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.

Chagas disease(American trypanosomiasis)is a zoonosis caused by Trypanosoma cruzi,which severely affects public health.Recently,with changes in economic globalization and increased population mobility,this disease has gradually spread from the original Latin American epidemic areas to non-epidemic areas,such as Europe,thus showing a trend of globalization.The main trans-mission routes have changed from transmission via the Triatomine vector to blood transfusion transmission,mother-to-child transmis-sion,oral transmission,and other routes.Consequently,Chagas disease is spreading globally,and more people are increasingly vul-nerable to infection.This article retrospectively reviews research on the transmission routes of Chagas disease,analyzes the changing trends in transmission routes,and provides a scientific basis for the formulation and optimization of Chagas disease prevention and con-trol strategies from a One Health perspective.

Chagas disease(American trypanosomiasis)is a zoonosis caused by Trypanosoma cruzi,which severely affects public health.Recently,with changes in economic globalization and increased population mobility,this disease has gradually spread from the original Latin American epidemic areas to non-epidemic areas,such as Europe,thus showing a trend of globalization.The main trans-mission routes have changed from transmission via the Triatomine vector to blood transfusion transmission,mother-to-child transmis-sion,oral transmission,and other routes.Consequently,Chagas disease is spreading globally,and more people are increasingly vul-nerable to infection.This article retrospectively reviews research on the transmission routes of Chagas disease,analyzes the changing trends in transmission routes,and provides a scientific basis for the formulation and optimization of Chagas disease prevention and con-trol strategies from a One Health perspective.

Objective To analyze the effect of tislelizumab combined with chemotherapy in the treatment of stage Ⅲb-Ⅳ non-small cell lung cancer(NSCLC)and its influence on T lymphocyte immunity and survival prognosis.Methods Patients with NSCLC were divided into control group and treatment group according to different treatment methods.The control group was treated with platinum-containing dual-drug combined chemotherapy regimen(PC regimen:intravenous drip of pemetrexed 500 mg·m-2 on the 1st day and intravenous drip of carboplatin with area under plasma concentration-time curve(AUC)=5 mg·mL-1·min-1 on the 1st day;TP regimen:intravenous drip of taxol 135 mg·m-2 on the 1st day,and intravenous drip of carboplatin with AUC=5 mg·mL-1·min-1 on the 1st day to 3rd day).The treatment group was given tislelizumab 200 mg intravenously once every 3 weeks on the basis of the control group.Both groups were treated for 2 cycles by taking 3 weeks as 1 treatment cycle.The clinical efficacy,serum tumor markers levels,T lymphocyte immune function,progression-free survival(PFS)and overall survival(OS)and occurrence of adverse drug reactions during treatment were compared between the two groups.Results There were 40 cases in control group and 40 cases in treatment group.After treatment,the total effective rates in control group and treatment group were 40.00％(16 cases/40 cases)and 62.50％(25 cases/40 cases),the disease control rates were 70.00％(28 cases/40 cases)and 90.00％(36 cases/40 cases),carcinoembryonic antigen(CEA)levels were(9.21±2.03)and(5.42±1.36)ng·mL-1,carbohydrate antigen 125(CA125)levels were(72.53±8.16)and(31.95±5.08)U·mL-1,carbohydrate antigen 19-9(CA19-9)levels were(25.79±3.31)and(10.38±2.04)U·mL-1,cytokeratin19 fragment antigen 21-1(CYFRA21-1)levels were(6.47±1.34)and(4.26±0.91)ng·mL-1,CD3+levels were(54.36±5.81)％and(61.85±4.96)％,CD4+levels were(31.28±2.93)％and(43.08±3.15)％,CD4+/CD8+were 1.43±0.40 and 1.91±0.46,survival rates were 47.37％(18 cases/38 cases)and 67.57％(25 cases/37 cases),PFS were 7.73 months(95％CI:6.42-9.03)and 9.75 months(95％CI:8.68-10.82),and OS were 8.96 months(95％CI:7.94-9.97)and 10.52 months(95％CI:9.78-11.27)respectively(all P＜0.05).There were no statistically significant differences in the incidence of gastrointestinal reactions,liver dysfunction,bone marrow suppression,hypothyroidism and non-infectious pneumonia between both groups(all P＞0.05).Conclusion Tislelizumab combined with chemotherapy has a good effect in the treatment of stage Ⅲb-Ⅳ NSCLC,and it can effectively reduce the levels of serum tumor markers,improve the T lymphocyte immune function,and prolong the survival time of patients,with good safety.

Objective To investigate the clinical efficacy and safety of the combination therapy of multi-targeted small molecule tyrosine kinase inhibitors(MTKIs)with immune checkpoint inhibitors(ICIs)for late-stage solid tumor in the patients with failed standard treatment regimens.Methods The patients with advanced solid tumors who had been hospitalized in our hospital from January 2021 to January 2023 after failure of≥2 standard treatment regimens were selected and treated with MTKIs combined with ICIs.The efficacy and safety of this regimen were retrospectively studied.Results A total of 21 patients were included.As of March 1,2022,the overall popula-tion had an ORR of 38%,a DCR of 67%,a median progression free survival(mPFS)of 10 months,and a median survival(mOS)of 15 months.Common adverse reactions were pneumonia and oral ulcers.Conclusion For the patients with advanced solid tumors who have failed standard treatment,MTKIs combined with ICIs may be a treat-ment option,but prospective studies with a larger sample size are needed to confirm the efficacy and safety of this combination therapy and to explore the population most likely to benefit from this treatment method.

Child ; Humans ; Malacoplakia/pathology* ; Intestines/pathology*

Background/Aims: Diagnosis of isolated laryngopharyngeal reflux symptoms (ILPRS), ie, without concomitant typical reflux symptoms (CTRS), remains difficult. Mean nocturnal baseline impedance (MNBI) reflects impaired mucosal integrity. We determined whether esophageal MNBI could predict pathological esophagopharyngeal reflux (pH+) in patients with ILPRS. Methods: In this cross-sectional study conducted in Taiwan, non-erosive or low-grade esophagitis patients with predominant laryngopharyngeal reflux symptoms underwent combined hypopharyngeal multichannel intraluminal impedance-pH monitoring when off acid suppressants. Participants were divided into the ILPRS (n = 94) and CTRS (n = 63) groups. Asymptomatic subjects without esophagitis (n = 25) served as healthy controls. The MNBI values at 3 cm and 5 cm above the lower esophageal sphincter (LES) and the proximal esophagus were measured. Results: Distal but not proximal esophageal median MNBI values were significantly lower in patients with pH+ than in those with pH– (ILPRS in pH+ vs pH–: 1607 Ω vs 2709 Ω and 1885 Ω vs 2563 Ω at 3 cm and 5 cm above LES, respectively; CTRS in pH+ vs pH–: 1476 vs 2307 Ω and 1500 vs 2301 Ω at 3 cm and 5 cm above LES, respectively, P < 0.05 for all). No significant differences of any MNBI exist between any pH– subgroups and healthy controls. The areas under the receiver operating characteristic curve in the ILPRS group were 0.75 and 0.80, compared to the pH– subgroup and healthy controls (P < 0.001 for both), respectively. Interobserver reproducibility was good (Spearman correlation 0.93, P < 0.0001). Conclusion Distal esophageal MNBI predicts pathological reflux in patients with ILPRS.

This article analyzed the mechanism of Danggui Sini Decoction(DSD) in improving kidney injury caused by blood stasis syndrome(BSS) in rats. Firstly, 32 female SD rats were randomly divided into the following four groups: a normal group and a BSS group, both receiving an equal amount of distilled water by gavage; a normal+DSD group and a BSS+DSD group, both receiving 5.103 g·kg~(-1) DSD orally for a total of 14 days. Daily cold water bath was given to establish the BSS model, and on the 14th day, BSS rats were subcutaneously injected with 0.8 mg·kg~(-1) adrenaline. Normal rats were subjected to the water bath at 37 ℃ and injected with an equal volume of distilled water. After the experiment, 24-hour urine, serum, and kidney samples were collected for metabolomic analysis, biochemical measurements, and hematoxylin-eosin(HE) staining. The study then employed ~1H-NMR metabolomic technology to reveal the metabolic network regulated by DSD in improving BSS-induced kidney injury and used network pharmacology to preliminarily elucidate the key targets of the effectiveness of DSD. Pathological and biochemical analysis showed that DSD intervention significantly reduced inflammation and abnormal levels of blood creatinine, blood urea nitrogen, and urine protein in the kidneys. Metabolomic analysis indicated that DSD attenuated BSS-induced kidney injury primarily by regulating 10 differential metabolites and three major metabolic pathways(taurine and hypotaurine metabolism, citrate cycle, and acetaldehyde and dicarboxylic acid metabolism). Network pharmacology analysis suggested that the protective effect of DSD against BSS-induced kidney injury might be related to two key genes, ATP citrate lyase(ACLY) and nitric oxide synthase 2(NOS2), and two main metabolic pathways, i.e., arginine biosynthesis, and arginine and proline metabolism. This study, from the perspective of network regulation, provides initial insights and evidence into the mechanism of DSD in improving kidney injury induced by BSS, offering a basis for further investigation into the molecular mechanisms underlying its efficacy.
Rats ; Female ; Animals ; Rats, Sprague-Dawley ; Network Pharmacology ; Drugs, Chinese Herbal/chemistry* ; Metabolomics ; Kidney ; Arginine ; Water

Pulmonary fibrosis is the end-stage pathological change of lung diseases, which seriously affects the respiratory function of human body. A large number of studies at home and abroad have confirmed that epithelial-mesenchymal transition (EMT) is an important intermediate stage in the development of pulmonary fibrosis. Inhibition of multiple pathways upstream and downstream of EMT, such as the classical Smads pathway and non-Smads pathway of TGF-1 can effectively inhibit the process of EMT and alleviate pulmonary fibrosis. This article will review the main conclusions of the mechanism of action of EMT as a target to improve the pathology of pulmonary fibrosis so far, and provide a theoretical basis and research direction for further research and development of anti-pulmonary fibrosis drugs.
Humans ; Epithelial-Mesenchymal Transition/drug effects* ; Fibrosis/drug therapy* ; Pulmonary Fibrosis/pathology* ; Signal Transduction ; Transforming Growth Factor beta1/metabolism* ; Antifibrotic Agents/therapeutic use*

Humans ; Presbycusis ; Speech Perception ; Hearing Aids ; Cognition ; Noise