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.

The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a cornerstone of host innate immunity, playing a central role in detecting cytosolic double-stranded DNA of both endogenous and exogenous origins. Upon activation, cGAS synthesizes the second messenger 2'3'-cyclic GMP-AMP (cGAMP), which binds and activates STING to trigger downstream immune responses, including the production of type I interferons and proinflammatory cytokines. Emerging studies highlight the cGAS-STING pathway as a promising therapeutic target for preventing and treating diverse pathologies, with particularly transformative potential in anticancer therapies. In this review, we dissect the key findings, functions, and associated components of the cGAS-STING pathway. In addition, we emphasize the factors that upregulate or downregulate the pathway, as well as the role of the cGAS-STING pathway in health and disease. By integrating mechanistic insights with clinical perspectives, this review aims to bridge fundamental discoveries with therapeutic applications of cGAS-STING biology.
Humans ; Nucleotidyltransferases/metabolism* ; Membrane Proteins/metabolism* ; Animals ; Immunity, Innate/physiology* ; Signal Transduction/physiology* ; Neoplasms/metabolism*

OBJECTIVE: By analyzing the differential miRNA in seminal plasma between individuals with normal and abnormal sperm DNA fragmentation index（DFI）, we aim to identify miRNA that may impact sperm DNA integrity and target genes, and attempt to analyze their potential mechanisms of action. METHODS: A total of 161 study subjects were collected and divided into normal control group, DFI-medium group and DFI-abnormal group based on the DFI detection values. Differential miRNA were identified through miRNA chip analysis. Through bioinformatics analysis and target gene prediction, miRNA related to DFI and specific target genes were identified. The relative expression levels of differential miRNA and target genes in each group were compared to explore the impact of their differential expression on DFI. RESULTS: Through miRNA chip analysis, a total of 11 differential miRNA were detected. Bioinformatics analysis suggested that miR-26a-5p may be associated with reduced sperm DNA integrity. And gene prediction indicated that PTEN was a specific target gene of miR-26a-5p. Compared to the normal control group, the relative expression levels of miR-26a-5p in both the DFI-medium group and the DFI-abnormal group showed a decrease, while the relative expression levels of PTEN showed an increase. The relative expression levels of miR-26a-5p in all groups were negatively correlated with DFI values, while the relative expression levels of PTEN showed a positive correlation with DFI values in the DFI-medium group and the DFI-abnormal group. The AUC of miR-26a-5p in the DFI-medium group was 0.740 (P<0.05), with a sensitivity of 73.6% and a specificity of 71.5%; the AUC of PTEN was 0.797 (P<0.05), with a sensitivity of 76.5% and a specificity of 78.4%. In the DFI-abnormal group, the AUC of miR-26a-5p was 0.848 (P<0.05), with a sensitivity of 81.3% and a specificity of 78.1%. While the AUC of PTEN was 0.763 (P<0.05), with a sensitivity of 77.2% and a specificity of 80.2%. CONCLUSION miR-26a-5p affects the integrity of sperm DNA by regulating the expression of PTEN negatively. The relative expression levels of seminal plasma miR-26a-5p and PTEN have good diagnostic value for sperm DNA integrity damage, which can help in the etiological diagnosis and prognosis analysis of abnormal DFI. This provides a diagnostic and treatment approach for the study and diagnosis of DFI abnormalities without clear etiology.
Male ; Humans ; MicroRNAs/genetics* ; PTEN Phosphohydrolase/genetics* ; Spermatozoa ; Semen/metabolism* ; DNA Fragmentation

OBJECTIVE: To investigate the inhibitory effect of Tanreqing Injection (TRQ) on the activation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome in macrophages infected with influenza A virus and the underlying mechanism based on mitophagy pathway. METHODS: The inflammatory model of murine macrophage J774A.1 induced by influenza A virus [strain A/Puerto Rico/8/1934 (H1N1), PR8] was constructed and treated by TRQ, while the mitochondria-targeted antioxidant Mito-TEMPO and autophagy specific inhibitor 3-methyladenine (3-MA) were used as controls to intensively study the anti-inflammatory mechanism of TRQ based on mitophagy-mitochondrial reactive oxygen species (mtROS)-NLRP3 inflammasome pathway. The levels of NLRP3, Caspase-1 p20, microtubule-associated protein 1 light chain 3 II (LC3II) and P62 proteins were measured by Western blot. The release of interleukin-1β (IL-1β) was tested by enzyme linked immunosorbent assay, the mtROS level was detected by flow cytometry, and the immunofluorescence and co-localization of LC3 and mitochondria were observed under confocal laser scanning microscopy. RESULTS: Similar to the effect of Mito-TEMPO and contrary to the results of 3-MA treatment, TRQ could significantly reduce the expressions of NLRP3, Caspase-1 p20, and autophagy adaptor P62, promote the expression of autophagy marker LC3II, enhance the mitochondrial fluorescence intensity, and inhibit the release of mtROS and IL-1β (all P<0.01). Moreover, LC3 was co-localized with mitochondria, confirming the type of mitophagy. CONCLUSION TRQ could reduce the level of mtROS by promoting mitophagy in macrophages infected with influenza A virus, thus inhibiting the activation of NLRP3 inflammasome and the release of IL-1β, and attenuating the inflammatory response.
Mitophagy/drug effects* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Animals ; Macrophages/virology* ; Inflammasomes/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Mice ; Mitochondria/metabolism* ; Reactive Oxygen Species/metabolism* ; Influenza A virus/physiology* ; Interleukin-1beta/metabolism* ; Cell Line ; Injections

Schizophrenia (SZ) stands as a severe psychiatric disorder. This study applied diffusion tensor imaging (DTI) data in conjunction with graph neural networks to distinguish SZ patients from normal controls (NCs) and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features, achieving an accuracy of 73.79% in distinguishing SZ patients from NCs. Beyond mere discrimination, our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis. These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers, providing novel insights into the neuropathological basis of SZ. In summary, our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.
Humans ; Schizophrenia/pathology* ; Diffusion Tensor Imaging/methods* ; Male ; Female ; Adult ; Brain/metabolism* ; Young Adult ; Middle Aged ; White Matter/pathology* ; Gene Expression ; Nerve Net/diagnostic imaging* ; Graph Neural Networks

The introduction of PD-1 blockades to chemotherapy and radiotherapy has shown promising outcomes in patients with nasopharyngeal carcinoma, but anti-PD-1 therapies are only effective in a small proportion of patients, indicating the need for reliable predictive biomarkers of benefit from immunotherapy. Here, we summarized recent advances in immunotherapy for nasopharyngeal carcinoma and studies on potential predictors that correlated with treatment response or long-term survival after immunotherapy, including biomarkers in both the tumor microenvironment and the tumor macroenvironment. Some of these biomarkers have been validated as truly predictive of immunotherapy benefit using cohorts from randomized controlled trials, while others still require further validation of their predictive value. We also summarized the challenges and future directions of biomarker studies, hopefully facilitating the development of predictive biomarkers for immunotherapy that can eventually enter clinical practice.
Humans ; Tumor Microenvironment/immunology* ; Nasopharyngeal Carcinoma/immunology* ; Immunotherapy/methods* ; Nasopharyngeal Neoplasms/immunology* ; Biomarkers, Tumor/metabolism* ; Immune Checkpoint Inhibitors/therapeutic use*

ObjectiveTo investigate the prevalence of cardiovascular diseases and their influencing factors in community-based schizophrenia patients in Shanghai, and to provide a scientific basis for the early identification and prevention of cardiovascular disease in this population. MethodsBased on the Shanghai community cohort with severe mental disorders in 2022, a total of 3 954 community-based schizophrenia patients were identified and included in this study through a stratified cluster sampling method. Basic information and relevant clinical data (including metabolic index data) were collected through questionnaire survey, physical examination and laboratory testing. Univariate analyses were performed using the chi-square tests, and multivariate logistic regression analyses were employed to identify influencing factors of comorbid cardiovascular diseases. ResultsA total of 3 954 community-based schizophrenia patients were included, of which a total of 1 237 (31.28%) patients had comorbid cardiovascular diseases. Multivariate logistic regression analyses showed that age 60 years old or above (OR=5.524, 95%CI: 3.716‒8.214), smoking behavior (OR=1.328, 95%CI: 1.042‒1.692), overweight (OR=1.900, 95%CI: 1.046‒3.451) or obesity (OR=2.678, 95%CI: 1.439‒4.985), elevated blood pressure (OR=1.546, 95%CI: 1.294‒1.846), abnormal fasting blood glucose (OR=1.552, 95%CI: 1.322‒1.823) and high-density lipoprotein cholesterol abnormalities (OR=1.283, 95%CI: 1.025‒1.606) were positively associated with the risk of comorbid cardiovascular diseases in patients with schizophrenia, while educational attainment of college/bachelor’s degree or above (OR=0.640, 95%CI: 0.450‒0.910) and being unmarried (OR=0.552, 95%CI: 0.457‒0.667) were negatively associated with the risk of cardiovascular diseases comorbidity. ConclusionAdvanced age, unhealthy behaviors and lifestyles, as well as abnormalities in blood pressure, blood glucose, and blood lipids, could all increase the risk of comorbid cardiovascular diseases in community schizophrenia patients. It is suggested to strengthen the monitoring and management of these risk factors in this population in the future, so as to achieve early detection, early diagnosis and early intervention of cardiovascular diseases.

Objective To explore the clinical characteristics of pediatric patients with cerebral palsy(CP)who also have comorbid epilepsy.Methods A retrospective analysis was conducted on the clinical data of 155 pediatric patients with CP and comorbid epilepsy admitted to the Third Affiliated Hospital of Zhengzhou University from January 2019 to December 2022.Patients were divided into 4 groups based on CP subtype:spastic diplegia group(n=29),spastic hemiplegia group(n=33),spastic quadriplegia group(n=73),and non-spastic group(n=20).Differences in sex,season of birth,birth weight,gestational age,and the relationship between gestational age and weight were compared among the groups.Additionally,the relationships between perinatal risk factors,MRI classification system(MRICS),gross motor function classification system(GMFCS),and the age of the first onset of epilepsy with respect to CP subtype were analyzed.Results Among the 155 patients,101 were male and 54 were female.A lower proportion of patients with spastic hemiplegia was observed with a gestational age of 28-31+6 weeks compared with those with spastic diplegia and spastic quadriplegia(P=0.009).The proportion of patients with a history of asphyxia in spastic hemiplegia group was significantly lower than that in the other 3 groups,and the proportion of patients with hypoxic-ischemic encephalopathy(HIE)in spastic hemiplegia group was significantly lower than in that both spastic quadriplegia group and non-spastic group(P<0.05).The proportion of patients in spastic quadriplegia group who had their first seizure at an age of<1 year was significantly higher than that in spastic diplegic group(P=0.041).The spastic diplegia group exhibited a higher percentage of white matter damage compared with the other 3 groups,and had a lower percentage of gray matter damage compared with both spastic hemiplegic group and non-spastic group(P=0.001).The proportion of patients with GMFCS levels Ⅳ-Ⅴ in spastic quadriplegia group was higher than those in the other 3 groups(P<0.001),and the proportion of patients with levels Ⅰ-Ⅲ in spastic hemiplegia group was significantly higher than those in spastic quadriplegia group and non-spastic group(P<0.001).Conclusion Significant differences were observed among pediatric patients with different subtypes of CP and comorbid epilepsy in factors such as gestational age,history of asphyxia,HIE history,age of first seizure,MRICS classification and GMFCS levels.

Objective To investigate the effects of different concentrations of adapalene on the morphology and functions of neuroblastoma cell line SH-SY5Y,as well as its role in inducing cell differentiation and apoptosis.Methods SH-SY5Y cells were divided into control group,low concentration(0.1 pM and 1 pM)adapalene groups,and high concentration(10 μM)adapalene group.Time-lapse microscopy was used to observe the morphological changes of SH-SY5Y cells.Immunofluorescence staining was performed to detect the expression of neuronal specific marker βⅢ-tubulin and mature neuronal marker neurofilament heavy polypeptide(NFH).Multi-electrode array was used to record the electrophysiological features of SH-SY5Y cells.Cell apoptosis was evaluated using a cell apoptosis detection kit.Results Low concentrations of adapalene promoted the formation of neurite outgrowth in SH-SY5Y cells,with the neurites interconnected to form a network.Spontaneous discharge activity was observed in SH-SY5Y cells treated with low concentrations of adapalene.Compared to the control group,the expression of βⅢ-tubulin and NFH increased in the 1 μM adapalene group,while the level of cell apoptosis increased in the high concentration adapalene group(P＜0.05).Conclusions Low concentrations of adapalene can induce differentiation of SH-SY5Y cells into mature functional neurons,while high concentrations of adapalene can induce apoptosis in SH-SY5Y cells.[Chinese Journal of Contemporary Pediatrics,2024,26(3):282-288]