Search Results (185)

Polygoni Multiflori Radix Praeparata (PMRP), a processed root of Polygonum multiflorum Thunb. (known as Zhiheshouwu in Chinese medicine), exhibits anti-aging properties and is used to improve ovarian aging. However, its therapeutic mechanism against premature ovarian insufficiency (POI) remains unclear. This study investigates whether PMRP alleviates POI by inhibiting PANoptosis—a cell death pathway characterized by the concurrent occurrence and interplay of pyroptosis, apoptosis, and necroptosis. POI was induced in rats using tripterygium glycosides. We evaluated the estrous cycle, serum hormone levels (follicle-stimulating hormone [FSH], estrogen [E₂], anti-Müllerian hormone [AMH]), follicular development, and the ultrastructure of granulosa cells. PANoptosome assembly (apoptosis-associated speck-like protein containing a CARD [ASC]/caspase-8/receptor-interacting protein kinase 3 [RIPK3] co-localization) and key effectors of PANoptosis (caspase 3, cleaved caspase 3, gasdermin D [GSDMD], cleaved GSDMD, GSDME, RIPK1, mixed-lineage kinase domain-like protein [MLKL], and p-MLKL) were analyzed. PMRP restored the estrous cycle, lowered FSH levels, and increased E₂ and AMH levels in POI rats. It reduced follicular atresia, preserved primordial follicles, and suppressed PANoptosis-like death in granulosa cells. Mechanistically, PMRP disrupted PANoptosome assembly and downregulated key effectors of PANoptosis. PMRP alleviates POI by inhibiting PANoptosis in granulosa cells, overcoming the previous limitations of targeting single death pathways and providing novel insights into the pathogenesis and treatment strategies for POI. Full article

Background: Necroptosis, a regulated form of inflammatory cell death, is increasingly recognized as a key driver of sepsis and critical illness. The balance between necroptosis and apoptosis may influence immune responses and outcomes in ICU patients. Objective: To evaluate necroptosis- and apoptosis-related protein expression in critically ill pediatric and adult patients with sepsis/septic shock, trauma/SIRS, or cardiac conditions, and assess their association with clinical outcomes. Methods: In this prospective, observational study, 88 patients admitted to a tertiary ICU were categorized into four groups: sepsis/septic shock, trauma/SIRS, cardiac disease, and healthy controls. Serum levels of RIPK1, RIPK3, MLKL, A20, caspase-8, IL-1β, and IL-18 were measured within 24 h of admission using ELISA. Biomarkers were analyzed by disease group, age, and severity indices. Results: Patients with sepsis—both adults and children—exhibited significantly elevated levels of RIPK1, IL-1β, and IL-18 (p < 0.001) and reduced levels of caspase-8 (p = 0.015), indicating activation of the necroptosis pathway. A20 was significantly upregulated (p < 0.001) and independently associated with lactate levels. RIPK1, IL-1β, and IL-18 were positively correlated with ICU length of stay and illness severity, whereas caspase-8 showed an inverse correlation. ROC analysis demonstrated strong predictive performance for sepsis/septic shock using RIPK1 (AUC = 0.81), IL-18 (AUC = 0.71), and A20 (AUC = 0.71); conversely, caspase-8 was inversely associated with sepsis (AUC = 0.32). Conclusions: Necroptosis appears to play a central role in the pathophysiology of sepsis across age groups. Elevated levels of RIPK1, IL-1β, IL-18, and A20 may serve as biomarkers of disease severity, while reduced caspase-8 supports a shift away from apoptosis toward necroptotic cell death. These findings highlight the potential of necroptosis-related pathways as targets for risk stratification and therapeutic intervention in critically ill patients of all ages. Full article

This study evaluated the therapeutic potential of 70% ethanol extracts from six medicinal plants (Chenopodium album, Cassia tora, Cudrania tricuspidata, Dioscorea polystachya, Lonicera japonica, Solidago virgaurea subsp. gigantea) through their antibacterial, antioxidant, cytotoxic, and immunomodulatory activities, targeting applications in aquaculture. All extracts exhibited potent antibacterial activity (MIC ≤ 10 μg/mL) against Aeromonas spp. and Photobacterium damselae subsp. damselae, but limited efficacy against Streptococcus parauberis. C. tricuspidata (CTR) and C. tora (CTO) demonstrated superior antioxidant activity (IC₅₀ = 1292 μg/mL and IC₅₀ = 227 μg/mL, respectively), correlating with high polyphenol content (1498 and 1409 mg GAE/g). CTR displayed significant concentration-dependent cytotoxicity (IC₅₀ = 904.2 μg/mL), while C. album (CA) promoted cell proliferation (132.3% viability). In LPS-stimulated CHSE-214 cells, D. polystachya (DP) induced the highest IL-8 expression (207-fold), followed by Chenopodium album (CA) (194-fold IL-8, 49-fold TNF-α) and CTR (245-fold RIPK2), activating NF-κB, MAPK, and NOD-like receptor pathways critical for teleost immunity. Lonicera japonica (LJ) suppressed TNF-α (0.4-fold) and IRF1 (0.3-fold), indicating anti-inflammatory potential, while S. virgaurea subsp. gigantea (SV) showed biphasic TNF-α modulation (79-fold at 10 μg/mL, 5-fold at 100 μg/mL). These diverse bioactivities, particularly the robust immunomodulatory effects, highlight the promise of these extracts as natural therapeutic agents for fish health management in aquaculture. Full article

The global burden of liver diseases continues to rise, encompassing diverse pathologies such as viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). In recent years, TNFR1-associated death domain protein (TRADD), a pivotal adaptor molecule in the TNF signaling pathway, has been found to play a dual regulatory role in the pathogenesis of liver diseases. Through its death domain, TRADD binds to TNFR1 and dynamically recruits downstream factors (e.g., TRAF2, RIPK1, FADD) to form Complex I or IIa, thereby activating pro-survival or pro-apoptotic signals that dictate hepatocyte fate and modulate the inflammatory microenvironment. This review systematically summarizes the molecular structure and functional networks of TRADD, along with its mechanistic roles in liver diseases: in HCC, TRADD expression correlates with tumor differentiation and is regulated by miRNA targeting; in ALD and MASLD, TRADD-mediated apoptosis is closely linked to fibrotic progression; and in acute liver injury, TRADD signaling is modulated by factors such as HO-1 to mitigate damage. Furthermore, TRADD inhibitors and antisense oligonucleotides demonstrate therapeutic potential. This review highlights the clinical translational value of TRADD as a diagnostic, therapeutic, and prognostic biomarker for liver diseases, providing a theoretical foundation for future precision medicine strategies. Full article

Diffuse gliomas (DGs) are malignant primary brain tumors originating from glial cells. This study aimed to investigate the role of Receptor-interacting protein kinase 1 (RIPK1) in DG pathology. The RIPK1 mRNA expression was analyzed in DG databases from The Cancer Genome Atlas (TCGA) containing clinical, genomic, and transcriptomic information from 670 patients. Transcriptomic studies were carried out using USC Xena and R, while in vitro assays were performed with the glioblastoma human cell line U251 and the commercial RIPK1 inhibitor GSK2982772. The results showed that high RIPK1 expression was linked to a lower survival probability in patients. Additionally, the RIPK1 expression was higher in the wtIDH samples compared to that in the mIDH samples. Significant differences in the expression of genes related to cellular dedifferentiation, proinflammatory cell death pathways, and tumor-infiltrating immune cells were found between high- and low-RIPK1 expression groups. To further characterize the role of RIPK1 in DG, the effects of the RIPK1 inhibitor were evaluated, alone or combined with cisplatin, on glioblastoma cell proliferation and apoptosis. The combined treatments effectively reduced cell proliferation and increased apoptosis. The overexpression of RIPK1 was associated with a poor prognosis for DG, suggesting that RIPK1 plays a critical role in glioma pathogenesis and should be considered in therapeutic decision-making. Full article

Resistance to cell death is one of the core hallmarks of cancer, with regulatory abnormalities particularly pronounced in the malignant progression and therapeutic resistance of melanoma. This review aims to systematically summarize the roles and mechanisms of regulated cell death (RCD) in melanoma. Currently, distinct types of RCD, including apoptosis, autophagy, pyroptosis, immunogenic cell death, necroptosis, and ferroptosis, have all been found to be involved in melanoma. Autophagy promotes the survival of melanoma cells under stress conditions through metabolic adaptation, yet its excessive activation can trigger cell death. Immunogenic cell death has the capacity to elicit adaptive immune responses in immunocompetent syngeneic hosts. Necroptosis, governed by the receptor-interacting protein kinase 1 (RIPK1)/RIPK3 mixed lineage kinase domain-like protein (MLKL) signaling axis, can synergize with immunotherapy to enhance anti-melanoma immune responses when activated. Pyroptosis, mediated by Gasdermin proteins, induces the release of inflammatory factors that reshape the tumor microenvironment and enhance the efficacy of immune checkpoint inhibitors. Ferroptosis, characterized by lipid peroxidation, can overcome melanoma resistance by targeting the solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis. Therapeutic strategies targeting RCD pathways have demonstrated breakthrough potential. Several agents have been developed to target RCD in order to suppress melanoma. Full article

Multiple myeloma is a neoplastic disease characterised by the proliferation of clonal, atypical plasma cells. In cancer cells, the balance between two paths of cell death, necroptosis and apoptosis, is disrupted. The aim of this study was to analyse the occurrence of polymorphisms in genes encoding key proteins for the necroptosis process, i.e., RIPK-1, RIPK-3 and MAPKAPK2. We investigated the potential relations between the occurrence of genetic variability and the clinical course of the disease. We analysed six single-nucleotide polymorphisms in a population of patients with multiple myeloma (n = 205) and healthy volunteers (n = 100): RIPK1 rs2272990, RIPK1 rs9391981, RIPK3 rs724165, RIPK3rs3212243, MAPKAPK2, rs45514798 and MAPKAPK2 rs4073250. We found that genotypes rs9391981 CG, rs724165 CG, rs3212243 GG, and rs4073250 AA were independent predictors of overall survival, while genotype MAPKAPK2 rs4073250 AA was an independent predictor of progression-free survival. MAPKAPK2 rs45514798 AA was associated with polyneuropathy after thalidomide therapy. In conclusion, some of the SNPs tested have potential prognostic value and could be used as marker of survival in patients with multiple myeloma. Full article

Although the global incidence of tuberculosis has declined in recent years, tuberculosis remains a major global public health challenge. The Mycobacterium tuberculosis complex (MTBC) including M. tuberculosis, M. bovis, M. microti, etc., is the deadliest Mycobacterium spp. that needs more attention. Research on M. microti is significant as it is a zoonotic pathogen that can spread between animals and humans. By exploring the function of a transglutaminase in M. microti (MmTG), which is widely distributed in Mycobacterium and other species, a potential cytotoxic effector has been characterized. MmTG inhibits cell proliferation by inducing the phosphorylation of RIPK1 (receptor-interacting serine/threonine-protein kinase 1) and the Cys159 of MmTG is the highly conserved residue related to its cytotoxicity. Understanding MmTG and its homologs can provide more insights into the pathogenic mechanisms of mycobacteria and contribute to the development of more effective therapeutic strategies against mycobacterial infections. Full article

The examination of PANoptosis in colorectal cancer is particularly important, as many tumor cells can evade apoptotic cell death while continuing to proliferate through inflammatory mediators and creating an immunosuppressive environment. The PANoptosome functions as a regulatory complex that unites proteins governing pyroptotic, apoptotic, and necroptotic pathways, rather than allowing distinct death pathways to compete. The expression and functional status of key molecules within the PANoptosome, such as ZBP1, RIPK1, RIPK3, CASP8, and ASC, may influence tumor viability and immune detection. The tumorigenic impact of PANoptosis is complex and predominantly manifests through chronic inflammation, immune response modulation, and changes in the tumor microenvironment. PANoptosis also aids in the defense against colon cancer by directly eradicating tumor cells and modifying the cellular environment. The expression profile of PANoptosis components may possess prognostic and predictive significance. The therapeutic ramifications of PANoptosis in colorectal cancer are now being investigated through many avenues. It provides an opportunity to develop targeted therapeutic techniques. In contrast, it may also be pertinent in conjunction with immunotherapy, as PANoptosis signifies an immunogenic type of cell death and may consequently enhance the anti-tumor immune response. A thorough comprehension of how these parameters influence PANoptosis is crucial for practical implementation. Full article

Scrub typhus is an emerging chigger-borne disease caused by the obligate intracellular bacterium Orientia tsutsugamushi. Necroptosis is a form of programmed cell death (PCD) mediated by RIPK3 (serine/threonine kinase receptor interacting protein 3) and its downstream effector MLKL (mixed-lineage kinase domain-like). While O. tsutsugamushi modulates apoptosis, another form of PCD, its interplay with necroptosis is unknown. Much of Orientia pathobiology is linked to its ankyrin repeat (AR)-containing effectors (Anks). Two of these, Ank1 and Ank6, share similarities with the cowpox AR protein, vIRD (viral inducer of RIPK3 degradation) that prevents necroptosis. Here, we show that Ank1 and Ank6 reduce RIPK3 cellular levels although not as robustly as and mechanistically distinct from vIRD. Orientia infection lowers RIPK3 amounts and does not elicit necroptosis in endothelial cells. In HeLa cells ectopically expressing RIPK3, Orientia fails to inhibit RIPK3 and MLKL phosphorylation as well as cell death. MLKL colocalization with Orientia or Listeria monocytogenes, another intracytoplasmic pathogen, was not observed. Thus, O. tsutsugamushi reduces cellular levels of RIPK3 and does not elicit necroptosis but cannot inhibit this PCD pathway once it is induced. This study is a first step toward understanding how the relationship between Orientia and necroptosis contributes to scrub typhus pathogenesis. Full article

Background: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H₂S) in sepsis-induced adrenal dysfunction. Methods: A cecal ligation and puncture (CLP)-induced sepsis mouse model was employed. Adrenocortical-specific mixed lineage kinase domain-like pseudokinase (MLKL) knockout (MLKL-KO) and cystathioneine β-synthase (CBS) knockout (CBS-KO) mice were generated using Cre-loxP technology and adrenocortical-specific Cre tool mice. In vitro experiments utilized TNFα-stimulated Y1 adrenocortical cells. The treatments included the H₂S donor NaHS, TNFα inhibitor R-7050, necroptosis inhibitor NSA and CBS inhibitor AOAA. Pathological assessment involved hematoxylin–eosin (H&E) staining and a Western blot analysis of necroptosis markers (the phosphorylation of MLKL (p-MLKL) and phosphorylation of receptor-interacting protein kinases 1 (p-RIPK1)). Results: Sepsis induced adrenal congestion, elevated TNFα levels, and activated necroptosis (increased p-MLKL/p-RIPK1) in wild-type mice. H₂S treatment attenuated adrenal damage, reduced TNFα, and suppressed necroptosis. MLKL knockout reduced septic adrenal dysfunction, whereas CBS knockout exacerbated septic adrenal dysfunction. In vitro, TNFα induced Y1 cell necroptosis, which was reversed by H₂S or NSA. AOAA exacerbated TNFα-induced necroptosis in Y1 cells. Conclusions: H₂S inhibits TNFα-mediated necroptosis, thereby preserving adrenal integrity in sepsis. Targeting the TNFα–necroptosis axis and enhancing endogenous H₂S production may represent novel therapeutic strategies for sepsis-associated adrenal dysfunction. Full article

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. Unfortunately, drug resistance limits the efficacy of chemotherapeutic treatment and compromises therapeutic outcomes in a substantial proportion of cases. Aberrant CpG island methylation-associated transcriptional silencing contributes to chemoresistance in pediatric solid tumors. Here, using whole-genome DNA methylation screening on 16 human primary OS specimens, we identify receptor interacting protein kinase-3 (RIPK3), a molecular regulator of the necroptosis programmed cell death pathway, as a gene target of aberrant CpG methylation and demonstrate its role in human OS chemoresistance. We validated these findings via enforced expression and DsiRNA silencing, and evaluated the role of RIPK3 in cisplatin chemosensitivity and necroptosis activation through MLKL phosphorylation. We found that CpG island methylation results in RIPK3 silencing in primary human OS samples and cell lines. Enforced RIPK3 expression significantly enhanced cisplatin cytotoxicity in OS cells and DsiRNA knockdown reversed the cisplatin-sensitive phenotype. In cells with enforced RIPK3 expression, cisplatin treatment significantly increased phosphorylation of both RIPK3 and its target, MLKL, indicative of induction of necroptosis. Here, we identify RIPK3 as an important mediator of chemoresistance in OS and a potential pharmacologic target to improve chemotherapy efficacy in drug-resistant tumors. Full article

Psoriasis, a chronic immune-mediated inflammatory skin disorder characterized by keratinocyte hyperproliferation and inflammatory cell infiltration, involves multiple distinct programmed cell death pathways in its pathogenesis. Following the Nomenclature Committee on Cell Death recommendations, we analyzed the current literature examining diverse modes of cellular death in psoriatic lesions, with particular focus on keratinocyte cell death patterns and their molecular signatures. Analysis revealed several distinct cell death mechanisms: autophagy dysfunction through IL-17A pathways, decreased apoptotic activity in lesional skin, medication targeting anoikis in psoriasis, upregulated necroptosis mediated by RIPK1/MLKL signaling, gasdermin-mediated pyroptosis with enhanced IL-1β secretion, coordinated PANoptotic activation through specialized complexes, PARP1-mediated parthanatos promoting cutaneous inflammation, iron-dependent ferroptosis correlating with Th22/Th17 responses, copper-dependent cuproptosis with elevated MTF1/ATP7B/SLC31A1 expression, and NETosis amplifying immune responses through interaction with the Th17 axis. The intricate interplay between these cell death mechanisms has led to the development of targeted therapeutic strategies, including mTOR inhibitors for autophagy modulation, RIPK1 inhibitors for necroptosis, and various approaches targeting ferroptosis and NETosis, providing new directions for more effective psoriasis treatments. Full article

Research on functional recovery after ischemic stroke has primarily focused on non-invasive brain stimulation and motor rehabilitation therapies, while direct pharmacological interventions are relatively underexplored. This study utilized a bidirectional Mendelian randomization approach to investigate the causal relationship between 191 resting-state functional magnetic resonance imaging (rs-fMRI) features and post-ischemic stroke functional recovery (PISFR). Significant rs-fMRI phenotypes were identified, and Mendelian randomization was employed to determine their associated proteins. Bidirectional Mendelian randomization identified four rs-fMRI phenotypes potentially associated with functional recovery after ischemic stroke. Subsequent MR analysis, using pheno12 as the outcome and plasma protein as the exposure, highlighted Fas-Associated protein with Death Domain (FADD) as a significant protein. Further exploration within the protein–protein interaction (PPI) network identified FADD, Cysteinyl Aspartate Specific Proteinase 8 (CASP8), and Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) as potential drug targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that these proteins are involved in the extrinsic apoptotic pathway, providing new insights for pharmacological strategies in post-ischemic stroke recovery. This study offers genetic evidence linking rs-fMRI to functional recovery post-ischemic stroke and identifies potential drug targets that may facilitate therapeutic interventions to enhance recovery after ischemic stroke. Full article

Infectious bronchitis virus (IBV) poses a major challenge to poultry health and productivity. This study examined how inflammatory cell death pathways influence the replication and pathogenesis of two IBV strains—respiratory Connecticut (Conn) A5968 and nephropathogenic Delmarva (DMV)/1639—in chicken macrophages. Low serum conditions enhanced viral replication, reduced cell viability, and promoted apoptosis and necroptosis, with DMV/1639 showing more pronounced effects. Modulation of the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway displayed strain-specific effects, mitigating necroptosis in DMV/1639-infected cells but exacerbating apoptosis and necroptosis in Conn A5968-infected cells. Broad caspase inhibition (z-VAD-FMK) reduced necroptosis, while selective caspase-1/4 inhibition heightened apoptotic responses. Caspase-8 inhibition selectively reduced necroptosis in DMV/1639 infections but increased apoptosis and necroptosis in Conn A5968 infections. NLRP3 inflammasome and RIPK1 inhibition decreased cell viability and increased apoptosis in both strains but had distinct effects on necroptosis. These findings reveal the strain-specific regulation of viral replication, apoptosis, and necroptosis, underscoring the intricate interplay between IBV and host inflammatory pathways. Understanding these mechanisms provides novel insights into IBV pathogenesis and highlights potential therapeutic strategies to mitigate its impact on poultry health. Full article