INTRODUCTION:Accumulating evidence has multilaterally proved the indispensable contribution of inflammation in mediating various diseases over the last decade, including sepsis, obesity, diabetes, and neurological disorders. This established correlation between inflammation and disease progression has positioned anti-inflammatory intervention as a promising therapeutic strategy for disease prevention and treatment. Naturally occurring flavonoids have emerged as a subject of extensive investigation due to their well-documented anti-inflammatory properties and molecular mechanisms. The current review provides a comprehensive analysis of isoliquiritigenin (ISL), a bioactive flavonoid compound isolated from Glycyrrhiza glabra (licorice), with particular emphasis on its pharmacological activities and molecular mechanisms in modulating inflammation- associated disorders. METHODS:A systematic literature review was executed across the PubMed and Google Scholar electronic databases spanning the period from January 2000 to December 2024, employing the following keyword combination: “isoliquiritigenin” (MeSH) AND “inflammation” (MeSH). RESULTS:ISL was found to exhibit significant therapeutic potential in mitigating both acute and chronic inflammatory responses. Particular attention was devoted to elucidating ISL's multi-target regulatory mechanisms in acute organ injury models, including neurological, pulmonary, hepatic, and renal systems. Furthermore, the compound's therapeutic effects were found to extend to chronic inflammatory pathologies associated with metabolic and neurodegenerative disorders, notably diabetes mellitus, obesity-related complications, and Alzheimer's disease-associated tissue damage, particularly manifesting in ocular, pulmonary, and cardiovascular systems. Systematic characterization of ISL's molecular targets and associated signalling cascades, like MAPK, JAK/STAT3, Nrf2, and SIRT1 pathways, substantially enhanced our mechanistic understanding of its anti-inflammatory properties. DISCUSSION:ISL demonstrated extensive protection in many inflammatory models. Its multi-target action implied broad therapeutic applicability. However, despite its excellent anti-inflammatory efficacy and safety profile, further study is required to investigate its effectiveness for clinical translation. CONCLUSION:This comprehensive analysis has provided a pharmacological foundation for developing ISL-based therapeutic interventions against inflammation-driven human pathologies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30-40% of the global population, making it the most prevalent chronic liver disorder worldwide. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), may advance to fibrosis, cirrhosis, and hepatocellular carcinoma, imposing a substantial socioeconomic and clinical burden. The recent FDA approval of Resmetirom for non-cirrhotic MASH has marked a significant therapeutic milestone; however, the multifactorial nature of MASLD continues to necessitate the identification of complementary therapeutic targets. The nitric oxide (NO) pathway has been increasingly recognized as a context-dependent regulator in MASLD pathogenesis, exhibiting dual and sometimes opposing biological effects. Under physiological conditions, low levels of NO derived from endothelial nitric oxide synthase (eNOS) contribute to hepatic microvascular homeostasis and limit lipid accumulation. In contrast, inducible nitric oxide synthase (iNOS) activity is enhanced during chronic metabolic inflammation, leading to excessive NO production, which may promote nitrosative stress through the formation of reactive nitrogen species including peroxynitrite (ONOO⁻). These processes have been associated with mitochondrial dysfunction, eNOS uncoupling, and progressive tissue injury. Accordingly, a more precise understanding of the spatial, temporal and concentration-dependent regulation of NO signaling is required. This review synthesizes current evidence on the dual role of NO in MASLD and critically evaluates emerging therapeutic strategies targeting this pathway, with the aim of informing future translational research.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder, but whether intrinsic capacity (IC), a multidomain measure of functional reserve, is associated with incident IBD remains unclear. We analysed 427,489 UK Biobank participants free of IBD at baseline and examined associations of baseline IC deficit burden with incident IBD, Crohn’s disease (CD), and ulcerative colitis (UC), as well as joint effects with polygenic risk scores (PRS). During a median follow-up of 13.73 years (interquartile range [IQR], 12.99–14.44 years), 3,719 participants developed IBD. Compared with participants with no IC deficits, those with 2, 3, and > = 4 deficits had progressively higher risks of incident IBD, and incidence rates increased from 0.556 to 1.067 per 1,000 person-years across IC categories. Associations were stronger for CD than for UC; participants with > = 4 deficits had hazard ratios of 2.614 for CD and 1.338 for UC. IC deficit burden provided complementary risk information across PRS strata, with the highest absolute risks observed among individuals with high PRS. These findings suggest that reduced IC is independently associated with increased IBD risk and may provide complementary information for risk stratification.

BackgroundMyocardial ischemia/reperfusion injury (MIRI) is a critical problem in cardiovascular medicine, often occurring after coronary revascularization procedures or cardiopulmonary bypass. The characters of MIRI are both energy metabolism disturbances and severe myocardium insulin resistance (IR), which exacerbated myocardial damage and cell death. Isoliquiritigenin (ISL), a flavonoid derived from licorice roots (Glycyrrhiza spp.), has demonstrated protective effects on MIRI. However, the potential cardio-protective effects and mechanism of ISL in MIRI remain unclear.ProposeIn this study, we aimed to investigate ISL’s therapeutic effects on MIRI. Moreover, we elucidate the underlying mechanisms of ISL regulated myocardium insulin resistance in vivo and in vitro.MethodsIn vivo, SD rats underwent left anterior descending coronary artery ligation/reperfusion to induce MIRI. Chest echocardiography was performed to monitor cardiac function post-reperfusion, followed by measurement of myocardial injury and IR markers. In vitro, H9C2 cardiomyocytes subjected to oxygen-glucose deprivation/reperfusion (OGD/R). Markers associated with myocardial injury and IR were assessed. Then, we identified potential therapeutic targets IGFBP5 for MIRI by network pharmacology and molecular docking analysis. Finally, lentivirus were used to silence or over-express IGFBP5 to elucidate the role of IGFBP5 in regulating the therapeutic effects of ISL on IR in MIRI.ResultsIn the present study, In vivo experiments demonstrated that ISL attenuated myocardial infarct size, decreased serum markers of myocardial injury, improved left ventricular systolic function, and enhanced insulin sensitivity. In vitro data revealed that ISL ameliorated glucose uptake and cell survival rate. Furthermore, ISL increased AKT phosphorylation and upregulated membrane-bound GLUT4 (M-GLUT4) protein expression levels. These effects of ISL are mediated by the induction of IGFBP5, as demonstrated using gene-specific shRNA or overexpression for IGFBP5.ConclusionOur results reveal that ISL protects against myocardial damage caused by MIRI through the regulation of IR via the IGFBP5/AKT/GLUT4 pathway.

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Background Associated with enzyme deficiencies causing glycosaminoglycans (GAGs) accumulation, mucopolysaccharidosis type VI (MPS VI) is lysosomal storage disorder. In the treatment of MPS VI, galsulfase (Naglazyme) is commonly used as an enzyme replacement therapy (ERT). There remains a need for comprehensive real-world data on its safety and associated adverse events (AEs).Objective An analysis of the FDA Adverse Event Reporting System (FAERS) database will be conducted to identify potential risks and adverse reactions associated with galsulfase in real-life settings.Methods The FAERS database was used to extract data from Q2 2005 to Q4 2023. A total of 20,281,876 reports were analyzed after duplicate elimination, with 3,195 AE reports related to galsulfase identified. The association between galsulfase and AEs was investigated by utilizing four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). The analysis focused on the timing of onset, signs of AEs, and clinical significance.Results Twenty seven organ systems were involved, and significant system organ classes (SOCs) included respiratory, thoracic and mediastinal disorders, and infections and infestations. At the PT level, 72 PTs corresponding to 15 SOCs were identified, with some AEs not previously mentioned in the product label. AEs associated with galsulfase had a median onset time of 1,471 days, with over half of the cases occurred within the first 5 years of treatment initiation.Conclusion This investigation delivers an exhaustive and indicative assessment of galsulfase's safety profile, grounded in authentic, real-world evidence. The findings emphasis the importance of continuous safety surveillance and the emergence of new AEs. The identification of previously unreported urologic adverse events, such as glomerulonephritis membranous and nephritic syndrome, warrants further investigation. The study emphasizes the need for enhanced pharmacovigilance to ensure patient safety and the effectiveness of galsulfase treatment.

BACKGROUND:Limonin is one of the most abundant active ingredients of Tetradium ruticarpum. It exerts antitumor effects on several kinds of cancer cells. However, whether limonin exerts antitumor effects on colorectal cancer (CRC) cells and cancer stem-like cells (CSCs), a subpopulation responsible for a poor prognosis, is unclear.AIM:To evaluate the effects of limonin on CSCs derived from CRC cells.METHODS:CSCs were collected by culturing CRC cells in serum-free medium. The cytotoxicity of limonin against CSCs and parental cells (PCs) was determined by cholecystokinin octapeptide-8 assay. The effects of limonin on stemness were detected by measuring stemness hallmarks and sphere formation ability.RESULTS:As expected, limonin exerted inhibitory effects on CRC cell behaviors, including cell proliferation, migration, invasion, colony formation and tumor formation in soft agar. A relatively low concentration of limonin decreased the expression stemness hallmarks, including Nanog and β-catenin, the proportion of aldehyde dehydrogenase 1-positive CSCs, and the sphere formation rate, indicating that limonin inhibits stemness without presenting cytotoxicity. Additionally, limonin treatment inhibited invasion and tumor formation in soft agar and in nude mice. Moreover, limonin treatment significantly inhibited the phosphorylation of STAT3 at Y705 but not S727 and did not affect total STAT3 expression. Inhibition of Nanog and β-catenin expression and sphere formation by limonin was obviously reversed by pretreatment with 2 μmol/L colievlin.CONCLUSION:Taken together, these results indicate that limonin is a promising compound that targets CSCs and could be used to combat CRC recurrence and metastasis.

As an inflammatory bowel disease, ulcerative colitis (UC) does not respond well to current treatments. It is of positive clinical significance to further study the pathogenesis of UC and find new therapeutic targets. B lymphocytes play an important role in the pathogenesis of UC. The effect of anti-CD20 therapy on UC also provides new evidence for the involvement of B cells in UC process additionally, suggesting the important role and potential therapeutic value of B cells in UC. In this study, we screened the most critical immune cell-related gene modules associated with UC and found that activated B cells were closely related to the gene modules. Subsequently, key activated B cell-associated gene (BRG) signatures were obtained based on WGCNA and differential expression analysis, and three overlapping BRG-associated genes were obtained by RF and LASSO algorithms as BRG-related diagnostic biomarkers for UC. Nomogram model was further performed to evaluate the diagnostic ability of BRG-related diagnostic biomarkers, subsequently followed by UC molecular subsets identification and immunoinfiltration analysis. We also further verified the expressions of the three screened BRGs in vitro by using an LPS-induced NCM460 cell line model. Our results provide new evidence and potential intervention targets for the role of B cells in UC from a new perspective.

BACKGROUND AND AIMS:Fecal incontinence (FI) is a common complaint that greatly affects the quality of life of patients with Crohn's disease (CD) and is associated with the clinical characteristics of CD. We aimed to identify risk factors related to FI and construct a risk prediction model for FI in patients with CD. METHODS:This retrospective study included 600 Chinese patients with CD from 4 IBD centers between June 2016 and October 2021. The patients were assigned to the training (n = 480) and testing cohorts (n = 120). Two nomograms were developed based on the logistic regression and Cox regression models to predict the risk factors for FI in patients with CD. The discriminatory ability and accuracy of the nomograms were evaluated using the receiver operating characteristic (ROC) curves and the area under the ROC curves (AUCs). Additionally, the Kaplan-Meier survival curve was also used further to validate the clinical efficacy of the Cox regression model. RESULTS:The overall prevalence of FI was 22.3% (n = 134 of 600). In the logistic regression model, age at diagnosis (odds ratio [OR], 1.032; P = .033), penetrating behavior of disease (OR, 3.529; P = .008) and Perianal Disease Activity Index score >4 (OR, 3.068; P < .001) were independent risk factors for FI. In the Cox regression model, age at diagnosis (hazard ratio [HR], 1.027; P = .018), Montreal P classification (HR, 2.608; P = .011), and Perianal Disease Activity Index score >4 (HR, 2.190; P = .001) were independent predictors of the prevalence of FI over time. Two nomograms were developed to facilitate risk score calculation, and they showed good discrimination ability according to AUCs. CONCLUSIONS:In this study, we identified 4 risk factors related to the prevalence of FI and developed 2 models to effectively predict the risk scores of FI in CD patients, helping to delay the course of FI and improve the prognosis with timely intervention.

Professor Zhu Bingyi thinks that the causes of the elderly with refractory functional constipation are Qi and blood deficiency, dysfunction of lung, spleen and kidney, intestinal dryness and loss of body fluid, loss of anal nourishment are the main characteristics of the pathogenesis, he adopts dispersing lung, invigorating spleen,nourishing Yin and the blood as the therapeutic method, applying a large number of raw Baizhu（Atractylodis Macrocephalae rhizoma） in subtle ways, presenting noticeable effects in the treatment of the disease.

Background:We aimed to explor the therapeutic effect and molecular mechanism of licochalcone A (LCA) on colon cancer.Methods:This study was carried out in 2020-2021 in Nanjing Tongren Hospital, China. Colon cancer HCT116 cells were treated with different concentrations of LCA. Cell counting kit-8, colony formation and flow cytometry assays were used to analyze cell viability, proliferation and apoptosis. Wound healing and transwell experiments were used to measure cell migration and invasion ability. The expression of ADAM9 and apoptosis-related proteins in different LCA treatment groups was detected by western blot. HCT116 cells were transfected with ADAM9 small interfering RNAs (siRNAs) or overexpression vectors. The database screened the upstream miRNA targeting ADAM9 and predicted the targeted binding site between miR-1270 and ADAM9, which was verified by a dual-luciferase reporter assay. Rescue experiments were performed to confirm the effects of the miR-1270/ADAM9 axis on cell proliferation and metastasis.Results:LCA decreased cell growth (P<0.05), migration (P<0.05), and invasion (P<0.05) of colon cancer cells and inhibited ADAM9 expression in a dose-dependent manner. LCA affected the functions of colon cancer cells by negatively regulating the expression of ADAM9. MiR-1270, increased by LCA, targeted and suppressed ADAM9 expression significantly (P<0.001). ADAM9 overexpression restrained miR-1270 mimic and LCA-induced changes in cell proliferation, migration, and invasion, and promoted apoptosis in HCT116 cells significantly (P<0.01). LCA and miR-1270 mimic inactivated the Akt/NF-κB pathway, while ADAM9 over-expression rescued it.Conclusion:LCA exhibited antitumor efficacy in HCT116 cells by inhibiting the Akt/NF-κB signaling pathway by regulating the miR-1270/ADAM9 axis.

目的 评估克罗恩病(Crohn's disease,CD)肛瘘患者基于磁共振成像(magnetic resonance imagin,MRI)下的Van Assche评分对临床愈合的预测意义,确定临床愈合的影响因素.方法 收集2010 年8 月至 2017 年 10 月在南京医科大学第四附属医院胃肠外科诊治的CD患者.纳入应用IFX联合挂线治疗、术前行MRI的CD肛瘘患者.收集MRI影像及临床数据,分析CD肛瘘患者基于术前MRI下的Van Assche评分对临床愈合的预测意义,通过logistic回归模型评估临床愈合的影响因素.结果 93 例符合标准的CD肛瘘患者纳入研究(男性73.1％),中位随访时间34.5(IQR,22～58)个月.临床愈合率和应答率分别为 60.2％(56/93)、39.8％(37/93).临床愈合组的 Van Assche 评分相对偏低(13.6 vs 16.4,P=0.005).受试者工作特征曲线是在Van Assche评分基础上构建的,用于预测临床愈合率.受试者工作特征曲线(receiver operating characteristic,ROS)下的面积为0.674,其敏感度、特异度分别为87.50％、40.54％.Van Assche评分的截断值是18.0,且评分>18.0 的患者更易达到临床愈合(OR=4.33,P=0.008).结论 Van Assche评分与CD肛瘘临床愈合之间存在较大的差异性,并非预测患者临床愈合的可靠指标.术前Van Assche评分≤18.0的患者,可能需要更密切的随访或积极的药物治疗.

Abstract Purpose. The clinical characteristicsand prognosis of anal cancer in the elderly have not received sufficient attention. The study aimed to evaluate the clinical features and prognostic factors of elderly patients with anal cancer. Method. The characteristics of anal cancer patients (aged <65 and ≥65) diagnosed during 2004-2017 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was used to correct age bias caused by assessed confounders. The chi-squared (χ2) test was used to assess differences in categorical variables of characteristics between two age groups., The Kaplan-Meier survival technique, Log-rank test, Cox regression, and nomogram were used for survival analysis. Results. The receipt of adjuvant age increases the risk of overall survival by 86% after propensity-score matching (HR=1.86, 95%CI=1.70-2.03,P<0.001). Compared with the younger population, the elderly accounted for a higher proportion of unmarried statuses and adenocarcinomas. COX regression analysis shows older age, non-squamous cell carcinoma, unmarried status, and advanced AJCC stage as independent risk prognostic factors for anal cancer in the elderly. The effects of chemotherapy, radiotherapy, and surgery all improved the prognosis of the elderly. Besides, senior score and survival probability could be accomplished by our nomogram with a c-index of 0.7179. Conclusion. Relatively low rates of chemoradiation and relatively conservative therapy regimens are associated with a poorer prognosis in elderly anal cancer. At the same time, surgery has a potential role in improving the prognosis of elderly anal cancer patients.

A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups (2b-2f, 2j, 2o, and 2q) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H2O2-induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g, 2h, 2j, 2m, 2o, and 2p. Besides, 2g, 2h, 2j, 2m, 2o, and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs.

Six Stemona alkaloids were synthesized racemically using stemoamide, obtained via a cascade cyclization or our reported transannular cyclization of parvistemoamide, as the common intermediate. Thioamides facilitated the separation of isosaxorumamide and saxorumamide, and promoted the first syntheses of other four N-oxide or pyrrolidine bearing Stemona alkaloids via chemoselective reduction and oxidation.

Thyroid hormone receptor interactor 13 (TRIP13), an AAA-ATPase, participates in the development of many cancers. This study explores the function of TRIP13 and synergistic effects of TRIP13 and PARP1 inhibitors in hepatocellular carcinoma (HCC). The dose-dependent effects of TRIP13 and PARP1 inhibitors on HCC cells proliferation or migration were investigated by the CCK-8 and Transwell assays. Using siRNA or lentivirus to knock down TRIP13, we tested HCC cell and tumor growth in vitro and in vivo. The DNA damage caused by TRIP13 and PARP1 inhibitors was measured by the phosphorylation of H2AX, one of the DNA damage biomarkers. The phosphorylation of H2AX was increased after treatment with DCZ0415 or TRIP13 knockdown. Combining DCZ0415 with PARP1 inhibitor, Olaparib induced synergistic anti-HCC activity. We also found that the overexpression of TRIP13 is significantly associated with early recurrent HCC and poor survival. Up-regulation of TRIP13 in HCC was regulated by transcription factor SP1. In conclusion, our study demonstrated that DCZ0415 targeting TRIP13 impaired non-homologous end-joining repair to inhibit HCC progression and had a synergistic effect with PARP1 inhibitor Olaparib in HCC, suggesting a potential treatment of HCC.

Background Recent studies have confirmed that combined surgery and anti-TNF therapy could improve outcomes in patients with perianal fistulising Crohn's disease (PFCD). However, the optimal timing for infliximab infusion after surgical intervention is uncertain. We aimed to determine the long-term efficacy of early initiation of infliximab following surgery among PFCD patients. Methods We performed a retrospective cohort study of PFCD patients who received combined infliximab and surgical treatment between 2010 and 2018 at a tertiary referral hospital. Patients were grouped according to the time interval between surgery and infliximab infusion, with < 6 weeks into early infliximab induction group and > 6 weeks into delayed infliximab induction group. The primary outcome was to compare surgical re-intervention between early and delayed infliximab induction groups. The secondary outcomes were fistula healing and predictors associated with these outcomes of early infliximab induction approach. Results One hundred and seventeen patients were included (73 in early infliximab induction, 44 in delayed infliximab induction). The median interval between surgery and infliximab initiation was 9.0 (IQR 5.5-17.0) days in early infliximab induction group and 188.0 (IQR 102.25-455.75) days in delayed infliximab induction group. After followed-up for a median of 36 months, 61.6% of patients in early infliximab induction group and 65.9% in delayed infliximab induction group attained fistula healing (p = 0.643). The cumulative re-intervention rate was 23%, 32%, 34% in early infliximab induction group and 16%, 25%, 25% in delayed infliximab induction group, at 1, 2, and 3 years respectively (p = 0.235). Presence of abscess at baseline (HR = 5.283; 95% CI, 1.61-17.335; p = 0.006) and infliximab maintenance therapy > 3 infusions (HR = 3.691; 95% CI, 1.233-11.051; p = 0.02) were associated with re-intervention in early infliximab induction group. Presence of abscess at baseline also negatively influenced fistula healing (HR = 3.429, 95% CI, 1.216-9.668; p = 0.02). Conclusion Although no clear benefit was shown compared with delayed infliximab induction group, early initiation of infliximab after surgery could achieve promising results for PFCD patients. Before infliximab infusion, durable drainage is required for patients with concomitant abscess or prolonged infliximab maintenance therapy.

Crohn′s disease (CD) -related rectovaginal fistula is a rare refractory disease in CD perianal lesions and its therapeutic strategy is not only to control intestinal inflammation but also to protect the anal and vaginal functions. It is also one of the treatment challenges for clinical surgeons. Clinically, medication and drug combined with surgery are mainly used for the treatment of CD-related rectovaginal fistula, but there is still lack of uniform standards. This article reviews the current treatment options for this disease in order to help clinical management.

Transformations among Stemona alkaloids with different ring systems have improved the synthetic efficiency toward diverse alkaloids. Recent advances in the transformations of different types of Stemona alkaloids were reviewed for the first time.

The following letter to the editor highlights the review titled "Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives" in World J Gastrointest Oncol 2022 March 15; 14(3): 547-567. It is necessary to explore the role of inflammation in promoting tumorigenesis and development of gastrointestinal cancers.