Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.

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.

Objective:To investigate the clinical efficacy of electrical stimulation, biofeedback, and radiofrequency therapy in combination for the treatment of pelvic floor dysfunction.Methods:A total of 144 patients with pelvic floor dysfunction who received treatment in Lianyungang Maternal and Child Health Hospital from June 2020 to June 2022 were included in this prospective randomized controlled study. They were randomly assigned to undergo electrical stimulation combined with biofeedback (electrical stimulation group, n = 48), treatment with a novel radiofrequency technique (radiofrequency therapy group, n = 48), or electrical stimulation, biofeedback, and treatment with a novel radiofrequency technique (combined group, n = 48). Pelvic floor dysfunction, stress urinary incontinence, and pelvic floor myofascial pain were compared among the three groups. Pelvic organ prolapse quantification was compared among the three groups before and after treatment. Quality of life was evaluated. Results:The effective rates of treatment against pelvic floor dysfunction, stress urinary incontinence, and pelvic floor myofascial pain in the combined group were 95.83% (46/48), 97.92% (47/48), and 93.75% (45/48), respectively, which were significantly higher than 79.17% (38/48), 79.17% (38/48), 77.08% (37/48) in the radiofrequency group, and 75.00% (36/48), 77.08% (37/48), 72.92% (35/48) in the electrical stimulation group ( χ2 = 8.40, 9.77, 7.66, all P < 0.05). After treatment, the severity of pelvic organ prolapse in the combined group was significantly milder than that in the novel radiofrequency technique group and electrical stimulation group (both P < 0.05). The scores of the pelvic floor dysfunction questionnaire and urinary incontinence questionnaire in the combined group were significantly lower than those in the radiofrequency therapy group and the electrical stimulation group (both P < 0.05). Conclusion:Electrical stimulation, biofeedback, and radiofrequency therapy in combination can greatly strengthen the muscle strength of the pelvic floor, relieve urinary incontinence, reduce pelvic floor myofascial pain, and improve the quality of life of patients with pelvic floor dysfunction.

Farnesoid X receptor (FXR) is widely accepted as a promising target for various liver diseases; however, panels of ligands in drug development show limited clinical benefits, without a clear mechanism. Here, we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury, which represents the major culprit that limits the clinical benefits of FXR agonists against liver diseases. Upon inflammatory and apoptotic stimulation, enhanced FXR acetylation at K217, closed to the nuclear location signal, blocks its recognition by importin KPNA3, thereby preventing its nuclear import. Concomitantly, reduced phosphorylation at T442 within the nuclear export signals promotes its recognition by exportin CRM1, and thereby facilitating FXR export to the cytosol. Acetylation governs nucleocytoplasmic shuttling of FXR, resulting in enhanced cytosolic retention of FXR that is amenable to degradation by CHIP. SIRT1 activators reduce FXR acetylation and prevent its cytosolic degradation. More importantly, SIRT1 activators synergize with FXR agonists in combating acute and chronic liver injuries. In conclusion, these findings innovate a promising strategy to develop therapeutics against liver diseases by combining SIRT1 activators and FXR agonists.

Disturbance of macrophage-associated lipid metabolism plays a key role in atherosclerosis. Crosstalk between autophagy deficiency and inflammation response in foam cells (FCs) through epigenetic regulation is still poorly understood. Here, we demonstrate that in macrophages, oxidized low-density lipoprotein (ox-LDL) leads to abnormal crosstalk between autophagy and inflammation, thereby causing aberrant lipid metabolism mediated through a dysfunctional transcription factor EB (TFEB)-P300-bromodomain-containing protein 4 (BRD4) axis. ox-LDL led to macrophage autophagy deficiency along with TFEB cytoplasmic accumulation and increased reactive oxygen species generation. This activated P300 promoted BRD4 binding on the promoter regions of inflammatory genes, consequently contributing to inflammation with atherogenesis. Particularly, ox-LDL activated BRD4-dependent super-enhancer associated with liquid-liquid phase separation (LLPS) on the regulatory regions of inflammatory genes. Curcumin (Cur) prominently restored FCs autophagy by promoting TFEB nuclear translocation, optimizing lipid catabolism, and reducing inflammation. The consequences of P300 and BRD4 on super-enhancer formation and inflammatory response in FCs could be prevented by Cur. Furthermore, the anti-atherogenesis effect of Cur was inhibited by macrophage-specific Brd4 overexpression or Tfeb knock-out in Apoe knock-out mice via bone marrow transplantation. The findings identify a novel TFEB-P300-BRD4 axis and establish a new epigenetic paradigm by which Cur regulates autophagy, inhibits inflammation, and decreases lipid content.

Gestational diabetes mellitus is one of the most common complications of pregnancy. Poor control of maternal blood glucose during pregnancy seriously threatens the short-term and long-term health of pregnant women and fetuses. Standardized blood glucose monitoring during pregnancy can significantly reduce the short-term and long-term complications of gestational diabetes mellitus mothers and infants, and blood glucose self-monitoring is currently the most widely used and most convenient blood glucose monitoring method in clinical practice. This article reviews the related concepts, main monitoring content, current situation, influencing factors and improvement strategies of blood glucose self-monitoring in patients with gestational diabetes mellitus. The aim is to raise the attention of medical and nursing staff to blood glucose self-monitoring in patients with gestational diabetes mellitus, and provide a theoretical basis for the prevention and treatment of adverse outcomes of gestational diabetes mellitus.

Objective:To evaluate the effect of using a walking support band on the gait of stroke survivors.Methods:Sixty stroke survivors were randomly divided into a walking support band group ( n=20), an ankle foot orthosis (AFO) group ( n=20) and a conventional rehabilitation group ( n=20). All three groups received conventional rehabilitation therapy, while the AFO group members were additionally provided with an ankle-foot orthosis and the walking support band group members received training wearing a walking support band. Before and after 4 weeks of treatment, all three groups were evaluated using three-dimensional gait analysis. Results:A total of 57 patients finished the study. After the interventions, the average step speed, frequency and step length of the three groups had all increased significantly, while the average stride width, the percentage of double stance phase, unaffected and affected side stance phase, and the ratio between unaffected and affected side stance phase had all decreased significantly. After the intervention, the average step speed, frequency and length of the AFO and walking support band groups had increased significantly compared with the conventional rehabilitation group, while the average stride width of the AFO group, and the stride width, the percentage of double stance phase and unaffected side stance phase of the walking support band group had decreased significantly. After the treatment, the average percentages of double stance phase and unaffected side stance phase of the walking support band group had decreased significantly more than in the AFO group.Conclusions:A walking support band can significantly improve the abnormal gait of stroke survivors and is superior to an ankle-foot orthosis when combined with conventional rehabilitation therapy.

Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl-injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNF (CHX/TNF)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

Objective Using meta-analysis method to compare the effect of liberal and restrictive transfusion strategies on the prognosis of adult patients undergoing cardiac surgery,and to provide evidence for evidence-based medicine.Methods By using the Cochrane system evaluation method,the database of Chinese and foreign countries,Chinese biomedical literature database,Chinese journal full-text database and so on were searched by computer.To search the literature from 1970 to 2018,and to collect clinical randomized controlled trials on blood transfusion strategy and prognosis in adult patients undergoing cardiac surgery.According to the evaluation method of Cochrane system,the effective data extracted is analyzed by meta with RevMan5.3 software.Results A total of 2 863 patients were included in 9 studies.Meta-analysis results showed that the death toll on 30 days after operation (RR value:1.02,95 ％ CI:0.79-1.32,I2 =2％,P =0.86),acute renal damage,infection,acute renal injury,pulmonary complications and hospital stay time were no statistical difference,but ICU retention time(RR value:-33.35,95％ CI:-61.7-1.01,I2 =38％,P =0.04) in the restrictive transfusion policy group was significantly lower than that of liberal blood transfusion strategy group.Conclusion The use of liberal or restrictive blood transfusion strategy in adult cardiac surgery has no significant impact on the prognosis and complications,but it can reduce the retention time of ICU after operation and significantly reduce the use of blood products and medical costs.

Objective To explore the relationship between individual difference in heparin sensitivity and postoperative bleeding,and lay the foundation for individualized heparin anticoagulant strategy. Methods A total of 120 patients undergoing cardiopulmonary bypass were enrolled in this study. Activated clotting time(ACT)of whole blood was established,and 2.5 mg/kg first heparin was given to the sternum.The value of ACT was measured after five minutes.The patients were divided into 3 groups according to the results of the first measured heparin.If the ACT value did not meet the transfer requirements,heparin 0.5 mg/kg was added,and the amount of bleeding was recorded. The general information of patients,blood transfusion and drainage and other information 24 hours postoperatively were recorded. Results Drainage volume 24 hours after the operation in 3 groups was statistically significant(P < 0.05). Drainage volume 24 hours after the operation in group with ACT>750 s and group with ACT<480 s was significantly higher than that in group with ACT ranging from 480 s to 750 s but the difference be-tween the group with ACT < 480 s and the group with ACT > 750 s was not statistically significant(P > 0.05). Conclusions Heparin sensitivity is associated with postoperative bleeding in patients with cardiopulmonary by-pass surgery,and patients with ACT ranging from 480 s to750 s have the lowest amount of bleeding.