Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To analyze the association between healthcare workers mental health,institu-tional supplies and facilities,inter-organizational coordination during infectious disease outbreaks,and the healthcare institution resilience.Methods:An online questionnaire survey was conducted among the healthcare workforce from 146 institutions in Beijing from January 13,2023 to February 9,2023,and a total of 1 434 eligible respondents were included.The sample comprised 408 responses from tertiary hos-pitals,117 from secondary hospitals,and 909 from primary care institutions.The resilience indicator for healthcare institutions was defined as the degree to which medical services met patient demands,with in-fluencing factors including physical factors,such as material shortages and facility space adaptation or ex-pansion,organizational factors such as information sharing and patient referral,and psychological factors were evaluated using job satisfaction(extrinsic satisfaction,intrinsic satisfaction),burnout(emotional exhaustion,depersonalization,reduced personal accomplishment),and depression status.Ordered mul-ticlassification Logistic regression was used to examine the impact of various factors on the degree to which healthcare services met patient needs;additionally,demographic factors that might influence institutional resilience were controlled.Results:During the emergency response phase,93％of hospitals maintained the capacity to meet patient needs,though tertiary hospitals demonstrated significantly higher rates of service inadequacy(21.05％).Material shortages were reported across all institutions,with tertiary hos-pitals experiencing more frequent multi-item shortages.Inter-institutional collaboration patterns revealed substantial variation:87.50％of primary care facilities,42.86％of secondary hospitals,and 31.58％of tertiary hospitals.Healthcare workers across all levels reported mild depressive symptoms and moderate-to-severe burnout levels.Regression analysis showed high satisfaction(overall satisfaction β=0.04,ex-trinsic satisfaction β=0.06,and intrinsic satisfaction β=0.08),low degree of job burnout(emotional exhaustion β=-0.04,depersonalization β=-0.07 and reduced personal accomplishment β=0.01),low degree of depression(β=-0.06)were significantly associated with higher healthcare institution re-silience.In addition,material shortages were significantly associated with lower resilience,and renova-tion and expansion of treatment spaces,and information sharing,were all associated with higher resilience.Demographic factors(age,gender,marital status,educational background,etc.)had no sig-nificant impact on resilience.Conclusion:Mental health status significantly influences healthcare institu-tion resilience.As human resources constitute the core asset of healthcare institutions,strategic optimiza-tion of workforce allocation and psychological support interventions can effectively strengthen resilience.Moreover,healthcare institution resilience is positively impacted by orderly material supply chains,timely resource distribution,and adaptive reconfiguration of clinical spaces.Finally,facilitating information sharing also enhances institutional resilience.

Objective: Fibromyalgia syndrome (FMS) is a chronic pain condition characterized by central sensitivity to pain, and it is universally acknowledged as a recalcitrant disease. A single-blind randomized controlled trial was conducted to assess the effectiveness and safety of the Roujin formula in treating FMS patients with liver depression and spleen deficiency syndrome, aiming to provide more scientific and effective treatment options. Methods: Forty-eight eligible participants were enrolled and randomly assigned to either the Roujin formula group (n = 24) or the placebo group (n = 24). The Roujin formula group received 150 mL of the Roujin formula twice daily, whereas the placebo group was given a tenth of the Roujin formula dosage, twice daily. The treatment lasted for 8 weeks, with a follow-up extending to 12 weeks. The primary outcome was the improvement in the pain Visual Analogue Scale (VAS) score, whereas secondary outcomes included enhancements in the Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory-II (BDI-II), Revised Fibromyalgia Impact Questionnaire (FIQR), and 36-item Short-Form Health Survey (SF-36) scores. These measures were assessed at baseline and after 4, 8, and 12 weeks. The Patients’ Global Impression of Change (PGIC) was collected at week 12. Safety assessments were based on routine blood tests, urine tests, and liver and kidney function evaluations. Results: The improvement in the pain VAS score was significantly greater in the Roujin formula group than that in the placebo group at the 4-, 8-, and 12-week follow-ups (p < 0.05). At the 8-week treatment and the 12-week follow-up, improvements in PSQI and FIQR scores were also superior in the Roujin formula group compared with the placebo group (p < 0.05). There were no differences between the 2 groups in the improvement of BDI-II scores, SF-36 physical component summary, and mental component summary scores at any observation time points. At the 12-week follow-up, PGIC ratings were significantly better in the Roujin formula group (p < 0.05). There were 4 adverse events, all of which occurred in the Roujin formula group, including 3 cases of diarrhea and 1 case of stomach pain; no serious adverse events were reported during the study. Conclusion: The Roujin formula can effectively enhance the overall condition of FMS patients, relieve pain, improve sleep quality, and elevate physical and mental well-being. Only mild gastrointestinal reactions were observed. The Roujin formula may be a viable candidate for clinical implementation.

Objective: Fibromyalgia syndrome (FMS) is a chronic pain condition characterized by central sensitivity to pain, and it is universally acknowledged as a recalcitrant disease. A single-blind randomized controlled trial was conducted to assess the effectiveness and safety of the Roujin formula in treating FMS patients with liver depression and spleen deficiency syndrome, aiming to provide more scientific and effective treatment options. Methods: Forty-eight eligible participants were enrolled and randomly assigned to either the Roujin formula group (n = 24) or the placebo group (n = 24). The Roujin formula group received 150 mL of the Roujin formula twice daily, whereas the placebo group was given a tenth of the Roujin formula dosage, twice daily. The treatment lasted for 8 weeks, with a follow-up extending to 12 weeks. The primary outcome was the improvement in the pain Visual Analogue Scale (VAS) score, whereas secondary outcomes included enhancements in the Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory-II (BDI-II), Revised Fibromyalgia Impact Questionnaire (FIQR), and 36-item Short-Form Health Survey (SF-36) scores. These measures were assessed at baseline and after 4, 8, and 12 weeks. The Patients’ Global Impression of Change (PGIC) was collected at week 12. Safety assessments were based on routine blood tests, urine tests, and liver and kidney function evaluations. Results: The improvement in the pain VAS score was significantly greater in the Roujin formula group than that in the placebo group at the 4-, 8-, and 12-week follow-ups (p < 0.05). At the 8-week treatment and the 12-week follow-up, improvements in PSQI and FIQR scores were also superior in the Roujin formula group compared with the placebo group (p < 0.05). There were no differences between the 2 groups in the improvement of BDI-II scores, SF-36 physical component summary, and mental component summary scores at any observation time points. At the 12-week follow-up, PGIC ratings were significantly better in the Roujin formula group (p < 0.05). There were 4 adverse events, all of which occurred in the Roujin formula group, including 3 cases of diarrhea and 1 case of stomach pain; no serious adverse events were reported during the study. Conclusion: The Roujin formula can effectively enhance the overall condition of FMS patients, relieve pain, improve sleep quality, and elevate physical and mental well-being. Only mild gastrointestinal reactions were observed. The Roujin formula may be a viable candidate for clinical implementation.

Objective: Fibromyalgia syndrome (FMS) is a chronic pain condition characterized by central sensitivity to pain, and it is universally acknowledged as a recalcitrant disease. A single-blind randomized controlled trial was conducted to assess the effectiveness and safety of the Roujin formula in treating FMS patients with liver depression and spleen deficiency syndrome, aiming to provide more scientific and effective treatment options. Methods: Forty-eight eligible participants were enrolled and randomly assigned to either the Roujin formula group (n = 24) or the placebo group (n = 24). The Roujin formula group received 150 mL of the Roujin formula twice daily, whereas the placebo group was given a tenth of the Roujin formula dosage, twice daily. The treatment lasted for 8 weeks, with a follow-up extending to 12 weeks. The primary outcome was the improvement in the pain Visual Analogue Scale (VAS) score, whereas secondary outcomes included enhancements in the Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory-II (BDI-II), Revised Fibromyalgia Impact Questionnaire (FIQR), and 36-item Short-Form Health Survey (SF-36) scores. These measures were assessed at baseline and after 4, 8, and 12 weeks. The Patients’ Global Impression of Change (PGIC) was collected at week 12. Safety assessments were based on routine blood tests, urine tests, and liver and kidney function evaluations. Results: The improvement in the pain VAS score was significantly greater in the Roujin formula group than that in the placebo group at the 4-, 8-, and 12-week follow-ups (p < 0.05). At the 8-week treatment and the 12-week follow-up, improvements in PSQI and FIQR scores were also superior in the Roujin formula group compared with the placebo group (p < 0.05). There were no differences between the 2 groups in the improvement of BDI-II scores, SF-36 physical component summary, and mental component summary scores at any observation time points. At the 12-week follow-up, PGIC ratings were significantly better in the Roujin formula group (p < 0.05). There were 4 adverse events, all of which occurred in the Roujin formula group, including 3 cases of diarrhea and 1 case of stomach pain; no serious adverse events were reported during the study. Conclusion: The Roujin formula can effectively enhance the overall condition of FMS patients, relieve pain, improve sleep quality, and elevate physical and mental well-being. Only mild gastrointestinal reactions were observed. The Roujin formula may be a viable candidate for clinical implementation.

Objective:To analyze the association between healthcare workers mental health,institu-tional supplies and facilities,inter-organizational coordination during infectious disease outbreaks,and the healthcare institution resilience.Methods:An online questionnaire survey was conducted among the healthcare workforce from 146 institutions in Beijing from January 13,2023 to February 9,2023,and a total of 1 434 eligible respondents were included.The sample comprised 408 responses from tertiary hos-pitals,117 from secondary hospitals,and 909 from primary care institutions.The resilience indicator for healthcare institutions was defined as the degree to which medical services met patient demands,with in-fluencing factors including physical factors,such as material shortages and facility space adaptation or ex-pansion,organizational factors such as information sharing and patient referral,and psychological factors were evaluated using job satisfaction(extrinsic satisfaction,intrinsic satisfaction),burnout(emotional exhaustion,depersonalization,reduced personal accomplishment),and depression status.Ordered mul-ticlassification Logistic regression was used to examine the impact of various factors on the degree to which healthcare services met patient needs;additionally,demographic factors that might influence institutional resilience were controlled.Results:During the emergency response phase,93％of hospitals maintained the capacity to meet patient needs,though tertiary hospitals demonstrated significantly higher rates of service inadequacy(21.05％).Material shortages were reported across all institutions,with tertiary hos-pitals experiencing more frequent multi-item shortages.Inter-institutional collaboration patterns revealed substantial variation:87.50％of primary care facilities,42.86％of secondary hospitals,and 31.58％of tertiary hospitals.Healthcare workers across all levels reported mild depressive symptoms and moderate-to-severe burnout levels.Regression analysis showed high satisfaction(overall satisfaction β=0.04,ex-trinsic satisfaction β=0.06,and intrinsic satisfaction β=0.08),low degree of job burnout(emotional exhaustion β=-0.04,depersonalization β=-0.07 and reduced personal accomplishment β=0.01),low degree of depression(β=-0.06)were significantly associated with higher healthcare institution re-silience.In addition,material shortages were significantly associated with lower resilience,and renova-tion and expansion of treatment spaces,and information sharing,were all associated with higher resilience.Demographic factors(age,gender,marital status,educational background,etc.)had no sig-nificant impact on resilience.Conclusion:Mental health status significantly influences healthcare institu-tion resilience.As human resources constitute the core asset of healthcare institutions,strategic optimiza-tion of workforce allocation and psychological support interventions can effectively strengthen resilience.Moreover,healthcare institution resilience is positively impacted by orderly material supply chains,timely resource distribution,and adaptive reconfiguration of clinical spaces.Finally,facilitating information sharing also enhances institutional resilience.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

The polycomb repressive deubiquitinase complex(PR-DUB)is a member of the polycomb group protein involved in the epigenetic modification of chromosomes by regulating histone modifications.The polycomb repressive complex 1(PRC1)and PR-DUB complex protect active genes from aberrant si-lencing through a balance of ubiquitination and deubiquitination modifications of H2AK119Ub.The deu-biquitination function of the PR-DUB complex is associated with the promotion of gene activation and the establishment of transcriptionally permissive chromatin states,in addition to the activation of enhancers and the facilitation of DNA damage repair at double-strand breaks.Additional sex combs-like 1(ASXL1)serves as an epigenetic scaffold for the assembly of chromatin-modifying complexes and tran-scription factors involved in epigenetic regulation.BRCA1-associated protein 1(BAP1)acts as a deubiq-uitinating enzyme to remove ubiquitination modification of substrates.The PR-DUB complex consists of a core dimer and other cofactors.BAP 1 forms a core dimer with ASXL1,and other subunits interact to reg-ulate the targeting and functioning of the PR-DUB complex.ASXL1 and BAP1 are the two subunits most relevant to the deubiquitination function of the PR-DUB complex,and the DEUBAD domain of ASXL1 activates BAP1 to exert its deubiquitination function to hydrolyze H2AK119Ub1.Understanding the struc-ture and interaction mechanism of ASXL1 and BAP1 is essential to study the mechanism of deubiquitina-tion specific to the PR-DUB complex.In humans,mutations in the components of the PR-DUB complex frequently cause a variety of hematologic neoplasms.Mutations in the ASSXL1 gene often result in prema-ture termination of protein translation,mostly due to the absence of the C-terminal PHD domain.The in-teraction of mutated ASXL1 or BAP1,epigenetic factors,and targets or signaling pathways such as Akt/mTOR in PR-DUB is now considered as a possible mechanism to promote the development of hematologi-cal tumors.This is crucial for the research and development of new specific targeted therapeutic agents a-gainst potential therapeutic targets.In this paper,focusing on ASXL1 and BAP1,we will introduce the structure and function of the PR-DUB complex,and its mechanism in the occurrence of hematological tumor diseases,and systematically summarize the potential targeted therapeutic drugs,with a view to pro-viding scientific references for the research of the PR-DUB complex in the prevention and treatment of he-matological diseases.

This study aims to investigate the molecular mechanism of tanshinone Ⅱ_(A )(TaⅡ_A) combined with endothelial progenitor cells-derived exosomes(EPCs-exos) in protecting the aortic vascular endothelial cells(AVECs) from oxidative damage via the phosphatidylinositol 3 kinase(PI3K)/protein kinase B(Akt) pathway. The AVECs induced by 1-palmitoyl-2-(5'-oxovaleroyl)-sn-glycero-3-phosphocholine(POVPC) were randomly divided into model, TaⅡ_A, EPCs-exos, and TaⅡ_A+EPCs-exos groups, and the normal cells were taken as the control group. The cell counting kit-8(CCK-8) was used to examine the cell proliferation. The lactate dehydrogenase(LDH) cytotoxicity assay kit, Matrigel assay, DCFH-DA fluorescent probe, and laser confocal microscopy were employed to examine the LDH release, tube-forming ability, cellular reactive oxygen species(ROS) level, and endothelial cell skeleton morphology, respectively. The enzyme-linked immunosorbent assay was employed to measure the expression of interleukin(IL)-1β, IL-6, and tumor necrosis factor(TNF)-α. Real-time fluorescence quantitative PCR(qRT-PCR) and Western blot were employed to determine the mRNA and protein levels, respectively, of PI3K and Akt. Compared with the control group, the model group showed decreased cell proliferation and tube-forming ability, increased LDH release, elevated ROS level, obvious cytoskeletal disruption, increased expression of IL-1β, IL-6, and TNF-α, and down-regulated mRNA and protein levels of PI3K and Akt. Compared with the model group, TaⅡ_A or EPCs-exos alone increased the cell proliferation and tube-forming ability, reduced LDH release, lowered the ROS level, repaired the damaged skeleton, decreased the expression of IL-1β, IL-6, and TNF-α, and up-regulated the mRNA and protein levels of PI3K and Akt. TaⅡ_A+EPCs-exos outperformed TaⅡ_A or EPCs-exos alone in regulating the above indexes. The results demonstrated that TaⅡ_A and EPCs-exos exerted a protective effect on POVPC-induced AVECs by activating the PI3K/Akt pathway, and the combination of the two had stronger therapeutic effect.
Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Signal Transduction ; Reactive Oxygen Species/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/metabolism* ; Endothelium, Vascular ; Oxidative Stress ; Endothelial Progenitor Cells ; RNA, Messenger/metabolism* ; Abietanes

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.