The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), C3 glomerular disease (C3G) and age-related macular degeneration (AMD). Complement factor B (CFB) is a trypsin-like serine protein that circulates in the human bloodstream in a latent form. As a key node of the alternative pathway, it is an important target for the treatment of diseases mediated by the complement system. With the successful launch of iptacopan, the CFB small molecule inhibitors has become a current research hotspot, a number of domestic and foreign pharmaceutical companies are actively developing CFB small molecule inhibitors. In this paper, the research progress of CFB small molecule inhibitors in recent years is systematically summarized, the representative compounds and their activities are introduced according to structural types and design ideas, so as to provide reference and ideas for the subsequent research on CFB small molecule inhibitors.

BACKGROUND: The main cause of restenosis after percutaneous transluminal angioplasty (PTA) is the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). Lin28a has been reported to play critical regulatory roles in this process. However, whether CCAAT/enhancer-binding proteins β (C/EBPβ) binds to the Lin28a promoter and drives the progression of restenosis has not been clarified. Therefore, in the present study, we aim to clarify the role of C/EBPβ-Lin28a axis in restenosis. METHODS: Restenosis and atherosclerosis rat models of type 2 diabetes ( n   =  20, for each group) were established by subjecting to PTA. Subsequently, the difference in DNA methylation status and expression of C/EBPβ between the two groups were assessed. EdU, Transwell, and rescue assays were performed to assess the effect of C/EBPβ on the proliferation and migration of VSMCs. DNA methylation status was further assessed using Methyltarget sequencing. The interaction between Lin28a and ten-eleven translocation 1 (TET1) was analysed using co-immunoprecipitation (Co-IP) assay. Student's t -test and one-way analysis of variance were used for statistical analysis. RESULTS: C/EBPβ expression was upregulated and accompanied by hypomethylation of its promoter in restenosis when compared with atherosclerosis. In vitroC/EBPβ overexpression facilitated the proliferation and migration of VSMCs and was associated with increased Lin28a expression. Conversely, C/EBPβ knockdown resulted in the opposite effects. Chromatin immunoprecipitation assays further demonstrated that C/EBPβ could directly bind to Lin28a promoter. Increased C/EBPβ expression and enhanced proliferation and migration of VSMCs were observed after decitabine treatment. Further, mechanical stretch promoted C/EBPβ and Lin28a expression accompanied by C/EBPβ hypomethylation. Additionally, Lin28a overexpression reduced C/EBPβ methylation via recruiting TET1 and enhanced C/EBPβ-mediated proliferation and migration of VSMCs. The opposite was noted in Lin28a knockdown cells. CONCLUSION Our findings suggest that the C/EBPβ-Lin28a axis is a driver of restenosis progression, and presents a promising therapeutic target for restenosis.
Animals ; Cell Proliferation/genetics* ; Cell Movement/genetics* ; Muscle, Smooth, Vascular/metabolism* ; Rats ; DNA Methylation/physiology* ; CCAAT-Enhancer-Binding Protein-beta/genetics* ; Male ; Myocytes, Smooth Muscle/cytology* ; Rats, Sprague-Dawley ; RNA-Binding Proteins/genetics* ; Cells, Cultured ; Coronary Restenosis/metabolism*

This study investigates the mechanism by which Xintong Granules improve myocardial ischemia-reperfusion injury(MIRI) through the regulation of gut microbiota and their metabolites, specifically short-chain fatty acids(SCFAs). Rats were randomly divided based on body weight into the sham operation group, model group, low-dose Xintong Granules group(1.43 g·kg~(-1)·d~(-1)), medium-dose Xintong Granules group(2.86 g·kg~(-1)·d~(-1)), high-dose Xintong Granules group(5.72 g·kg~(-1)·d~(-1)), and metoprolol group(10 mg·kg~(-1)·d~(-1)). After 14 days of pre-administration, the MIRI rat model was established by ligating the left anterior descending coronary artery. The myocardial infarction area was assessed using the 2,3,5-triphenyltetrazolium chloride(TTC) staining method. Apoptosis in tissue cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay. Pathological changes in myocardial cells and colonic tissue were observed using hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), creatine kinase MB isoenzyme(CK-MB), and cardiac troponin T(cTnT) in rat serum were quantitatively measured using enzyme-linked immunosorbent assay(ELISA) kits. The activities of lactate dehydrogenase(LDH), creatine kinase(CK), and superoxide dismutase(SOD) in myocardial tissue, as well as the level of malondialdehyde(MDA), were determined using colorimetric assays. Gut microbiota composition was analyzed by 16S rDNA sequencing, and fecal SCFAs were quantified using gas chromatography-mass spectrometry(GC-MS). The results show that Xintong Granules significantly reduced the myocardial infarction area, suppressed cardiomyocyte apoptosis, and decreased serum levels of pro-inflammatory cytokines(TNF-α, IL-1β, and IL-6), myocardial injury markers(CK-MB, cTnT, LDH, and CK), and oxidative stress marker MDA. Additionally, Xintong Granules significantly improved intestinal inflammation in MIRI rats, regulated gut microbiota composition and diversity, and increased the levels of SCFAs(acetate, propionate, isobutyrate, etc.). In summary, Xintong Granules effectively alleviate MIRI symptoms. This study preliminarily confirms that Xintong Granules exert their inhibitory effects on MIRI by regulating gut microbiota imbalance and increasing SCFA levels.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Myocardial Reperfusion Injury/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Apoptosis/drug effects* ; Humans ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/genetics* ; Malondialdehyde/metabolism*

OBJECTIVE: To elucidate the specific mechanisms by which electroacupuncture (EA) alleviates anxiety and fear behaviors associated with posttraumatic stress disorder (PTSD), focusing on the role of lipocalin-2 (Lcn2). METHODS: The PTSD mouse model was subjected to single prolonged stress and shock (SPS&S), and the animals received 15 min sessions of EA at Shenmen acupoint (HT7). Behavioral tests were used to investigate the effects of EA at HT7 on anxiety and fear. Western blotting and enzyme-linked immunosorbent assay were used to quantify Lcn2 and inflammatory cytokine levels in the prefrontal cortex (PFC). Additionally, the activity of PFC neurons was evaluated by immunofluorescence and in vivo electrophysiology. RESULTS: Mice subjected to SPS&S presented increased anxiety- and fear-like behaviors. Lcn2 expression in the PFC was significantly upregulated following SPS&S, leading to increased expression of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6 and suppression of PFC neuronal activity. However, EA at HT7 inhibited Lcn2 release, reducing neuroinflammation and hypoexcitability in the PFC. Lcn2 overexpression mitigated the effects of EA at HT7, resulting in anxiety- and fear-like behaviors. CONCLUSION EA at HT7 can ameliorate PTSD-associated anxiety and fear, and its mechanism of action appears to involve the inhibition of Lcn2-mediated neural activity and inflammation in the PFC. Please cite this article as: Yang YD, Zhong W, Chen M, Tang QC, Li Y, Yao LL, et al. Electroacupuncture alleviates behaviors associated with posttraumatic stress disorder by modulating lipocalin-2-mediated neuroinflammation and neuronal activity in the prefrontal cortex. J Integr Med. 2025; 23(5):537-547.
Electroacupuncture ; Stress Disorders, Post-Traumatic/metabolism* ; Animals ; Lipocalin-2/metabolism* ; Prefrontal Cortex/physiopathology* ; Male ; Mice ; Neurons/physiology* ; Disease Models, Animal ; Fear ; Behavior, Animal ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/metabolism* ; Anxiety/therapy* ; Acupuncture Points

Aconiti Lateralis Radix Praeparata (Fuzi) represents a significant traditional Chinese medicine (TCM) that exhibits both notable pharmacological effects and toxicity. Various processing methods are implemented to reduce the toxicity of raw Fuzi by modifying its toxic and effective components, primarily diterpenoid alkaloids. To comprehensively analyze the chemical variations between different Fuzi products, ultra-high performance liquid chromatography-linear ion trap quadrupole Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS) was employed to systematically characterize Shengfuzi, Heishunpian and Baifupian. A total of 249 diterpenoid alkaloids present in Shengfuzi were identified, while only 111 and 61 in Heishunpian and Baifupian were detected respectively, indicating substantial differences among these products. An untargeted metabolomics approach combined with multivariate statistical analysis revealed 42 potential chemical markers. Through subsequent validation using 52 batches of commercial Heishunpian and Baifupian samples, 8 robust markers distinguishing these products were identified, including AC1-propanoic acid-3OH, HE-glucoside, HE-hydroxyvaleric acid-2OH, dihydrosphingosine, N-dodecoxycarbonylvaline and three unknown compounds. Additionally, the MS imaging (MSI) technique was utilized to visualize the spatial distribution of chemical constituents in raw Fuzi, revealing how different processing procedures affect the chemical variations between Heishunpian and Baifupian. The distribution patterns of different diterpenoid alkaloid subtypes partially explained the chemical differences among products. This research provides valuable insights into the material basis for future investigations of different Fuzi products.
Diterpenes/chemistry* ; Alkaloids/chemistry* ; Chromatography, High Pressure Liquid/methods* ; Aconitum/chemistry* ; Drugs, Chinese Herbal/chemistry* ; Metabolomics ; Mass Spectrometry/methods* ; Plant Roots/chemistry* ; Molecular Structure

Objective To explore the molecular mechanism of miR-125b promoting invasion,metastasis and epithelial-mesenchymal transition(EMT)of gastric cancer cells.Methods The expression of miR-125b in gastric cancer and its adjacent tissues was studied by qRT-PCR.After upregulating or downregulating miR-125b in gastric cancer cells,the protein expressions of DKK3 and SERPINA4 were detected by Western blotting.Dual luciferase reporting assay was used to verify whether miR-125b can target DKK3 and SERPINA4.MKN45 cells were co-transfected with miR-125b inhibitor and target gene siRNA.Migration and invasion experiments were conducted to explore whether miR-125b can regulate the biological function of MKN45 cells through DKK3 and SERPINA4.Then,the regulatory mechanism of SRF on miR-125b was investigated.Finally,by in vivo experiments,the expression of SRF in gastric cancer cells was upregulated or downregulated by lentivirus transfection;the number of lung metastases in nude mice was detected to explore the effect of SRF on gastric cancer cell metastasis.Results In this study,the expression of miR-125b increased in gastric cancer tissues,which was correlated with clinical stage and lymph node metastasis.Dual luciferase reporting experiments showed that DKK3 and SERPINA4 were the direct targets of miR-125b in gastric cancer cells,and could activate the Wnt/β-catenin signaling pathway,thereby promoting the transcription process of EMT-related transcription factors Twist1 and Slug,inducing the occurrence of EMT,and promoting the metastasis of gastric cancer.In vitro and in vivo experiments confirmed that SRF promoted the invasion and metastasis of gastric cancer cells by positively regulating the expression of miR-125b.Conclusion Taken together,SRF/miR-125b axis promotes the EMT and metastasis of gastric cancer cells,and these regulators represent new potential therapeutic targets or biomarkers for gastric cancer.

Objective To evaluate the inhibitory effects of infigratinib and its pharmacologically active metabolites,BHS697 and CQM157,on cytochrome P450(CYPs)and UDP-glucuronosyltransferases(UGTs)in rat liver microsomes.Methods By adopting in vitro incubation method,the tested compounds(infigratinib,BHS697 or CQM157)and rat liver microsomes were incubated with the specific probe substrates of CYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,CYP3 A4,respectively,or the specific probe substrates of UGT1A1,UGT1A3,UGT1A6,UGT1A9,UGT2B7,respectively.The production of characteristic metabolites was detected by high performance liquid chromatography-tandem mass spectrometry.The half maximal inhibitory concentration(IC50)and inhibition constant(Ki)were calculated by GraphPad Prism 8.0.Results Infigratinib,BHS697 and CQM157 weakly inhibited CYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,CYP3 A4 and UGT1A6,UGT2B7 in rat liver microsomes,with IC50 values all more than 10 μmol·L-1,and moderately inhibited UGT1Al with IC50 values of 2.70,3.17,7.43 μmol·L-,respectively.Infigratinib had a moderate inhibitory effect on UGT1A9 and CQM157 had a moderate inhibitory effect on UGTIA3,with IC50 values of 5.61 and 9.57 μmol·L-1,respectively.The reversible inhibition analysis showed that infigratinib,BHS697 and CQM157 all non-competitively inhibited UGTIA1,with Ki values of 1.83,2.51 and 5.84 μmol·L-1,respectively.Conclusion Infigratinib had moderate inhibitory effects on UGT1A1 and UGT1A9 in rat liver microsomes and its pharmacologically active metabolites,BHS697 and CQM157,also had moderate inhibitory effects on UGT1A1.

ObjectiveTo assess the quality of randomized controlled trials （RCTs） of compound traditional Chinese medicine （TCM） prescriptions in the treatment of nonalcoholic steatohepatitis （NASH）， and to provide recommendations for standardizing the design and reporting of RCTs in this field. MethodsDatabases such as PubMed， Web of Science， Embase， the Cochrane Library， CNKI， VIP， and Wanfang Data were searched for RCTs of compound TCM prescriptions in the treatment of NASH published from January 1， 2018 to December 31， 2023， and the articles were screened and assessed based on the Cochrane risk-of-bias assessment tool （RoB 2）， the unified standard for clinical trial reporting （CONSORT 2010）， and CONSORT-CHM Formulas 2017 for compound TCM prescriptions. ResultsA total of 45 articles were finally included， and most of these studies were rated as high-risk bias by RoB 2.0. The analysis based on the CONSORT control checklist showed a relatively low reporting rate for most of the key items regarding the quality of RCT studies. ConclusionA relatively large risk of bias is observed in the clinical studies on compound TCM prescriptions in the treatment of NASH published in the past six years， which may lead to the poor quality of reporting and evidence. It is suggested that the top-level design of clinical studies should be taken seriously in addition to investigating the advantages of TCM， so as to improve the quality of clinical studies.

Objective:To evaluate the difference in efficacy between liposuction combined with single-port endoscopic subcutaneous adenomectomy and traditional open surgery in treating adolescent male breast development disorder,and to compare their effects on patients'anxiety levels and quality of life.Methods:A total of sixty-four patients with adolescent male mammary gland dysplasia who underwent surgery at our hospital between March 2022 and June 2023 were included in this retrospective analysis,with 28 cases in the open surgery group and 36 cases in the single-hole endoscopic group.The study compared various parameters including surgery duration,intraoperative bleeding,incision length,hospitalization duration,treatment cost,and postoperative complications,alongside collecting GAD-7,SF-36,and SCAR questionnaire scores from the pa-tients.Results:The single-port endoscopy group,in comparison to the open surgery group,showed a slightly longer operation time and higher treatment cost but had a shorter hospitalization duration and smaller incision.There was no significant difference observed between the two groups concerning intraoperative bleeding.Notably,the single-port endoscopy group exhibited more significant improvements in SCAR,SF-36,and GAD-7 scores(P＜0.05).Conclusion:Com-pared with traditional open surgery,liposuction combined with single-port endoscopic subcutane-ous adenomectomy is more effective in treating adolescent gynecomastia.This approach not only offers better aesthetic outcomes but also proves effective in reducing patient anxiety and signifi-cantly enhancing their quality of life.

Objectives:To retrieve,evaluate and summarize the contemporary evidence of strategies for weaning from extracorporeal membrane oxygenation(ECMO)of adult patients,and to provide evidence-based reference for clinical practice. Methods:The Web of Science,Embase,Cochrane Library,PubMed,Wanfang Database,CNKI,VIP website,SinoMed,BMJ Best Practice,National Institute for Health and Care Excellence,Joanna Briggs Institute Library,UpToDate and the website of Agency for Healthcare Research and Quality,Society of Critical Care Medicine,American Association of Critical-Care Nurses,European Society of Intensive Care Medicine and Extracorporeal Life Support Organization were researched to collect the literature related to randomized controlled trials,systematic reviews,guidelines,evidence summaries,expert consensuses and clinical decisions in this field.The time limit for the retrieval is from the inception of databases until July 2023. Results:A total of 13 related literature were retrieved,including 4 guidelines,4 expert consensuses,3 clinical decisions and 2 system reviews.Totally 42 evidences were formulated based on retrieved literature,including adequately accessing the ability of gas exchange before weaning from veno-venous ECMO(V-V ECMO)and withdrawing from veno-arterial ECMO(V-A ECMO)as soon as possible when patients's heart function has recovered,involving six aspects such as team composition,anticoagulation measures,assessment before weaning,weaning implementation,cannula and wound management and quality measures. Conclusions:It is suggested to build a professional ECMO team based on the actual hospital situation,to follow the contemporary evidence to standardize the weaning process of patients from ECMO to ensure the patients'safety and improve the outcomes.