Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is the primary cause of mortality in sepsis, with its core pathophysiological mechanism being severe ischemia and hypoxia in critical units—composed of microcirculation and the mitochondria of functional cells—resulting from disruptions in blood flow and oxygen flow following a dysregulated host response. Due to the systemically convergent yet clinically heterogeneous nature of the host response, current understanding and management strategies for hemodynamics remain inconsistent, often leading to inadequate resuscitation or overtreatment. To improve the quality of care, based on a systematic review of the "blood flow-oxygen flow" theory, an expert panel emphasizes reevaluating septic shock from an integrated perspective of blood flow and oxygen flow, and has formulated the Expert Consensus on Blood Flow and Oxygen Delivery Phenotyping and Clinical Management of Septic Shock (2025). The consensus proposes that clinical typing of blood flow-oxygen flow should comprehensively consider cardiac function, vascular tone, oxygen flow utilization status in critical units, and disease trajectory, while optimizing subtype identification by integrating host response phenotypes and artificial intelligence technologies. It advocates establishing a continuous assessment system through multi-site oxygen flow monitoring for organ perfusion, peripheral perfusion monitoring, and critical care ultrasound. Under the framework of the "critical care triangle", the consensus promotes the implementation of individualized, bundled management strategies, providing guidance for multiple management points to restore blood flow-oxygen flow matching, reduce the risk of organ failure, and decrease patient mortality.

Objective To elucidate the changes in the gut microbiota and molecular mechanism of huaier in enhancing the efficacy of oxaliplatin (OXA) chemotherapy in gastric cancer (GC). Methods The effects of huaier on the gut microbiota structure and intestinal barrier function in MKN45-bearing mice were analyzed by using 16S rRNA sequencing, RT-qPCR, and IHC. UPLC-MS and network pharmacology, as well as in vivo experimental approaches, were employed to investigate the key bioactive constituents of huaier systematically and elucidate the underlying mechanisms by which huaier exerts therapeutic effects against GC. The expression of the PI3K/AKT/SREBP pathway was detected in cancer cells and tissues via Western blot analysis. The safety profile of huaier combined with OXA was verified through serum biochemistry and HE-stained tissue section analyses. Results Huaier inhibited the PI3K/AKT/SREBP pathway by increasing the abundance of Akkermansia muciniphila, reduced lipid droplet deposition, and ultimately enhanced the sensitivity to OXA in the treatment of GC. Conclusion This study demonstrates the value of huaier in gastric cancer treatment by enhancing chemosensitivity and provides novel insights into its systemic therapeutic effects through molecular mechanisms and gut microbiota modulation.

OBJECTIVE: To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. METHODS: Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). RESULTS: In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. CONCLUSION This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families.
Humans ; Female ; Male ; Pedigree ; Exostoses, Multiple Hereditary/diagnosis* ; N-Acetylglucosaminyltransferases/genetics* ; Adult ; Exostosin 1 ; Asian People/genetics* ; Genetic Testing ; Exostosin 2 ; Mutation ; China ; Prenatal Diagnosis ; Pregnancy ; Genetic Counseling ; Preimplantation Diagnosis ; Exome Sequencing ; East Asian People

Background Silicosis, caused by inhalation of silica (SiO₂) dust, remains the most prevalent occupational pneumoconiosis in China. While galectin-3 (Gal-3) is known to play pro-inflammatory and pro-fibrotic roles in various diseases, its specific mechanism in the pathogenesis of silicosis has not been fully clarified. Objective To investigate the role and underlying mechanisms of Gal-3 in silicosis using clinical samples of silicosis and a silicosis mouse model. Methods Lung nodule biopsy samples were collected from patients with stage III pneumoconiosis. Concurrently a silicosis mouse model was constructed via non-exposed tracheal intubation with instillation of a SiO₂ suspension. The expression levels of Gal-3 mRNA and protein in the lung tissues of the silicosis model mice were then detected using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) staining. Single-cell transcriptomic sequencing (scRNA-seq) was performed on both human and murine lung samples to analyze the expression of the Gal-3-encoding gene Lgals3 across different cell types. In vitro, RAW264.7 macrophages were treated with varying concentrations of SiO₂ suspension for 24 h and 48 h; the expression levels of Gal-3 mRNA and protein were measured by RT-qPCR and Western blot. The Gal-3 inhibitor TD139 was used to intervene in the SiO₂-induced in vitro macrophage model, and Western blot was used to detect the intracellular expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1). Finally, mouse embryonic lung fibroblasts NIH/3T3 and Mlg2908 were treated with varying concentrations of recombinant mouse Gal-3 protein (rmGal-3) for 48 h, and Western blot was used to detect the expression of fibrosis markers [(Collagen I, Collagen III, Fibronectin, and α smooth muscle actin (α-SMA)] and proteins associated with the TGF-β1/Smads signaling pathway. Results RT-qPCR and IHC staining showed that both the gene and protein expression levels of Gal-3 were significantly elevated at all consecutive time points in the silicosis mouse model (P < 0.05). scRNA-seq revealed that Lgals3 was aberrantly highly expressed in lung tissues from pneumoconiosis patients and silicosis mouse models, with the highest expression observed in macrophages. After treatment of macrophages with different concentrations of SiO₂ for 24 h and 48 h, the mRNA and protein expression levels of Gal-3 were significantly upregulated compared with the control group (P < 0.05). Following TD139 intervention, the protein expression levels of IL-1β, TNF-α, and TGF-β1 in dust-exposed macrophages were markedly downregulated (P < 0.0001). After 48 h of stimulation with rmGal-3, the protein expression levels of Collagen I, Fibronectin, and α-SMA in mouse embryonic lung fibroblasts (NIH/3T3 and Mlg2908) were significantly increased in all treatment groups compared with the control group (P < 0.01). Moreover, Gal-3 treatment markedly upregulated TGF-β1 protein expression in Mlg2908 cells and enhanced the phosphorylation levels of Smad2 and Smad3 (P < 0.0001). Conclusion Gal-3 is abnormally expressed in silicotic lung tissues, which primarily originates from macrophages, and inhibition of Gal-3 suppresses SiO₂-induced inflammatory and pro-fibrotic responses. In addition, Gal-3 promotes fibroblast differentiation and extracellular matrix production by activating the TGF-β1/Smads signaling pathway.

Background Silicosis, caused by inhalation of silica (SiO₂) dust, remains the most prevalent occupational pneumoconiosis in China. While galectin-3 (Gal-3) is known to play pro-inflammatory and pro-fibrotic roles in various diseases, its specific mechanism in the pathogenesis of silicosis has not been fully clarified. Objective To investigate the role and underlying mechanisms of Gal-3 in silicosis using clinical samples of silicosis and a silicosis mouse model. Methods Lung nodule biopsy samples were collected from patients with stage III pneumoconiosis. Concurrently a silicosis mouse model was constructed via non-exposed tracheal intubation with instillation of a SiO₂ suspension. The expression levels of Gal-3 mRNA and protein in the lung tissues of the silicosis model mice were then detected using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) staining. Single-cell transcriptomic sequencing (scRNA-seq) was performed on both human and murine lung samples to analyze the expression of the Gal-3-encoding gene Lgals3 across different cell types. In vitro, RAW264.7 macrophages were treated with varying concentrations of SiO₂ suspension for 24 h and 48 h; the expression levels of Gal-3 mRNA and protein were measured by RT-qPCR and Western blot. The Gal-3 inhibitor TD139 was used to intervene in the SiO₂-induced in vitro macrophage model, and Western blot was used to detect the intracellular expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1). Finally, mouse embryonic lung fibroblasts NIH/3T3 and Mlg2908 were treated with varying concentrations of recombinant mouse Gal-3 protein (rmGal-3) for 48 h, and Western blot was used to detect the expression of fibrosis markers [(Collagen I, Collagen III, Fibronectin, and α smooth muscle actin (α-SMA)] and proteins associated with the TGF-β1/Smads signaling pathway. Results RT-qPCR and IHC staining showed that both the gene and protein expression levels of Gal-3 were significantly elevated at all consecutive time points in the silicosis mouse model (P < 0.05). scRNA-seq revealed that Lgals3 was aberrantly highly expressed in lung tissues from pneumoconiosis patients and silicosis mouse models, with the highest expression observed in macrophages. After treatment of macrophages with different concentrations of SiO₂ for 24 h and 48 h, the mRNA and protein expression levels of Gal-3 were significantly upregulated compared with the control group (P < 0.05). Following TD139 intervention, the protein expression levels of IL-1β, TNF-α, and TGF-β1 in dust-exposed macrophages were markedly downregulated (P < 0.0001). After 48 h of stimulation with rmGal-3, the protein expression levels of Collagen I, Fibronectin, and α-SMA in mouse embryonic lung fibroblasts (NIH/3T3 and Mlg2908) were significantly increased in all treatment groups compared with the control group (P < 0.01). Moreover, Gal-3 treatment markedly upregulated TGF-β1 protein expression in Mlg2908 cells and enhanced the phosphorylation levels of Smad2 and Smad3 (P < 0.0001). Conclusion Gal-3 is abnormally expressed in silicotic lung tissues, which primarily originates from macrophages, and inhibition of Gal-3 suppresses SiO₂-induced inflammatory and pro-fibrotic responses. In addition, Gal-3 promotes fibroblast differentiation and extracellular matrix production by activating the TGF-β1/Smads signaling pathway.

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Real-world study (RWS), based on multi-source data from real medical environments, is gradually becoming an important supplement to traditional randomized controlled trials, and its application in the field of transfusion medicine is becoming increasingly widespread. This article systematically reviews the definition and methodological system of RWS, examines its application cases in clinical blood transfusion research, and discusses the advantages, limitations, and future research directions of RWS, aiming to provide a reference for evidence-based research in blood transfusion medicine.

Real-world study (RWS), based on multi-source data from real medical environments, is gradually becoming an important supplement to traditional randomized controlled trials, and its application in the field of transfusion medicine is becoming increasingly widespread. This article systematically reviews the definition and methodological system of RWS, examines its application cases in clinical blood transfusion research, and discusses the advantages, limitations, and future research directions of RWS, aiming to provide a reference for evidence-based research in blood transfusion medicine.

BackgroundRumination can play a certain degree role of psychological adjustment in cancer patients. Previous studies have focused on studying the level of rumination in a single type of cancer patient， but there is a lack of comprehensive investigation and influencing factor research on rumination levels in different types of cancer patients. ObjectiveTo explore the level of rumination and its influencing factors among middle-advanced cancer inpatients， so as to provide certain guidance for targeted psychological care in clinical practice. MethodsFrom January 2021 to December 2022， a systematic sampling technique was used to recruit 346 patients with TNM stage III or above tumors hospitalized in Nuclear Industry 416 Hospital， Chengdu Sixth People's Hospital and the First People's Hospital of Yibin. All individuals were assessed using Perceived Social Support Scale （PSSS） and the Chinese version of Event-Related Ruminant Inventory （C-ERRI）， and Logistic regression analysis was utilized to identify the influencing factors of rumination. ResultsIn terms of C-ERRI， patients scored （15.59±5.61） on intrusive rumination and （14.59±5.43） on deliberate rumination. Education levels of junior high school/high school/vocational training school （OR=0.817， P<0.01） and junior college and above （OR=0.579， P<0.05） were the protective factors of intrusive rumination， whereas annual personal incomes of <10 000 yuan （OR=4.918， P<0.01） or 10 000~50 000 yuan （OR=2.076， P<0.01） and low （OR=6.882， P<0.01） or middle （OR=3.114， P<0.01） level of social support were the risk factors of intrusive rumination. For deliberate rumination， education levels of junior high school/high school/vocational training school （OR=0.574， P<0.01） and junior college and above （OR=0.449， P<0.05） were the protective factors， and low （OR=1.391， P<0.01） or middle （OR=1.161， P<0.05） levels of social support were the risk factors. ConclusionThe level of intrusive rumination of inpatients with middle-advanced cancer is related to education level， economic status and social support， furthermore， the level of deliberate rumination is related to the educational level and social support. ［Funded by Medical Research Project of Chengdu Health Commission （ number， 2020119）］