Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

PURPOSE: Septic shock is associated with high mortality and poor outcomes among sepsis patients with coagulopathy. Although traditional statistical methods or machine learning (ML) algorithms have been proposed to predict septic shock, these potential approaches have never been systematically compared. The present work aimed to develop and compare models to predict septic shock among patients with sepsis. METHODS: It is a retrospective cohort study based on 484 patients with sepsis who were admitted to our intensive care units between May 2018 and November 2022. Patients from the 908th Hospital of Chinese PLA Logistical Support Force and Nanchang Hongdu Hospital of Traditional Chinese Medicine were respectively allocated to training (n=311) and validation (n=173) sets. All clinical and laboratory data of sepsis patients characterized by comprehensive coagulation indexes were collected. We developed 5 models based on ML algorithms and 1 model based on a traditional statistical method to predict septic shock in the training cohort. The performance of all models was assessed using the area under the receiver operating characteristic curve and calibration plots. Decision curve analysis was used to evaluate the net benefit of the models. The validation set was applied to verify the predictive accuracy of the models. This study also used Shapley additive explanations method to assess variable importance and explain the prediction made by a ML algorithm. RESULTS: Among all patients, 37.2% experienced septic shock. The characteristic curves of the 6 models ranged from 0.833 to 0.962 and 0.630 to 0.744 in the training and validation sets, respectively. The model with the best prediction performance was based on the support vector machine (SVM) algorithm, which was constructed by age, tissue plasminogen activator-inhibitor complex, prothrombin time, international normalized ratio, white blood cells, and platelet counts. The SVM model showed good calibration and discrimination and a greater net benefit in decision curve analysis. CONCLUSION The SVM algorithm may be superior to other ML and traditional statistical algorithms for predicting septic shock. Physicians can better understand the reliability of the predictive model by Shapley additive explanations value analysis.
Humans ; Shock, Septic/blood* ; Machine Learning ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; Sepsis/complications* ; ROC Curve ; Cohort Studies ; Adult ; Intensive Care Units ; Algorithms ; Blood Coagulation ; Critical Illness

Objective To explore the effect of mangiferin(MF)on pyroptosis in an amyotrophic lateral sclerosis(ALS)cell model by regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1(Nrf2/HO-1)signaling pathway.Methods(1)Mouse NSC-34 cell lines transfected with hSOD1WT and hSOD1G93A plasmids were randomly divided into blank group,model group,MF(100 μmol/L)group,MF(200 μmol/L)group.MF was added into the culture plate for 24 hours.Cell viability was assessed using CCK-8 kit.Lactate dehydrogenase(LDH)release was measured using LDH cytotoxicity detection kit.Levels of inflammatory factors interleukin(IL)-1β and IL-18 in cell supernatant were determined by enzyme-linked immunosorbent assay(ELISA).The expression of Nrf2,HO-1,NADPH quinone oxidoreductase-1(NQO-1),NOD-like receptor protein 3(NLRP3),gasdermin D(GSDMD)-N and caspase-1 was detected by Western blotting.(2)Mouse hSOD1G93A NSC-34 cells were randomly divided into model group,MF(200 μmol/L)group,Nrf2-siRNA group and Nrf2-siRNA+MF(200 μmol/L)group.The cells were transiently transfected with Nrf2-siRNA using LipofectamineTM 3000.Western blotting was used to detect the protein expression levels of Nrf2,HO-1,NQO-1,NLRP3,caspase-1 and GSDMD-N.Results(1)The results of the CCK-8 assay showed that after the hSOD1G93A NSC-34 cells were treated with MF at concentrations of 300 μmol/L and below for 24 hours,the changes in cell viability were not significant(P>0.05).Compared with blank group,the release of LDH,the contents of IL-1β and IL-18 in the cell culture supernatant of model group were increased(P<0.001);the protein expression levels of Nrf2,HO-1,and NQO-1 were decreased(P<0.05 or P<0.01);the protein expression levels of NLRP3,caspase-1,and GSDMD-N were increased(P<0.05 or P<0.01 or P<0.001).Compared with model group,the release of LDH,the contents of IL-18 and IL-1β in the culture supernatant in MF(100 μmol/L)and MF(200 μmol/L)groups were decreased(P<0.001);the protein expression levels of NLRP3,caspase-1 and GSDMD-N were decreased(P<0.05 or P<0.001),and the expression levels of Nrf2,HO-1 and NQO-1 were increased(P<0.05 or P<0.01).(2)Compared with model group,the protein expession levels of Nrf2,NO-1 and NQO-1 were increased(P<0.05 or P<0.001)in MF(200 μmol/L)group,while the protein expression levels of NLRP3,caspase-1 and GSDMD-N were decreased(P<0.001);the protein expression levels of Nrf2 and HO-1 were decreased in Nrf2-siRNA group(P<0.01 or P<0.001),while the protein expression levels of NLRP3,caspase-1 and GSDMD-N were increased(P<0.001).Compared with Nrf2-siRNA group,the protein expression levels of Nrf2,HO-1 and NQO-1 in Nrf2-siRNA+MF(200 μmol/L)group were increased(P<0.01 or P<0.001),and the protein expression levels of NLRP3,caspase-1 and GSDMD-N were decreased(P<0.001).Conclusion MF can inhibit pyroptosis in the ALS cell model through Nrf2/HO-1 signaling pathway,playing a protective role.

Objective To investigate plasma protein expression changes in heatstroke patients using proteomics technology and to identify reliable prognostic biomarkers.Methods A retrospective analysis was conducted on 20 heatstroke patients hospitalized at the 908th Hospital of the Chinese PLA Joint Logistics Support Force from July 2022 to February 2024.Patients were divided into survival(n=16)and death groups(n=4)based on 28-day outcomes.Fasting venous blood samples were collected from both groups for proteomic analysis.Liquid chromatography-mass spectrometry(LC-MS/MS)was used to identify and screen differentially expressed proteins.Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)enrichment analyses were performed.LASSO regression was applied to screen key prognostic biomarkers,and receiver operating characteristic(ROC)curve analysis was used to evaluate their predictive value.Results A total of 27 upregulated and 90 downregulated proteins were identified between the two groups.These proteins were primarily involved in biological processes such as immune responses,complement activation,and metabolic processes.LASSO regression analysis indicated that actin-related protein 2(ARP2),cysteine-rich scavenger receptor type 1 M130(CD163),and catalase(CAT)could serve as effective biomarkers for evaluating heatstroke prognosis.ROC curve analysis demonstrated that ARP2 had higher diagnostic efficacy(AUC=0.98,sensitivity=0.80,specificity=1.00)compared to CD163(AUC=0.94,sensitivity=0.76,specificity=1.00),CAT(AUC=0.96,sensitivity=0.67,specificity=1.00),and acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ)score(AUC=0.79,sensitivity=0.44,specificity=1.00).Conclusion Elevated plasma ARP2 level has good clinical value for predicting poor prognosis in heatstroke patients.

The heat shock protein 90 (Hsp90) protein family is a cluster of highly conserved molecules that play an important role in maintaining cellular homeostasis. Hsp90 and its co-chaperones regulate a variety of pathways and cellular functions, such as cell growth, cell cycle control and apoptosis. Hsp90 is closely associated with the occurrence and development of tumors and other diseases, making it an attractive target for cancer therapeutics. Inhibition of Hsp90 expression can affect multiple oncogenic pathways simultaneously. Most Hsp90 small molecule inhibitors are in clinical trials due to their low efficacy, toxicity or drug resistance, but they have obvious synergistic anti-tumor effect when used with histone deacetylase (HDAC) inhibitors, tubulin inhibitors or topoisomerase II (Topo II) inhibitors. To address this issue, the design of Hsp90 dual-target inhibitors can improve efficacy and reduce drug resistance, making it an effective tumor treatment strategy. In this paper, the domain and biological function of Hsp90 are briefly introduced, and the design, discovery and structure-activity relationship of Hsp90 dual inhibitors are discussed, in order to provide reference for the discovery of novel Hsp90 dual inhibitors and clinical drug research from the perspective of medicinal chemistry.

Objective:To describe and analyze suicide risk of patients with schizophrenia,major depressive disorder,and bipolar disorder.Methods:A total of 2 016 patients with schizophrenia,903 patients with major de-pressive disorder,and 381 patients with bipolar disorder from inpatients,clinics,or communities who met the diag-nostic criteria of the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition were recruited.All patients were interviewed by psychiatrists using the Mini International Neuropsychiatric Interview to diagnose mental disor-ders and assess suicide risk,as well as Clinical-Rated Dimensions of Psychosis Symptom Severity(CRDPSS)to as-sess symptoms.Differences and risk factors of suicide risk among three types of mental disorders were explored u-sing multivariate logistic regression analysis.Results:In the past one month,37 patients with schizophrenia(1.8％),516 patients with major depressive disorder(57.1％),and 102 patients with bipolar disorder(26.8％)had suicide risk.Compared with patients with schizophrenia,suicide risk in patients with major depressive disorder(OR=36.50)and bipolar disorder(OR=20.10)increased.Female(OR=1.87),smoking(OR=1.76),family history of suicide(OR=5.09),higher score of CRDPSS hallucination(OR=1.80),and higher score of CRDPSS depression(OR=1.54)were risk factors of suicide risk of patients.Conclusions:Suicide risk of patients with ma-jor depressive disorder and bipolar disorder is higher than that of patients with schizophrenia.In clinical practice,it is important to regularly assess suicide risk of patients.Patients who experience symptoms of hallucination and de-pression should be paid more attention to.

Objective:To investigate the efficacy and safety of Guihuang Formula(GHF)in the treatment of type Ⅲ prostatitis with the syndrome of damp-heat stasis in the essence chamber.Methods:This study included 120 cases of type Ⅲ prostatitis with damp-heat stasis syndrome in the essence chamber,which were randomly and equally divided into a GHF and a control group,the for-mer treated with GHF and the latter with Tamsulosin Hydrochloride Sustained-Release Capsules,both for 6 successive weeks.We fol-lowed up the patients for 4 weeks,recorded the NIH-CPSI,TCM symptom scores,and results of prostatic fluid routine,blood and u-rine routine,liver and kidney function and electrocardiogram examinations,and compared them between the two groups of patients be-fore and after treatment.Results:Compared with the baseline,the total NIH-CPSI scores were significantly decreased in both the GHF and control groups after 6 weeks of treatment,even more significantly in the former group(28.34±9.23 vs 6.78±3.53,P＜0.05)than in the latter(27.81±8.28 vs 14.48±4.27,P＜0.05),so were the scores on pain,voiding symptoms,quality of life(QOL)impact,TCM symptoms and WBC count(all P＜0.05),while the number of lecithin bodies remarkably increased(P＜0.05).There were statically significant differences in the above parameters at 4,6 and 10 weeks of medication(P＜0.05),but not at 2 weeks(P＞0.05).No obvious abnormalities or adverse reactions were observed in either of the two groups during the treatment.Conclusion:Guihuang Formula is safe and effective in the treatment of type Ⅲ prostatitis with the syndrome of damp-heat stasis in the essence chamber.

Purpose::In patients with heatstroke, disseminated intravascular coagulation (DIC) is associated with greater risk of in-hospital mortality. However, time-consuming assays or a complex diagnostic system may delay immediate treatment. Therefore, the present study proposes a new heatstroke-induced coagulopathy (HIC) score in patients with heat illness as an early warning indicator for DIC.Methods::This retrospective study enrolled patients with heat illness in 24 Chinese hospitals from March 2021 to May 2022. Patients under 18 years old, with a congenital clotting disorder or liver disease, or using anticoagulants were excluded. Data were collected on demographic characteristics, routine blood tests, conventional coagulation assays and biochemical indexes. The risk factors related to coagulation function in heatstroke were identified by regression analysis, and used to construct a scoring system for HIC. The data of patients who met the diagnostic criteria for HIC and International Society on Thrombosis and Haemostasis defined-DIC were analyzed. All statistical analyses were performed using SPSS 26.0.Results::The final analysis included 302 patients with heat illness, of whom 131 (43.4%) suffered from heatstroke, including 7 death (5.3%). Core temperature ( OR = 1.681, 95% CI 1.291 - 2.189, p < 0.001), prothrombin time ( OR = 1.427, 95% CI 1.175 - 1.733, p < 0.001) and D-dimer ( OR = 1.242, 95% CI 1.049 - 1.471, p = 0.012) were independent risk factors for heatstroke, and therefore used to construct an HIC scoring system because of their close relation with abnormal coagulation. A total score ≥ 3 indicated HIC, and HIC scores correlated with the score for International Society of Thrombosis and Hemostasis-DIC ( r = 0.8848, p < 0.001). The incidence of HIC (27.5%) was higher than that of DIC (11.2%) in all of 131 heatstroke patients. Meanwhile, the mortality rate of HIC (19.4%) was lower than that of DIC (46.7%). When HIC developed into DIC, parameters of coagulation dysfunction changed significantly: platelet count decreased, D-dimer level rose, and prothrombin time and activated partial thromboplastin time prolonged ( p < 0.05). Conclusions::The newly proposed HIC score may provide a valuable tool for early detection of HIC and prompt initiation of treatment.