The innate immune system detects cellular stressors and microbial infections, activating programmed cell death (PCD) pathways to eliminate intracellular pathogens and maintain homeostasis. Among these pathways, pyroptosis, apoptosis, and necroptosis represent the most characteristic forms of PCD. Although initially regarded as mechanistically distinct, emerging research has revealed significant crosstalk among their signaling cascades. Consequently, the concept of PANoptosis has been proposed—an inflammatory cell death pathway driven by caspases and receptor-interacting protein kinases (RIPKs), and regulated by the PANoptosome, which integrates key features of pyroptosis, apoptosis, and necroptosis. The core mechanism of PANoptosis involves the assembly and activation of the PANoptosome, a macromolecular complex composed of three structural components: sensor proteins, adaptor proteins, and effector proteins. Sensors detect upstream stimuli and transmit signals downstream, recruiting critical molecules via adaptors to form a molecular scaffold. This scaffold activates effectors, triggering intracellular signaling cascades that culminate in PANoptosis. The PANoptosome is regulated by upstream molecules such as interferon regulatory factor 1 (IRF1), transforming growth factor beta-activated kinase 1 (TAK1), and adenosine deaminase acting on RNA 1 (ADAR1), which function as molecular switches to control PANoptosis. Targeting these switches represents a promising therapeutic strategy. Furthermore, PANoptosis is influenced by organelle functions, including those of the mitochondria, endoplasmic reticulum, and lysosomes, highlighting organelle-targeted interventions as effective regulatory approaches. Cardiovascular diseases (CVDs), the leading global cause of morbidity and mortality, are profoundly impacted by PCD. Extensive crosstalk among multiple cell death pathways in CVDs suggests a complex regulatory network. As a novel cell death modality bridging pyroptosis, apoptosis, and necroptosis, PANoptosis offers fresh insights into the complexity of cell death and provides innovative strategies for CVD treatment. This review summarizes current evidence linking PANoptosis to various CVDs, including myocardial ischemia/reperfusion injury, myocardial infarction, heart failure, arrhythmogenic cardiomyopathy, sepsis-induced cardiomyopathy, cardiotoxic injury, atherosclerosis, abdominal aortic aneurysm, thoracic aortic aneurysm and dissection, and vascular toxic injury, thereby providing critical clinical insights into CVD pathophysiology. However, the current understanding of PANoptosis in CVDs remains incomplete. First, while PANoptosis in cardiomyocytes and vascular smooth muscle cells has been implicated in CVD pathogenesis, its role in other cell types—such as vascular endothelial cells and immune cells (e.g., macrophages)—warrants further investigation. Second, although pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are known to activate the PANoptosome in infectious diseases, the stimuli driving PANoptosis in CVDs remain poorly defined. Additionally, methodological challenges persist in identifying PANoptosome assembly in CVDs and in establishing reliable PANoptosis models. Beyond the diseases discussed, PANoptosis may also play a role in viral myocarditis and diabetic cardiomyopathy, necessitating further exploration. In conclusion, elucidating the role of PANoptosis in CVDs opens new avenues for drug development. Targeting this pathway could yield transformative therapies, addressing unmet clinical needs in cardiovascular medicine.

BACKGROUND:The phosphatidylinositol 3-kinase/protein kinase(PI3K/AKT)signaling pathway plays a pivotal role in regulating osteoclast activation,which is essential for maintaining bone homeostasis.Bone destruction in osteoarticular tuberculosis is caused by aberrant osteoclastogenesis induced by Mycobacterium tuberculosis infection.However,the role of the PI3K signaling pathway in Mycobacterium tuberculosis-induced aberrant osteoclastogenesis remains unclear. OBJECTIVE:To investigate the effects and mechanisms of the PI3K/AKT signaling pathway inhibitor BYL-719 on aberrant osteoclastogenesis induced by Mycobacterium tuberculosis. METHODS:RAW264.7 cells were infected with bovine Mycobacterium tuberculosis bacillus calmette-cuerin vaccine,and Ag85B was used for cellular immunofluorescence staining.The cell counting kit-8 assay was employed to determine the safe concentration of BYL-719.There were four groups in the experiment:blank control group,BYL-719 group,BCG group,and BCG+BYL-719 group.Under the induction of receptor activator of nuclear factor kappa-B ligand,the effects of BYL-719 on post-infection osteoclast differentiation and fusion were explored through tartrate-resistant acid phosphatase staining and phalloidin staining.RT-PCR and western blot were used to detect the expression of osteoclast-related genes and proteins,and further investigate the mechanism of action. RESULTS AND CONCLUSION:Immunofluorescence staining showed that RAW264.7 cells phagocytosed Mycobacterium tuberculosis.Cell counting kit-8 data indicated that 40 nmol/L BYL-719 was non-toxic to cells.Tartrate-resistant acid phosphatase staining and phalloidin staining showed that BYL-719 inhibited the generation and fusion ability of osteoclasts following infection.RT-PCR and western blot results also indicated that BYL-719 suppressed the upregulation of osteoclast-specific genes(including c-Fos,NFATc1,matrix metalloproteinase 9,and CtsK)induced by Mycobacterium tuberculosis infection(P<0.05).Western blot and immunofluorescence staining revealed that BYL-719 inhibited excessive osteoclast differentiation induced by Mycobacterium tuberculosis by downregulating the expression of IκBα-p65.To conclude,BYL-719 inhibits aberrant osteoclastogenesis induced by Mycobacterium tuberculosis through the downregulation of IκBα/p65.Therefore,the IκBα/p65 signaling pathway is a potential therapeutic target for osteoarticular tuberculosis,and BYL-719 holds potential value for the preventing and amelioration of bone destruction in osteoarticular tuberculosis.BYL-719 has the potential to prevent and ameliorate bone destruction in osteoarticular tuberculosis.

Objective: To investigate the mechanism of Yishen Tongluo Formula in ameliorating renal pyroptosis in diabetic nephropathy mice by regulating the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. Methods: Sixty C57BL/6 male mice were randomly divided into control (10 mice) and intervention groups (50 mice) using random number table method. The diabetes nephropathy model was established by intraperitoneally injecting streptozotocin(50 mg/kg). After modeling, the intervention group was further divided into model, semaglutide (40 μg/kg), and high-, medium-, and low-dose Yishen Tongluo Formula groups (15.6, 7.8, and 3.9 g/kg, respectively) using random number table method. The high-, medium-, and low-dose Yishen Tongluo Formula groups were administered corresponding doses of medication by gavage, the semaglutide group received a subcutaneous injection of semaglutide injection, and the control group and model groups were administered distilled water by gavage for 12 consecutive weeks. Random blood glucose levels of mice in each group were monitored, and the 24-h urinary protein content was measured using biochemical method every 4 weeks; after treatment, the serum creatinine and urea nitrogen levels were measured using biochemical method. The weight of the kidneys was measured, and the renal index was calculated. Hematoxylin and eosin, periodic acid-Schiff, periodic Schiff-methenamine, and Masson staining were used to observe the pathological changes in renal tissue. An enzyme-linked immunosorbent assay was used to detect urinary β2-microglobulin (β2-MG), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) levels. Western blotting and real-time fluorescence PCR were used to detect the relative protein and mRNA expression levels of nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3), Caspase-1, gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18) in renal tissue. Immunohistochemistry was used to detect the proportion of protein staining area of the TLR4, MyD88, and NF-κB in renal tissue. Results: Compared with the control group, the random blood glucose, 24-h urinary protein, serum creatinine, urea nitrogen, and renal index of the model group increased, and the urine β2-MG, NGAL, and KIM-1 levels increased. The relative protein and mRNA expression levels of NLRP3, Caspase-1, GSDMD, IL-1β, and IL-18 in renal tissue increased, and the proportion of TLR4, MyD88, and NF-κB protein positive staining areas increased (P<0.05). Pathological changes such as glomerular hypertrophy were observed in the renal tissue of the model group. Compared with the model group, the Yishen Tongluo Formula high-dose group showed a decrease in random blood glucose after 12 weeks of treatment (P<0.05). The Yishen Tongluo Formula high- and medium-dose groups showed a decrease in 24-h urinary protein, creatinine, urea nitrogen, and renal index, as well as decreased β2-MG, NGAL, and KIM-1 levels. NLRP3, Caspase-1, GSDMD, IL-1 β, and IL-18 relative protein and mRNA expression levels were also reduced, and the proportion of TLR4, MyD88, and NF-κB protein positive staining areas was reduced (P<0.05). Pathological damage to renal tissue was ameliorated. Conclusion Yishen Tongluo Formula may exert protective renal effects by inhibiting renal pyroptosis and alleviating tubular interstitial injury in diabetic nephropathy mice by regulating the TLR4/MyD88/NF-κB signaling pathway.

Objective To explore and analyse the signals of adverse events of esketamine,and to provide references for rational clinical use of the drug.Methods The adverse event reports of esketamine from the first quarter of 2019 to the fourth quarter of 2023 in the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database were collected.The reporting odds ratio(ROR)method and information component(IC)method in the disproportionality analysis and random forest(RF)algorithm,K-nearest neighbor algorithm and extreme gradient boosting(XGBoost)algorithm in machine learning algorithms were used for signal mining of target medicines respectively.The accuracy of machine learning signal detection results was assessed by the area under the curve(AUC).Results A total of 5 247 adverse event records with esketamine as the primary suspect drug were obtained.Using the traditional detection measures of dis-proportionality,138 positive signal results were detected,6 new adverse events including anticholinergic syndrome,urinary incontinence,double vision,pyelonephritis,spontaneous pneumothorax,biliary obstruction,were not included in the FDA drug inserts,and it was found that the drug may be more likely to cause cardiovascular problems.The results of the machine learning training showed that XGBoost algorithm and RF algorithm performed moderately well,with AUC means of 0.928 and 0.921,respectively.A total of 4 new potential adverse drug event signals,diplopia,deterioration of general physical health,suicidal ideation and withdrawal syndrome were detected by XGBoost algorithm and RF algorithm.Conclusion Esketamine is accompanied by some unknown risks while obtaining significant efficacy and adverse events not mentioned in the specification may occur in clinical practice.Healthcare professionals should be fully alert to the relevant adverse events when applying them in clinical treatment and take timely measures to ensure the safety of the treatment.

Aim To investigate the possible mechanism of action of Qingjie Huagong decoction(QJHGD)on acute lung injury(ALI)associated with severe acute pancreatitis(SAP)using network pharmacology,and to verify it by animal experiments.Methods The TC-MSP,BATMAN-TCM,ETCM,and SwissTargetPredic-tion databases were searched to obtain the action tar-gets of the blood-entering active ingredients of each drug in the QJHGD.The GeneCard database was searched to obtain SAP-ALI disease targets.The drug targets and disease targets were intersected to obtain common targets.Subsequently,the common targets were analyzed by STRING database and Cytoscape 3.7.1 software for protein interaction network analysis.GO and KEGG enrichment analysis was performed with the help of DAVID database.Finally,the key signa-ling pathways were verified by animal experiments.Results A total of 28 active ingredients were screened out for the treatment of SAP-ALI with 42 common tar-gets.PPI network analysis showed that STAT3,IL-6,and TGFB1 might be core targets;GO and KEGG en-richment analysis mainly involved cell proliferation,PI3K/AKT signaling pathways,etc.Animal experi-ments confirmed that QJHGD could improve the pathol-ogy of pancreas and lung tissues in SAP-ALI rat mod-el,down-regulate the expression levels of α-amylase,lipase,IL-1 β,IL-6,and TNF-α in serum,and down-regulate the expression levels of proteins and mRNAs related to PI3K/AKT1 signaling pathway in lung tis-sues.Conclusion QJHGD synergistically treats SAP-ALI through multi-component,multi-target,and multi-pathway,with a mechanism that may be related to the inhibition of PI3K/AKT signaling pathway activation.

Aim To investigate the effect of Huazhuo Jiedu Yikui decoction(HJYD)on Th1/Th2 balance,stress response and intestinal mucosal in rats with ul-cerative colitis.Methods Wistar rats of SPF grade were randomly divided into six groups:control group,model group,HJYD low,medium and high dose groups(1.25,2.5,5 kg·L-1),and positive me-salazine group(0.05 kg·L-1).Except for the con-trol group,the rats in other groups were established in-to ulcerative colitis animal models and were intragastri-cally administered with drug.TNF-α,IL-8,IL-13,IL-10,IFN-γ and IL-4 were detected by ELISA.The levels of SOD,MDA and GSH-Px were detected by re-lated kits.The pathological morphology of intestinal tissue was observed using HE staining and the score was calculate.The apoptosis rate of intestinal epithelial cells was detected by TUNEL method.The protein lev-els of NF-κB,TLR4,MyD88,Bcl-2 and Bax in intes-tinal tissue were detected by Western blot.Results Compared with the model group,the levels of TNF-α,IL-8,IL-13,MDA,IFN-γ,pathological score,intes-tinal epithelial cell apoptosis rate,NF-κB,TLR4,MyD88 and Bax in the HJYD groups were reduced(P＜0.05),and the levels of IL-10,IL-4,SOD,GSH-Px and Bcl-2 were raised(P＜0.05).Conclu-sions HJYD can significantly inhibit oxidative stress and inflammatory response in rats with ulcerative coli-tis,promote Th1/Th2 balance,and play a protective role in intestinal mucosa.The mechanism is related to the inhibition of NF-κB/TLR4/MyD88 signaling path-way.

Objective To investigate the application effect of grid-like locator in percutaneous transforaminal endoscopic discectomy(TESSYS)technology for lumbar disc herniation(LDH)in young adults.Methods Using a randomized controlled study method,102 young adults with LDH were included and divided into the control group and the observation group,with 51 cases in each group.Patients in the control group underwent TESSYS technology,while patients in the observation group underwent TESSYS technology with a grid-like locator.The perioperative indicators,complications,good to excellent surgical rate,the pre-and post-operative pain mediators[5-hydroxy-tryptamine(5-HT),substance P(SP)],Oswestry disability index(ODI),visual analogue scale(VAS),Cobb angle,and lumbar curvature index were compared between the two groups.Results The operation time of patients in the observation group was shorter than that of the control group,and the intraoperative blood loss and the number of intraoperative fluoroscopy were less than those of the control group(P＜0.05).The levels of serum 5-HT and SP,and VAS score 3 days after surgery in the observation group were lower than those in the control group(P＜0.05).There was no significant difference in the serum pain mediators,VAS scores,ODI scores,Cobb angles,or lumbar curvature indexes 3 months,6 months,and 12 months after surgery between the two groups(P＞0.05).There was no significant difference between the observation group and the control group in the incidence of complications(4.16％vs.10.64％),good to excellent surgical rate(89.58％vs.85.11％)12 months after surgery(P＞0.05).Conclusion The application of a grid-like locator in TESSYS technology for young adults with LDH can help to reduce the intraoperative fluoroscopy,alleviate pain symptoms,and shorten the operation time.

Objective To explore the risk factors for bile leakage after laparoscopic common bile duct exploration(LCBDE)with primary closure.Methods The clinical data of 560 patients with choledocholithiasis who underwent LCBDE with primary closure in Tianjin Hospital of Integrated Traditional Chinese and Western Medicine from September 2021 to September 2023 were retrospectively analyzed,and the patients were divided into the bile leak group and the non-bile leak group according to the occurrence of postoperative bile leakage.The risk factors affecting the occurrence of postoperative bile leakage were analyzed by multivariate analysis.Results A total of 64 cases(11.4% )experienced varying degrees of bile leakage,including 55 cases of grade A bile leakage,7 cases of grade B,and 2 cases of grade C.The thin common bile duct(OR=0.07,P<0.001),history of hypertension(OR=4.56,P<0.001),and high BMI(OR=1.17,P=0.002)were the risk factors for postoperative bile leakage in patients with choledocholithiasis.Conclusion Patients with thin common bile duct,hypertension and obesity are more likely to occur postoperative bile leakage.Patients with choledocholithiasis who have the above high-risk factors should be cautious in choosing LCBDE with primary closure.

Objective To monitor the antifungal resistance of clinical isolates of Candida spp.in the East China region.Methods MALDI-TOF MS or molecular methods were used to re-identify the strains collected from January 2018 to December 2022.Antifungal susceptibility testing was performed using the broth microdilution method.The susceptibility test results were interpreted according to the breakpoints of 2022 Clinical and Laboratory Standards Institute(CLSI)documents M27 M44s-Ed3 and M57s-Ed4.Results A total of 3 026 strains of Candida were collected,65.33％of which were isolated from sterile body sites,mainly from blood(38.86％)and pleural effusion/ascites(10.21％).The predominant species of Candida were Candida albicans(44.51％),followed by Candida parapsilosis complex(19.46％),Candida tropicalis(13.98％),Candida glabrata(10.34％),and other Candida species(0.79％).Candida albicans showed overall high susceptibility rates to the 10 antifungal drugs tested(the lowest rate being 93.62％).Only 2.97％of the strains showed dose-dependent susceptibility(SDD)to fluconazole.Candida parapsilosis complex had a SDD rate of 2.61％and a resistance rate of 9.42％to fluconazole,and susceptibility rates above 90％to other drugs.Candida glabrata had a SDD rate of 92.01％and a resistance rate of 7.99％to fluconazole,resistance rates of 32.27％and 48.24％to posaconazole and voriconazole non-wild-type strains(NWT),respectively,and susceptibility rates above 90％to other drugs.Candida tropicalis had resistance rates of 29.55％and 26.24％to fluconazole and voriconazole,respectively,resistance rates of 76.60％and 21.99％to posaconazole and echinocandins non-wild-type strains(NWT),and a resistance rate of 2.36％to echinocandins.Conclusions The prevalence and species distribution of Candida spp.in the East China region are consistent with previous domestic and international reports.Candida glabrata exhibits certain degree of resistance to fluconazole,while Candida tropicalis demonstrates higher resistance to triazole drugs.Additionally,echinocandins resistance has emerged in Candida albicans,Candida glabrata,Candida tropicalis,and Candida parapsilosis.

Objective:To retrieve, evaluate, and integrate evidence related to balance function management in stroke patients with hemiplegia.Methods:A systematic search was conducted on BMJ Best Practice, UpToDate, National Institute for Health and Care Excellence, Guidelines International Network, Scottish Intercollegiate Guidelines Network, Australia Joanna Briggs Institute Evidence-Based Practice Center, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, VIP, China Biology Medicine disc, PubMed, Web of Science, Medlive, and other websites or data platforms for relevant guidelines, best practices, evidence summaries, systematic reviews, and Meta-analyses on balance function management in stroke patients with hemiplegia, with a retrieval period from March 2014 to March 2024. Two researchers trained in evidence-based practices evaluated the methodological quality of the literature and extracted and summarized the relevant evidence.Results:Based on the inclusion and exclusion criteria, a total of eight guidelines and seven systematic reviews were included, yielding 29 pieces of best evidence across nine aspects: the importance of balance function training, organizational management, assessment tools, assessment timing, assessment content, assessment frequency, balance exercise programs, exercise duration, and health education.Conclusions:This study summarizes the best evidence for balance function management in stroke patients with hemiplegia, providing accurate evidence-based support for clinical practice among medical professionals. It is recommended that healthcare providers appropriately apply this evidence based on clinical scenarios to improve measures related to balance function management in stroke patients with hemiplegia.