ObjectiveTo observe the clinical efficacy of Sanren Runchang formula in treating constipation-predominant irritable bowel syndrome （IBS-C） by regulating the brain-gut axis and the effects of the formula on serum levels of 5-hydroxytryptamine （5-HT）， vasoactive intestinal peptide （VIP）， and substance P （SP）. MethodsA randomized controlled design was adopted， and 72 IBS-C patients meeting Rome Ⅳ criteria were randomized into observation and control groups （36 cases）.The observation group received Sanren Runchang formula granules twice daily， and the control group received lactulose oral solution daily for 4 weeks. IBS Symptom Severity Scale （IBS-SSS）， IBS Quality of Life Scale （IBS-QOL）， and Bristol Stool Form Scale （BSFS） were used to assess clinical symptoms， and bowel movement frequency was recorded. The Self-Rating Anxiety Scale （SAS） and Self-Rating Depression Scale （SDS） were employed to evaluate psychological status. ELISA was employed to measure the serum levels of 5-HT， VIP， and SP. ResultsThe total response rate in the observation group was 91.67% （33/36）， which was higher than that （77.78%， 28/36） in the control group （χ²=4.50， P<0.05）. After treatment， both groups showed increased defecation frequency and BSFS scores， decreased IBS-SSS total score， abdominal pain and bloating scores， IBS-QOL health anxiety， anxiety， food avoidance， and behavioral disorders scores， SAS and SDS scores， serum 5-HT and VIP levels， and increased SP levels （P<0.05， P<0.01）. Moreover， the observation group showed more significant changes in the indicators above than the control group （P<0.05， P<0.01）. The SP level showed no significant difference between the two groups. During the 4-week follow-up， the recurrence rate was 5.88% in the observation group and 31.25% in the control group. No adverse events occurred in observation group， and 2 cases of mild diarrhea occurred in the control group. ConclusionSanren Runchang formula demonstrated definitive efficacy in alleviating gastrointestinal symptoms and improving the psychological status and quality of life in IBS-C patients， with a low recurrence rate. The formula can regulate serum levels of neurotransmitters such as 5-HT and VIP， suggesting its potential regulatory effect on the brain-gut axis through modulating neurotransmitters and neuropeptides. However， its complete mechanism of action requires further investigation through detection of additional brain-gut axis-related biomarkers.

Microbial-derived metabolites are important mediators of host-microbial interactions. In recent years, the role of intestinal microbial metabolites in colorectal cancer has attracted considerable attention. These metabolites, which can be derived from bacterial metabolism of dietary substrates, modification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyamines, microbial tryptophan metabolites, and polyphenols are involved in the tumorigenesis and development of CAC through inflammation and immunity. Given the heated debate on the metabolites of microbiota in maintaining gut homeostasis, serving as tumor molecular markers, and affecting the efficacy of immune checkpoint inhibitors in recent years, strategies for the prevention and treatment of CAC by targeting intestinal microbial metabolites are also discussed in this review.
Humans ; Gastrointestinal Microbiome/physiology* ; Animals ; Carcinogenesis/metabolism* ; Colitis-Associated Neoplasms/microbiology* ; Fatty Acids, Volatile/metabolism* ; Bile Acids and Salts/metabolism* ; Colitis/microbiology*

Based on the interleukin-17(IL-17) signaling pathway, this study explores the effect and mechanism of Bufei Decoction on Klebsiella pneumoniae pneumonia in rats. SD rats were randomly divided into the control group, model group, Bufei Decoction low-dose group(6.68 g·kg~(-1)·d~(-1)), Bufei Decoction high-dose group(13.36 g·kg~(-1)·d~(-1)), and dexamethasone group(1.04 mg·kg~(-1)·d~(-1)), with 10 rats in each group. A pneumonia model was established by tracheal drip injection of K. pneumoniae. After successful model establishment, the improvement in lung tissue damage was observed following drug administration. Core targets and signaling pathways were screened using transcriptomics techniques. Real-time fluorescence quantitative polymerase chain reaction was used to detect the mRNA expression of core targets interleukin-6(IL-6), interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and chemokine CXC ligand 6(CXCL6). Western blot was used to assess key proteins in the IL-17 signaling pathway, including interleukin-17A(IL-17A), nuclear transcription factor-κB activator 1(Act1), tumor necrosis factor receptor-associated factor 6(TRAF6), and downstream phosphorylated p38 mitogen-activated protein kinase(p-p38 MAPK), and phosphorylated nuclear factor-κB p65(p-NF-κB p65). Apoptosis of lung tissue cells was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling(TUNEL). The results showed that, compared with the control group, the model group exhibited significant pathological damage in lung tissue. The mRNA expression of IL-6, IL-1β, TNF-α, and CXCL6, as well as the protein levels of IL-17A, Act1, TRAF6, p-p38 MAPK/p38 MAPK, and p-NF-κB p65/NF-κB p65, were significantly increased, and the number of apoptotic cells was notably higher, indicating successful model establishment. Compared with the model group, both low-and high-dose groups of Bufei Decoction showed reduced pathological damage in lung tissue. The mRNA expression levels of IL-6, IL-1β, TNF-α, and CXCL6, and the protein levels of IL-17A, Act1, TRAF6, p-p38 MAPK/p38 MAPK, and p-NF-κB p65/NF-κB p65, were significantly decreased, with a significant reduction in apoptotic cells in the high-dose group. In conclusion, Bufei Decoction can effectively improve lung tissue damage and reduce inflammation in rats with K. pneumoniae. The mechanism may involve the regulation of the IL-17 signaling pathway and the reduction of apoptosis.
Animals ; Interleukin-17/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Rats ; Male ; Klebsiella pneumoniae/physiology* ; Klebsiella Infections/immunology* ; Humans ; Lung/drug effects*

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Pelvic organ prolapse (POP), whose etiology is influenced by genetic and clinical risk factors, considerably impacts women's quality of life. However, the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored. This study constructed the first polygenic risk score (PRS) for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study. We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls. Results showed that the case group exhibited a significantly higher PRS than the control group. Moreover, the odds ratio of the top 10% risk group was 2.6 times higher than that of the bottom 10%. A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths. As far as we know, the integrated prediction model, which combined PRS and clinical risk factors, demonstrated better predictive accuracy than other existing PRS models. This combined risk assessment model serves as a robust tool for POP risk prediction and stratification, thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
Humans ; Female ; Pelvic Organ Prolapse/epidemiology* ; Middle Aged ; Risk Assessment/methods* ; China/epidemiology* ; Multifactorial Inheritance ; Aged ; Risk Factors ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Case-Control Studies ; Adult ; Polymorphism, Single Nucleotide ; Genetic Risk Score ; East Asian People

Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of A ldoa strikingly decreased HCC development in vivo. Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.

Sodium-glucose co-transporter protein 2 inhibitor(SGLT2i)has steadily demonstrated benefits in the treatment of type 2 diabetes complicated with cardiovascular diseases based on evidence-based medicine,but its precise mechanism is yet unknown.We identified type 2 diabetes patients with HFpEF by searching PubMed,Web of Science,China knowledge network(CNKI),and other databases.We then summarized the pathological mechanism of HFpEF caused by type 2 diabetes.At the same time,to link to evidence-based medical,we explored the future of SGLT2i in clinical application.

Objective:To investigate the molecular mechanisms of chronic rhinosinusitis (CRS), to identify key cell subgroups and genes, to construct effective diagnostic models, and to screen for potential therapeutic drugs.Methods:Key cell subgroups in CRS were identified through single-cell transcriptomic sequencing data. Essential genes associated with CRS were selected and diagnostic models were constructed by hdWGCNA (high dimensional weighted gene co-expression network analysis) and various machine learning algorithms. Causal inference analysis was performed using Mendelian randomization and colocalization analysis. Potential therapeutic drugs were identified using molecular docking technology, and the results of bioinformatics analysis were validated by immunofluorescence staining. Graphpad Prism, R, Python, and Adobe Illustrator software were used for data and image processing.Results:An increased proportion of basal and suprabasal cells was observed in CRS, especially in eosinophilic CRS with nasal polyps (ECRSwNP), with P=0.001. hdWGCNA revealed that the "yellow module" was closely related to basal and suprabasal cells in CRS. Univariate logistic regression and LASSO algorithm selected 13 key genes ( CTSC, LAMB3, CYP2S1, TRPV4, ARHGAP21, PTHLH, CDH26, MRPS6, TENM4, FAM110C, NCKAP5, SAMD3, and PTCHD4). Based on these 13 genes, an effective CRS diagnostic model was developed using various machine learning algorithms (AUC=0.958). Mendelian randomization analysis indicated a causal relationship between CTSC and CRS (inverse variance weighted: OR=1.06, P=0.006), and colocalization analysis confirmed shared genetic variants between CTSC and CRS (PPH4/PPH3>2). Molecular docking results showed that acetaminophen binded well with CTSC (binding energy:-5.638 kcal/mol). Immunofluorescence staining experiments indicated an increase in CTSC +cells in CRS. Conclusion:This study integrates various bioinformatics methods to identify key cell types and genes in CRS, constructs an effective diagnostic model, underscores the critical role of the CTSC gene in CRS pathogenesis, and provides new targets for the treatment of CRS.

Objective:To analyze the disease characteristics, diagnosis and treatment methods of venous pulsatile tinnitus treated by intervention of sigmoid sinus.Methods:Fifty patients (from Shandong Provincial ENT Hospital, Shandong University between February 2014 and July 2020) with venous pulsatile tinnitus treated by sigmoid sinus surgery were analyzed retrospectively. The tinnitus characteristics, imaging findings, surgical methods, intraoperative findings and postoperative tinnitus changes were recorded. The patients were followed up for 6-12 months. The sign rank sum test was used to analyze the difference in tinnitus grading before and after surgery. There were 50 patients with unilateral venous pulsatile tinnitus, including 49 females and 1 male. The age ranged from 17 to 67 years, with a median age of 44 years. There were 45 cases of right tinnitus and 5 cases of left tinnitus. The degree of tinnitus before operation was grade Ⅱ or above, including 4 cases of gradeⅡ, 11 cases of grade Ⅲ, 22 cases of grade Ⅳ and 13 cases of grade Ⅴ.Results:Thirty-seven cases were cured, 8 cases were ineffective (no change in tinnitus), 3 cases were markedly effective (tinnitus grade decreased by 3 in 2 cases, 4 in 1 case), and 2 cases were effective (tinnitus grade decreased by 1). The difference of tinnitus grade before and after operation was statistically significant ( Z=-5.70, P<0.05). Temporal bone CT showed 36 cases of sigmoid diverticulum (including 17 cases with sigmoid sinus dehiscence), 12 cases of sigmoid sinus dehiscence and 2 cases of absence of the temporal bone cortex abutting to sigmoid sinus. Thirty-five cases were performed with closure of sigmoid sinus diverticulum, 4 cases were performed with resurfacing of the sigmoid plate, 5 cases were performed with narrowing of sigmoid sinus, 4 cases were performed with simple opening of pre sigmoid mastoid air chamber, 1 case of opening was performed with pre sigmoid mastoid air chamber combined with narrowing of sigmoid sinus, and 1 case was performed with opening of pre sigmoid mastoid air chamber combined with closure of sigmoid sinus diverticulum. Conclusions:Venous pulsatile tinnitus is common in women. The common causes may be sigmoid sinus wall abnormalities such as sigmoid sinus diverticulum and perisigmoid bone defect. Imaging examinations are helpful for diagnosis. Venous pulsatile tinnitus can be treated with surgery.