics of the mass balance and pharmacokinetics of[14 C]birociclib in Chinese male healthy volunteers after a single oral administration.Methods This study used a 14 C labeled method to investigate the mass balance and biological transformation of birociclib in human.Subjects were given a single oral dose of 360 mg/50 pCi of[14 C]birociclib suspension after meals.The blood,urine,and fecal samples were collected at specified time points/intervals after administration.The radiation levels of 14 C labeled birociclib-related compounds in the blood,plasma,urine,and feces were analyzed using liquid scintillation counting.In addition,a combination of high-performance liquid chromatography and on-line/off-line isotope detectors was used to obtain radioactive isotope metabolite spectra of plasma,urine,and fecal samples,and high-resolution mass spectrometry was used to identify the main metabolites.Results A total of 6 healthy male subjects were enrolled in this study.The median peak time of radioactive components in plasma was 5.00 h and the average terminal elimination half-life was 43.70 h after administration.The radioactive components were basically excreted and cleared from the body within 288.00 hours after administration,and average cumulative recovery rate of radioactive drugs was(94.10±8.19)％.The radioactive drugs were mainly excreted through feces,accounting for(84.60±7.10)％of the dose of radioactive drugs administered.Urine was the secondary excretory pathway,accounting for 9.41％of the dose of radioactive drugs administered.Metabolic analysis indicated that the prototype drug was the main radioactive components in plasma samples.The main metabolites in plasma were RM4(XZP-5286),RM6(XZP-3584),and RM7(XZP-5736).The drugs were mainly cleared from the body in the form of prototype drugs and metabolites.In addition to prototype drugs,a total of 9 metabolites were identified and analyzed in plasma,urine,and fecal samples,all of which were phase 1 metabolites.The main metabolic and clearance pathways of drugs in the body were deethylation,diisopropylat ion,oxidation,etc.Conclusion After a single oral administration of[14C]birociclib suspension to healthy subjects,it was mainly cleared from the body in the form of prototype drugs and metabolites,with feces as the main excretory pathway and urine as the secondary excretory pathway.Drugs mainly undergo metabolic reactions in the body,such as deethylation,diisopropylation,and oxidation.The subjects were well tolerance after administration.

Objective The high incidence, disability, and mortality rates of stroke result in a heavy economic and social burden. The aim of this study was to investigate the relationship between triglyceride-glucose (TyG) index and new-onset stroke to assist in the identification of high-risk groups for stroke and to provide ideas for effective prevention. Methods The study was based on data from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018 and included 7630 eligible middle-aged and elderly participants. The association between TyG index and new-onset stroke was assessed by logistic regression modelling and restricted triple spline analysis. Results A total of 431 participants had a new stroke. The TyG index was found to be a risk factor for stroke occurrence when it was >8.523, and there was a positive linear association moderated by gender. Conclusion Elevated TyG index is a risk factor for new stroke. This study provides new ideas for the identification of high-risk groups for stroke and for intervention measures and timing.

ObjectiveTo investigate the effects of Shegan Mahuangtang and its pungent and bitter Chinese herbs on the expression of transient receptor potential vanilloid-1 （TRPV1） and bitter taste receptor 14 （TAS2R14） in the lung tissue of the rat model of cold asthma. MethodSeventy SD rats were randomized into 7 groups： normal， model， Shegan Mahuangtang， pungent Chinese herbs， bitter Chinese herbs （6.43 g·kg^-1）， dexamethasone （0.5 g·kg^-1）， and Guilong Kechuanning （10 g·kg^-1）. The rat model of cold asthma was established by intraperitoneal injection and subcutaneous injection of 10% ovalbumin （OVA） and aluminium hydroxide in the limbs， combined with 2% OVA atomization and cold （2-4 ℃） stimulation. The rats were treated with corresponding drugs by gavage and atomization， and the normal and model groups were treated with the same amount of normal saline for 3 weeks. After the last excitation， airway inflammation and cell proliferation were observed by hematoxylin-eosin （HE）， periodic acid-Schiff （PAS）， and Masson staining of the lung tissue. The levels of interleukin-5 （IL-5）， tumor necrosis factor-α （TNF-α）， thymic stromal lymphopoietin （TSLP）， and transforming growth factor-β₁ （TGF-β₁） in the serum were measured by enzyme-linked immunosorbent assay （ELISA）. The expression of TRPV1 and TAS2R14 was detected by immunofluorescence. The expression of TRPV1， TAS2R14， phospholipase Cβ₂ （PLCβ₂）， B-cell lymphoma-2 （Bcl-2）， and α-smooth muscle actin （α-SMA） in the lung tissue was determined by Western blot. ResultCompared with the normal group， the model group showed decreased water intake， food intake， and body weight， increased airway inflammatory cell infiltration， goblet cell proliferation， tissue fibrosis and collagen deposition， elevated levels of IL-5， TNF-α， TSLP， and TGF-β₁ in the serum （P<0.01）， upregulated expression of TRPV1， PLCβ₂， and α-SMA， and downregulated expression of TAS2R14 and Bcl-2 （P<0.05， P<0.01）. Compared with model group， Shecgan Mahuangtang， pungent Chinese herbs， and bitter Chinese herbs increased the water intake， food intake， and body weight， reduced the inflammatory cell infiltration and goblet cell proliferation， alleviated tissue fibrosis and collagen deposition， lowered the levels of IL-5， TNF-α， TSLP， and TGF-β₁ in the serum （P<0.01）， downregulated the expression of TRPV1， PLCβ₂， and α-SMA， and upregulated the expression of TAS2R14 and Bcl-2 （P<0.05， P<0.01）. ConclusionShegan Mahuangtang and its pungent and bitter Chinese herbs can reduce OVA-induced airway inflammation， downregulate the expression of TRPV1， PLCβ₂， and α-SMA， and upregulate the expression of TAS2R14 and Bcl-2 in asthmatic rats. Moreover， bitter Chinese herbs outperformed pungent Chinese herbs， and the combination of them enhanced the therapeutic effect. It is suggested that Shegan Mahuangtang and its pungent and bitter Chinese herbs may ameliorate the OVA-induced airway inflammation by inhibiting TRPV1 and activating TAS2R14.

Perimenopausal syndrome （MPS）， a common endocrine system disease， is one of the diseases responding specifically to traditional Chinese medicine （TCM）. The China Association of Chinese Medicine organized experts in endocrinology， gynecology， and interdisciplinary fields of both Western and Chinese medicine to discuss the advantages and challenges of diagnosing and treating MPS with Western medicine， TCM， and integrative medicine. Experts at the conference believe that MPS is initiated by estrogen decline and rooted in deficiency， with the pathogenesis being imbalance between Yin and Yang in the kidney. The hormone replacement therapy in Western medicine for menopause can rapidly alleviate related symptoms by quickly restoring the estrogen level and timely detect and delay complications of menopause， whereas such a therapy has certain risks， necessitating close monitoring of adverse reactions. Moreover， the various contraindications and precautions limit the clinical application of the hormone replacement therapy. TCM has advantages in synergistically alleviating symptoms such as hot flashes， sweating， sleep disorders， and emotional abnormalities of MPS without causing obvious adverse reactions. However， its efficacy is slower than the hormone replacement therapy， and the TCM evidence for preventing and treating complications of menopause remains unclear. Three suggestions were proposed for the future development of both Western and TCM for ameliorating MPS. First， an integrated diagnosis and treatment system for MPS with both Western and Chinese medicine should be established. Second， high-quality evidence-based interventions for MPS should be developed with TCM alone or in combination with Western medicine. Third， efforts should be made to promote the new TCM drug development and the interdisciplinary cooperation for treating MPS.

This work aims to evaluate a rapid detection method of carbapenem resistance genes in blood cultures based on Xpert Carba-R and preliminarily evaluate its clinical application.Methods:Sixteen strains of Enterobacterales carrying different carbapenem resistance genes were selected to prepare simulated positive blood culture samples and Xpert Carba-R was used to directly detect carbapenem resistance genes in the simulated positive blood culture. From January 2022 to June, a prospective study was conducted on a total of 117 Enterobacteriaceae-positive blood culture samples in the First Affiliated Hospital of Nanjing Medical University. Xpert Carba-R, detecting five kinds of carbapenem resistance genes in these samples, was evaluated in sensitivity and specificity compared to polymerase chain reaction sequencing. Meanwhile clinical data of positive patients was collected for prognostic analysis. Results:Of the 16 simulated specimens, 14 strains had carbapenem resistance genes detected by Xpert Carba-R, including 8 bla KPC, 5 bla NDM and 1 bla IMP, showing 100% agreement with the known results. As of the 117 clinical specimens, 28 cases were determined to be Enterobacterales harboring carbapenem resistance genes, including 24 bla KPC, 2 bla NDM and 2 bla KPC+ bla NDM. In comparison to the PCR sequencing, the sensitivity and specificity of Xpert Carba-R were both 100% for blood culture samples, and furthermore, the detection time was significantly reduced. Of the 25 positive patients, 9 cases were treated with monotherapy and 5 cases were effective, other 16 cases received combined treatment and 12 cases were effective. A total of 17 cases were effective, 8 cases were ineffective and 3 of them died, the mortality rate was 12% (3/25). Conclusion:Xpert Carba-R can rapidly and accurately detect carbapenem resistance genes in blood culture, which can provide evidence for rational drug therapy in early clinical stage.

Objective:To investigate the incidence of venous thromboembolism (VTE) in patients with esophageal cancer (EC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 8 458 EC patients who were admitted to Sichuan Cancer Hospital from January 2017 to December 2021 were collected. There were 6 923 males and 1 535 females, aged (64±9)years. There were 3 187 patients undergoing surgical treatment, and 5 271 cases undergoing non-surgical treatment. Observation indicators: (1) incidence of VTE in EC patients; (2) treatment and outcomes of patients with VTE. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was analyzed using the t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was analyzed using the nonparameter rank sum test. Count data were expressed as absolute numbers or percentages, and comparison between groups was analyzed using the chi-square test or Fisher exact probability. Comparison of ordinal data was analyzed using the nonparameter rank sum test. Results:(1) Incidence of VTE in EC patients. Of 8 458 EC patients, 175 cases developed VTE, with an incidence rate of 2.069%(175/8 458). Among 175 VTE patients, there were 164 cases of deep venous thrombosis (DVT), 4 cases of pulmonary embolism (PE), 7 cases of DVT and PE. There were 59 surgical patients and 116 non-surgical patients. There was no significant difference in thrombus type between surgical and non-surgical EC patients with VTE ( χ2=1.95, P>0.05). Of 3 187 surgical patients, the incidence of VTE was 1.851%(59/3 187), including an incidence of 0.157%(5/3 187) of PE. PE accounted for 8.475%(5/59) of surgical patients with VTE. Of 5 271 non-surgical patients, the incidence of VTE was 2.201%(116/5 271), including an incidence of 0.114%(6/5 271) of PE. PE accounted for 5.172%(6/116) of non-surgical patients with VTE. There was no significant difference in the incidence of VTE or PE between surgical patients and non-surgical patients ( χ2=1.20, 0.05, P>0.05). (2) Treatment and outcomes of patients with VTE. Among 175 EC patients with VTE, 163 cases underwent drug treatment, and 12 cases did not receive treatment. Among 163 cases with drug therapy, 158 cases underwent anticoagulant therapy, 5 cases were treated with thrombolysis. All the 163 patients were improved and discharged from hospital. Conclusions:The incidence of VTE in patients with EC is relatively low, as 2.069%. There is no significant difference in the incidence of VTE or thrombus type between surgical EC patients and non-surgical EC patients.