ObjectiveTo investigate the mechanism of Qinggan Jianpi Houxue prescription against hepatic fibrosis in mice using metabolomics. MethodsA hepatic fibrosis mouse model was established by intraperitoneal injection of 20% carbon tetrachloride （CCl₄， diluted with olive oil at a ratio of 4∶1） at a dose of 2.5 mL·kg^-1 for 4 weeks. A total of 54 C57BL/6J mice were randomly divided into the blank control group， model group， Qinggan Jianpi Houxue prescription high-dose group （47.32 g·kg^-1）， medium-dose group （23.66 g·kg^-1）， low-dose group （11.83 g·kg^-1）， and Biejiajian pill group （1.365 g·kg^-1）， with 9 mice in each group. Concurrently with modeling， each administration group received the corresponding dose continuously for 4 weeks， once daily. After 4 weeks， liver tissues and blood samples were collected for liver function and hepatic pathological examinations. Non-targeted metabolomics was employed to detect hepatic metabolites. Principal component analysis （PCA）， partial least squares discriminant analysis （PLS-DA） and orthogonal partial least squares discriminant analysis （OPLS-DA） were performed to explore the metabolites and their involved metabolic pathways in the liver tissues of mice in the blank control group， model group and Qinggan Jianpi Houxue prescription high-dose group. Western blot validation was conducted at both the cellular and animal levels. ResultsCompared with the blank control group， the model group showed significantly increased levels of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） （P<0.01）， along with increased inflammatory cell infiltration， and formation of fibrous septa. The predominantly enriched pathway was the forkhead box O （FoxO） signaling pathway. Compared with the model group， the Qinggan Jianpi Huoxue prescription high-dose group exhibited significantly decreased ALT and AST levels （P<0.01）. In all administration groups of Qinggan Jianpi Huoxue prescription， inflammatory cell infiltration was reduced， fibrous septa were narrowed and diminished， collagen fibers were reduced， and the collagen area was significantly decreased. Non-targeted metabolomics identified 79 differential metabolites， among which 49 were up-regulated and 30 down-regulated， primarily enriched in the tricarboxylic acid （TCA） cycle and pyruvate metabolism pathways. Western blot results demonstrated that， compared with the blank control group， the model group exhibited significantly upregulated protein expressions of α-smooth muscle actin （α-SMA）， lactate dehydrogenase A （LDHA）， FoxO1， pyruvate kinase M2 （PKM2）， hexokinase 2 （HK2）， and phosphofructokinase 1 （PFK1） in liver tissues （P<0.05， P<0.01）. In hepatic stellate cells， the glucose concentration increased， and the protein expression of α-SMA， LDHA， FoxO1， PKM2， glucose transporter 1 （GLUT1）， and PFK1 were significantly up-regulated （P<0.05， P<0.01）. Conversely， compared with the model group， the Qinggan Jianpi Huoxue prescription high-dose group showed significantly downregulated protein expression of α-SMA， LDHA， FoxO1， PKM2， HK2， and PFK1 in liver tissues （P<0.05， P<0.01）. In hepatic stellate cells， the glucose concentration decreased， and the protein expression of α-SMA， LDHA， FoxO1， PKM2， GLUT1， and PFK1 were significantly down-regulated （P<0.05， P<0.01）. ConclusionQinggan Jianpi Huoxue prescription can alleviate the pathological progression of hepatic fibrosis in mice， potentially by regulating the TCA cycle and pyruvate metabolism through FoxO1， and by modulating glycolytic metabolic reprogramming in hepatic stellate cells， thereby promoting liver tissue repair.

Objective To investigate the direct stimulatory effects of calprotectin S100A8/A9 on hepatic stellate cells(HSCs)and underlying regulatory mechanisms.Methods Primary HSCs of mice were stimulated with S100A8/A9 heterodimer recombinant protein at 200 and 1000 ng/mL.Data on quantitative proteomics was obtained using the tandem mass tag(TMT)-labeled method before changes in the protein level of HSCs were analyzed.Differentially expressed proteins(DEPs)were screened using Significance B method and P＜0.05,followed by Reactome pathway enrichment analysis.Furthermore,protein-protein interactions between the DEPs enriched in the pathways were analyzed using the STRING database.Results The protein expression profile of HSCs was significantly altered after treatment with S100A8/A9 at 1000 ng/mL.Reactome pathway enrichment analysis revealed significant enrichment in such pathways as transforming growth factor-beta(TGF-β)signaling,nuclear factor kappa-B(NF-κB)signaling activation,cytokine-mediated immune regulation,and collagen biosynthesis.The analysis of protein-protein interactions identified NF-kappa-B transcription factor subunit(RELB),chemokine(C-X-C motif)ligand 10(CXCL10)and Notch receptor 1(NOTCH1)as key hub proteins in the regulatory network.Conclusion S100A8/A9 can directly stimulate the activation of HSCs,through NF-κB signaling,TGF-β signaling,and Notch signaling pathways potentially.This study sheds light on the mechanisms underlying the activation of HSCs stimulated by S100A8/A9.

BACKGROUND: China has made significant progress in medical accessibility and quality over the past decades, and quality improvements in gastroenterology and digestive endoscopy have been consistent. The study aimed to describe the status quo of gastroenterology and digestive endoscopy in the Chinese mainland based on the data from the National Clinical Improvement System (NCIS) and the Hospital Quality Monitoring System (HQMS). METHODS: Data were extracted from the NCIS and the HQMS. Data analysis included general information from the Department of Gastroenterology and Endoscopy centers, management of inpatients and outpatients, and annual volume and quality indicators of digestive endoscopy. Acute pancreatitis, gastrointestinal bleeding, inflammatory bowel disease, and cirrhosis were identified as priority diseases and were subjected to detailed analysis. RESULTS: Data from 4620 and 7074 hospitals were extracted from the NCIS and HQMS, respectively. In 2023, 9.6 gastroenterologists, 6.7 endoscopists, and 37.3 gastroenterology beds per hospital nationwide were observed, achieving 19,252.4 outpatient visits, 1615.2 hospitalizations (97.0 for acute pancreatitis, 146.1 for gastrointestinal bleeding, 40.2 for inflammatory bowel disease, and 111.4 for cirrhosis), and 9432.7 digestive endoscopic procedures per hospital. Overall, the quality of practice improved significantly. The proportion of early cancer among gastrointestinal cancers increased from 11.1% in 2015 to 23.4% in 2023, and the adenoma detection rate during colonoscopy increased from 19.3% in 2019 to 26.9% in 2023. Regarding priority diseases, hospitalizations increased, and 31-day unplanned readmission rates decreased between 2019 and 2023. The median hospitalization costs and median proportion of medication costs decreased for acute pancreatitis, gastrointestinal bleeding, and cirrhosis. However, it increased for inflammatory bowel disease. CONCLUSION This report evaluates the status quo and development of gastroenterology and digestive endoscopy in the Chinese mainland, providing guidance for future quality improvements.
Humans ; China ; Gastroenterology/statistics & numerical data* ; Gastrointestinal Hemorrhage ; Endoscopy, Gastrointestinal/statistics & numerical data* ; Endoscopy, Digestive System/statistics & numerical data*

Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA⁺ dental follicle stem cells (DFSCs) and CD31⁺ Endomucin⁺ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA⁺ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA⁺ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism* ; Humans ; Neovascularization, Physiologic/physiology* ; Dental Sac/cytology* ; Single-Cell Analysis ; Transcriptome ; Mesenchymal Stem Cells/metabolism* ; Bone Regeneration ; Animals ; Dental Papilla/cytology* ; Periodontium/physiology* ; Stem Cells/metabolism* ; Regeneration ; Angiogenesis

Mesangial cell proliferation is an early pathological indicator of diabetic nephropathy (DN). Growing evidence highlights the pivotal role of paired-related homeobox 1 (Prrx1), a key regulator of cellular proliferation and tissue differentiation, in various disease pathogenesis. Notably, Prrx1 is highly expressed in mesangial cells under DN conditions. Both in vitro and in vivo studies have demonstrated that Prrx1 overexpression promotes mesangial cell proliferation and contributes to renal fibrosis in db/m mice. Conversely, Prrx1 knockdown markedly suppresses hyperglycemia-induced mesangial cell proliferation and mitigates renal fibrosis in db/db mice. Mechanistically, Prrx1 directly interacts with the Yes-associated protein 1 (YAP) promoter, leading to the upregulation of YAP expression. This upregulation promotes mesangial cell proliferation and exacerbates renal fibrosis. These findings emphasize the crucial role of Prrx1 upregulation in high glucose-induced mesangial cell proliferation, ultimately leading to renal fibrosis in DN. Therefore, targeting Prrx1 to downregulate its expression presents a promising therapeutic strategy for treating renal fibrosis associated with DN.

Macrophages are the key cells in the process of hepatic fibrosis. Therefore, they promote the progression and regression of liver fibrosis by participating in all stages. The treatment of liver fibrosis is significantly identified by the main subtypes of intrahepatic macrophages. This article summarizes the types and functions of macrophages according to the inflammatory phenotype, origin, and surface markers and their effect on fibrosis; introduces the new subtypes and mode of action in the occurrence and development of hepatic fibrosis, as revealed by the single-cell sequencing technique; and analyzes the limitations of traditional antifibrotic therapy and the advantages of macrophage-targeting therapeutics, which could indicate the new direction for the study of new macrophage subtypes in hepatic fibrosis.

Macrophages are the key cells in the process of hepatic fibrosis. Therefore, they promote the progression and regression of liver fibrosis by participating in all stages. The treatment of liver fibrosis is significantly identified by the main subtypes of intrahepatic macrophages. This article summarizes the types and functions of macrophages according to the inflammatory phenotype, origin, and surface markers and their effect on fibrosis; introduces the new subtypes and mode of action in the occurrence and development of hepatic fibrosis, as revealed by the single-cell sequencing technique; and analyzes the limitations of traditional antifibrotic therapy and the advantages of macrophage-targeting therapeutics, which could indicate the new direction for the study of new macrophage subtypes in hepatic fibrosis.

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.How-ever,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive rela-tionship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 over-expression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

Objective To observe the neuropsychiatric behavioral performance of kainic acid(KA)-induced epilepsy rats;investigate gender differences in acute seizure and behavioral performance tasks relating to sense,motor,learning,and memory in the remission phase;and explore the potential neurobiological mechanisms of action.Methods Healthy SD rats aged 4 weeks were randomly divided into control and model groups,with 22 rats in each group(11 males and 11 females).An epileptic rat model was induced by intraperitoneal injection of KA.Seizure latency and frequency within 2 hours of KA injection were observed,seizure grade was assessed using the Racine grade standard,and a cortical electroencephalogram(EEG)was recorded.Behavioral performance was observed in a series of tasks including open field testing,balance beam walking,elevated plus maze,Y-maze,and novel object recognition.The level of GABA in the hippocampus was detected by ELISA,injury to hippocampal neurons was observed by Nissl staining,and the protein expression of synapsin-1 and synaptotagmin 1 in the hippocampus were detected by Western Blot.Results Both male and female rats presented typical epileptic behaviors after KA injection.However,compared with the effects in males,the latency of the first seizure(P=0.014)and Ⅳ～Ⅴ grading in female model rats were more pronounced(P＜0.01),and the frequency of epileptic seizures within 2 hours was significantly reduced(P=0.019).In the open field testing,KA-induced epileptic rats presented more motor but fewer hedonic behaviors,as indicated by the decrease in total movement distance in the central area,compared with the control group.Moreover,grooming frequency was significantly reduced in the female model rats compared with not only that in the control but also that in male model rats(P＜0.01).The model rats spent more time completing and had a higher score in the balance beam walking task,indicating their poorer stability and balance.In the elevated plus maze,the exploration times of male model rats in the closed arm was increased.The preference index of rats for the novel arm or object decreased in the Y-maze and novel object recognition,suggesting impairments to their learning and memory abilities.Moreover,neuronal injuries were found in the hippocampus of the model rats that were accompanied with a decline in GABA concentration and protein expression of synapsin-1 and synaptotagmin 1,with no gender differences.Conclusions Intraperitoneal injection of KA successfully induced an epilepsy rat model.However,there was a gender difference in the characters of acute seizures and performance of sensory,motor,and learning memory during epileptic remission.There was no gender differences in the hippocampal GABA concentration or expression of synaptic plasticity-related proteins,and thus no evidence was found for the mechanisms underlying the gender differences.

Objective To systematically evaluate the efficacy and safety of finerenone in treating the pa-tients with heart failure.Methods The databases of Pubmed,Embase,Cochrane Library,Web of Science and Scopus were retrieved.The retrieval time was from the establishment of the database to April 21,2024.The data of randomized controlled trials(RCTs)on finerenone in treating heart failure were collected.After screening the literatures and extracting the data,the Jadad scale and Cochrane bias risk assessment tool were used to evaluate the quality of included literatures.The RevMan5.4 software was adopted to conduct the meta analysis.Results Five RCTs involving in a total of 2 518 patients with heart failure were finally included.In the aspect of effectiveness outcome indicators,there was no statistical difference in improving NT-proBNP lev-els and cardiovascular mortality risk between finerenone and eplerenone(P＞0.05).Compared with placebo,finerenone could reduce the ris k of first hospitalization due to heart failure(RR=0.68,95％CI:0.49-0.94,P=0.02)and the risk of cardiovascular composite endpoint event(RR=0.79,95％CI:0.64-0.98,P=0.03).In the aspects of safe outcome indicators,the occurrence risk of adverse events of finerenone was slight-ly lower than that of placebo(RR=0.95,95％CI:0.90-1.01),the risk of finerenone induced hyperkalemia was slightly lower than that of eplerenone(RR=0.90,95％CI:0.46-1.76),but the difference was not statis-tically significant(P＞0.05).Finerenone had a higher risk for causing hyperkalemia than placebo(RR=2.07,95％CI:1.46-2.95,P＜0.01).Conclusion Finerenone could reduce the NT-proBNP level,risk of first time HHF and the cardiovascular composite endpoint event,moreover its safe and tolerance are good.