Objective To explore the potential role and underlying mechanism of the functionally uncharacterized gene Gm49394 on regulating β-cell apoptosis under diabetic conditions.Methods The expression and translational activity of Gm49394 in pancreatic β-cell lines and non-β-cell lines were validated using RNA fluorescence in situ hybridization(RNA-FISH),quantitative real-time PCR(qPCR),Western blotting,and immunofluorescence(IF)assay.The β-cell lines(NIT-1/Min6)with Gm49394 overexpression or knockdown were constructed.The proliferation,apoptosis,mitochondrial function,as well as oxidative stress and endoplasmic reticulum stress markers in these β-cell lines under physiological homeostasis or pathological stress conditions,such as high glucose(30 mmol/L),inflammation(10 ng/mL IFN-γ alone or combined with 10 ng/mL IL-6),and hydrogen peroxide(100 μmol/L H2O2)were detected by flow cytometry and Western blotting.Results RNA-FISH and qPCR indicated that Gm49394 was specifically expressed in pancreatic β-cell lines and up-regulated under high glucose or inflammatory stimulation.IF assay and Western blotting showed that Gm49394 had protein-coding activity.Flow cytometry and Western blotting identified that Gm49394 overexpression did not affect β-cell proliferation,but promoted β-cell apoptosis and increased reactive oxygen species(ROS)and mitochondrial superoxide(MitoSOX)levels in β cells under physiological homeostasis or pathological stress conditions(P<0.05).Under physiological conditions,Gm49394 knockdown failed to induce significant alterations on β-cell apoptosis,ROS,or MitoSOX levels.Under pathological stress conditions,Gm49394 knockdown significantly suppressed β-cell proliferation,apoptosis,as well as oxidative and endoplasmic reticulum stress(P<0.05).Conclusion Gm49394 may promote β-cell apoptosis via oxidative stress and endoplasmic reticulum stress.

By combining the origin and research progress of the combination of disease and syndrome, the core pathogenesis, this article explored the research ideas and methods of the core pathogenesis of TCM. It is found that modern TCM is mostly guided by the idea of classification-staging-syndrome differentiation, the main prescription of the main disease, the special prescription of the special disease, and the idea of "dynamic-fixed sequential". The tongue image syndrome differentiation method, clustering analysis method, drug test syndrome method, compound pathogenesis method, "evidence-based pathogenesis-syndrome treatment system" research model, and the integration of traditional Chinese and Western medicine theory were used to explore the core pathogenesis of TCM under the condition of disease. Combined with the advantages of modern medical disease differentiation and TCM syndrome differentiation, the individualized diagnosis and treatment methods of integrated traditional Chinese and Western medicine have been continuously improved, in order to solve the stage contradictions of different clinical stages, effectively delay the progression of the disease and improve the prognosis of the disease.

Approximately 20% to 30% of the global workforce is engaged in shift work. As a significant cause of circadian disruption, shift work is closely associated with an increased risk for periodontitis. Nevertheless, how shift work-related circadian disruption functions in periodontitis remains unknown. Herein, we employed a simulated shift work model constructed by controlling the environmental light-dark cycles and revealed that shift work-related circadian disruption exacerbated the progression of experimental periodontitis. RNA sequencing and in vitro experiments indicated that downregulation of the core circadian protein brain and muscle ARNT-like protein 1 (BMAL1) and activation of the Gasdermin D (GSDMD)-mediated pyroptosis were involved in the pathogenesis of that. Mechanically, BMAL1 regulated GSDMD-mediated pyroptosis by suppressing NOD-like receptor protein 3 (NLRP3) inflammasome signaling through modulating nuclear receptor subfamily 1 group D member 1 (NR1D1), and inhibiting Gsdmd transcription via directly binding to the E-box elements in its promoter. GSDMD-mediated pyroptosis accelerated periodontitis progression, whereas downregulated BMAL1 under circadian disruption further aggravated periodontal destruction by increasing GSDMD activity. And restoring the level of BMAL1 by circadian recovery and SR8278 injection alleviated simulated shift work-exacerbated periodontitis via lessening GSDMD-mediated pyroptosis. These findings provide new evidence and potential interventional targets for circadian disruption-accelerated periodontitis.
Pyroptosis/physiology* ; ARNTL Transcription Factors/metabolism* ; Animals ; Periodontitis/etiology* ; Mice ; Phosphate-Binding Proteins/metabolism* ; Shift Work Schedule/adverse effects* ; Intracellular Signaling Peptides and Proteins/metabolism* ; Mice, Inbred C57BL ; Male ; Disease Models, Animal ; Gasdermins

Drug development remains a critical issue in the field of biomedicine. With the rapid advancement of information technologies such as artificial intelligence (AI) and the advent of the big data era, AI-assisted drug development has become a new trend, particularly in predicting drug-target associations. To address the challenge of drug-target prediction, AI-driven models have emerged as powerful tools, offering innovative solutions by effectively extracting features from complex biological data, accurately modeling molecular interactions, and precisely predicting potential drug-target outcomes. Traditional machine learning (ML), network-based, and advanced deep learning architectures such as convolutional neural networks (CNNs), graph convolutional networks (GCNs), and transformers play a pivotal role. This review systematically compiles and evaluates AI algorithms for drug- and drug combination-target predictions, highlighting their theoretical frameworks, strengths, and limitations. CNNs effectively identify spatial patterns and molecular features critical for drug-target interactions. GCNs provide deep insights into molecular interactions via relational data, whereas transformers increase prediction accuracy by capturing complex dependencies within biological sequences. Network-based models offer a systematic perspective by integrating diverse data sources, and traditional ML efficiently handles large datasets to improve overall predictive accuracy. Collectively, these AI-driven methods are transforming drug-target predictions and advancing the development of personalized therapy. This review summarizes the application of AI in drug development, particularly in drug-target prediction, and offers recommendations on models and algorithms for researchers engaged in biomedical research. It also provides typical cases to better illustrate how AI can further accelerate development in the fields of biomedicine and drug discovery.

Objective : To investigate the factors affecting the outcome of high-risk human papillomavirus ( HR- HPV) infection in patients with normal cervix examined by colposcopy in Hefei area and the relationship between persistent HR-HPV infection and cervical cytology． Methods : Data of colposcopy patients were collected from 478 HR-HPV infected patients with normal cervix through colposcopy．Their age，number of sexual partners，contracep- tive methods and other relevant basic information were recorded．Vaginal interferon use，HR-HPV infection at year 1 and year 2，and cervical liquid-based cytology test ( LCT) results were tracked，univariate and multivariate ana- lyses were performed based on basic information，and ROC curves were plotted． Results : The HR-HPV clearance rate at 1 year was 59. 41% ，and the clearance rate at 2 years was 66. 75%．The other 12 types of infection ( 31， 33，35，39，45，51，52，56，58，59，66，68) were more common than the 16 and 18 types．Univariate and mult- ivariate analyses showed that age＞50 years，number of sexual partners ≥2，and history of cervical conectomy in- creased the risk of persistent HR-HPV infection ( χge = 21. 676，P ＜0. 001; χumber of sexual partners = 8. 262，P =0. 004; χistory of cervical conectomy = 11. 267，P = 0. 001 ) ． The risk of HR-HPV infection was significantly lower when condom or vaginal interferon was used ( χondom use = 10. 885，P = 0. 001; χnterferon use = 4. 099，P = 0. 043) ．The area under the ROC curve (AUC) of combined diagnosis of HR-HPV persistent infection was higher than that of single diagnosis，and the AUC of combined diagnosis was 0. 737．Persistent HR-HPV infection was an independent risk factor for abnormal LCT，and the AUC predicted by the model was 0. 755．No cancer was found in patients with persistent HR-HPV infection for 2 years，and the proportion of abnormal LCT was higher than that in patients with negative HR-HPV．The difference was statistically significant ( χ2 = 39. 64，P＜0. 001) ． Conclusion The combined ROC model constructed for patients＞50 years old，with multiple sexual partners，history of cervical surgery， no vaginal interferon use，and no condom use has certain value in predicting persistent HR-HPV infection，and per- sistent HR-HPV infection has predictive value in predicting LCT abnormalities．

Objective:To explore effect of curculigoside on neuronal pyroptosis in rats with acute cerebral infarction(CI)by regulating cyclic guanosine-adenosine synthase(cGAS)-interferon gene stimulating factor(STING)signaling pathway.Methods:Fifteen rats were randomly selected as sham operation group,and remaining rats were constructed CI models by modified Longa suture method,CI rats successfully modeled were randomly divided into CI group,curculigoside group(5 mg/kg),SR-717 group(3 mg/kg cGAS-STING signaling pathway activator SR-717)and curculigoside+SR-717 group(5 mg/kg curculigoside+3 mg/kg SR-717),with 15 rats in each group,injected once a day for 7 consecutive days,sham operation group and CI group were given equal amounts of nor-mal saline.Neural function was evaluated by Zea-Longa score;inflammatory factors levels were detected by ELISA;TTC staining was used to evaluate volume of CI;TUNEL staining was used to detect neuronal apoptosis;immunofluorescence staining was used to detect GSDMD-N expression;Western blot was used to detect expression of pyroptosis and cGAS-STING pathway proteins.Results:Com-pared with sham operation group,Zea-Longa score,CI volume,IL-1β and IL-18 levels,apoptosis rate,number of GSDMD-N positive cells,NLRP3,cleaved-Caspase-1/Caspase-1,GSDMD-N,cGAS and STING protein expressions in CI group were significantly increased(P<0.05);compared with CI group,Zea-Longa score,CI volume,IL-1β and IL-18 levels,apoptosis rate,number of GSDMD-N positive cells,NLRP3,cleaved-Caspase-1/Caspase-1,GSDMD-N,cGAS and STING protein expressions in curculigoside group were significantly decreased(P<0.05),while the above indexes in SR-717 group had opposite trend(P<0.05);SR-717 reversed improvement effect of curculigoside on neuronal pyroptosis in CI rats.Conclusion:Curculigoside may improve neuronal pyroptosis in CI rats by down-regulating cGAS-STING signaling pathway.

Ulcerative colitis(UC)is a chronic inflammatory bowel disease affecting the colon(particularly the descending colon and sigmoid)and rectum.UC primarily presents with persistent or recurrent diarrhea,abdominal pain,bloody stools,and other symptoms.The primary pathological mechanism of UC involves intestinal barrier injury.When the intestinal barrier function is compromised,characterized by loss of epithelial layer integrity,thinning of the mucus layer,and microbiota dysregulation,pathogenic microorganisms can infiltrate the lamina propria from the intestinal lumen through the damaged barrier,triggering and exacerbating the intestinal inflammatory response.Current treatments for UC are limited by high costs,numerous adverse reactions,and a high likelihood of relapse.Consequently,there is an urgent need for the development of new drugs that can effectively and safely treat UC.Natural products have become significant research targets in treating various diseases due to their broad biological activity,multiple action targets,low toxicity,and easy availability.They play a crucial role in the targeted repair of the intestinal barrier,with potential mechanisms including enhancing intes-tinal epithelial cells and their secreted proteins,regulating gut microbiota and its metabolism,and balancing immune cell subsets.Additionally,it is essential to consider the synergistic effects,bioavailability,and safety of natural products.This paper summarizes the natural products reported in the past five years for their anti-UC properties by repairing the intestinal barrier,providing a theoretical basis for the development and application of natural products in anti-UC drugs.

Background:To compare the efficacy and safety of monthly administrations of gonadotropin releasing hormone (GnRH) agonists LY01005 and Zoladex ? in Chinese patients with premenopausal breast cancer. Methods:From October 2020 to November 2021, 188 premenopausal breast cancer patients were enrolled in 34 hospitals and randomized 1:1 to receive either LY01005 or Zoladex ? every 28 days for a total of three injections. All patients concomitantly received oral tamoxifen (TAM). The primary efficacy endpoint was cumulative probability of maintaining menopausal level [oestradiol (E2) ≤30 pg/ml] from day 29 to day 85. The second efficacy endpoint included changes in E2, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) compared with the baseline. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were analyzed. The study also evaluated the pharmacokinetic and pharmacodynamic characteristics of LY01005. Results:A total of 188 patients were randomised and 187 patients received either LY01005 or Zoladex ?. Cumulative probabilities of maintaining menopausal level (E2≤30 pg/ml) from day 29 to day 85 were 93.1% for LY01005 and 86.3% for Zoladex ?. The between-group difference was 6.8% (95% CI: -2.3%, 15.9%) and primary efficacy in the LY01005 group was not inferior to that in the Zoladex ? group. Changes in E2, LH, and FSH levels compared with the baseline were equivalent between the two groups (E2: 89.34% to 90.23% vs. 82.11% to 85.02%; LH: 88.89% to 95.52% vs. 89.70% to 97.02%; FSH: 75.36% to 80.85% vs.73.07% to 80.24%, respectively). After three consecutive doses of LY01005, the LH and FSH levels of the subjects showed a transient increase after the first dose, reached a peak on the second day and then started to decrease. The LH and FSH reached a lower level and remained at or below that level until the 85th day. Both treatments were well-tolerated. Conclusion:LY01005 is as effective as Zoladex ? in suppressing E2 to menopausal levels in Chinese patients with premenopausal breast cancer, with a similar safety profile.

Objective To explore the mechanism of malt alcohol extract improving depression-like behavior induced by CUMS in rats by regulating gut microbiota.Methods The depression model of rats was established using an 8-weeks CUMS procedure,and the administration group was given low(59.6 mg·kg-1)and high(178.8 mg·kg-1)doses of malt alcohol extract,respectively.The depression-like behavior of rats was evaluated by classic behavioral test.The composition of intestinal microbiota of rats was analyzed by 16S rRNA sequencing.The morphological changes of colon were observed by hematoxylin and eosin(HE),the expression of ZO-1 and Occludin in colon was detected by immunofluorescence(IF),and the expression of IL-10,IL-1βand 5-HT were detected by ELISA.Results The low dose of malt alcohol extract attenuated the depressive behavior and restored the expression of 5-HT in the brain of CUMS rats.16S rRNA sequencing results showed that the diversity and relative abundance of gut microbiota changed after treatment with the low dose of malt alcohol extract.ELISA results showed that the low dose of malt alcohol extract significantly reversed the CUMS-induced reduction of IL-10 and elevation of IL-1 β.HE results showed that the low dose of malt alcohol extract significantly ameliorated CUMS-induced structural damage in colon.IF results showed increased protain expression of intestinal epithelial barrier tight junction proteins ZO-1 and Occludin by the low dose of malt alcohol extract.Conclusion The low dose of malt alcohol extract can ameliorate CUMS-induced depressive-like behavior in rats by modulating intestinal flora,restoring 5-HT expression in the brain,inhibiting inflammation,and repairing the intestinal barrier.