Search Results (138)

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

Increasing evidence reveals that the deregulation of cellular antioxidant response with advancing age, resulting in the continuing amplification of oxidative stress-induced inflammatory response, is a pre-eminent cause for the onset of aging-related disease states, including blinding diseases. However, several safeguards, like an antioxidant defense system, are genetically in place to maintain redox homeostasis. Nonetheless, if the homeostatic capacity of such systems fails (like in aging), an inflammatory pathway elicited by excessive oxidative stress-evoked aberrant NLRP3 (NOD, LRR- and pyrin domain-containing protein 3) inflammasome activation can become pathogenic and lead to disease states. Among all known inflammasomes, NLRP3 is the most studied and acts as an intracellular sensor to detect danger(s). Upon activation, NLRP3 recruits apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and facilitates the recruitment of activated Caspase-1 (Cas-1), which results in the release of inflammatory cytokines, IL-1β and IL-18 and the activation of GasderminD, an executor of pyroptosis. NLRP3 inflammasome is tightly regulated in favor of cell health. However, when and how the activation of NLRP3 and its inflammatory components goes awry, leading to cellular derangement, and what regulatory factors are involved in the normal physiological and aging/oxidative conditions will be included in this review. Also, we address the latest findings to highlight the connection between oxidative stress, antioxidants, and NLRP3 activation as this begets aging diseases and explore the cellular pathways that are in place to regulate oxidative-induced inflammations and the pathobiological consequences of dysregulated inflammatory responses and vice versa. Full article

Sepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes—cytosolic multiprotein complexes of the innate immune system—serve as critical platforms for sensing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Key sensors such as NLRP3, AIM2, and IFI16 initiate caspase-1 activation, IL-1β and IL-18 maturation, and gasdermin D–mediated pyroptosis. In sepsis, excessive inflammasome activation drives oxidative stress, endothelial dysfunction, immunothrombosis, and immune exhaustion. This maladaptive cascade is further aggravated by the release of DAMPs and procoagulant factors, compromising vascular integrity and immune homeostasis. Prolonged activation contributes to immunoparalysis, lymphopenia, and increased susceptibility to secondary infections. Inflammasome signaling also intersects with necroptosis and ferroptosis, amplifying systemic inflammation and tissue injury. Additionally, various pathogens exploit immune evasion strategies to modulate inflammasome responses and enhance virulence. Therapeutic interventions under investigation include selective NLRP3 inhibitors, IL-1 blockers, gasdermin D antagonists, and extracorporeal cytokine hemoadsorption. Emerging approaches emphasize biomarker-guided immunomodulation to achieve personalized therapy. While preclinical studies have shown promising results, clinical translation remains limited. Targeting inflammasomes may offer a path toward precision immunotherapy in sepsis, with potential to reduce organ dysfunction and improve survival. Full article

Background: This study aims to investigate the association between pyroptosis and the outer membrane virulence factor of H. pylori in patients with gastritis and ulcers. Methods: DNA, RNA, and protein were extracted from a single tissue sample taken from the antrum region of the stomach of volunteer patients. The expression of bacterial outer membrane virulence genes was analyzed at the gene level, and the expression levels of key pyroptosis markers were compared between H. pylori-infected and uninfected gastritis and ulcer patient groups. Results: H. pylori infection induced significant alterations in the expression levels of pyroptosis markers, including ASC, NLRP3, caspase-1, GSDMD, IL-18, and IL-1β, indicating a strong association with gastritis and ulcer pathology. Statistically significant correlations were observed between elevated levels of these markers and the activation of caspase-1 across different patient cohorts, supporting effective detection of pyroptosis. Both pro and active forms of caspase-1, GSDMD, IL-18, and IL-1β were assessed, revealing pyroptotic activity in specific patient samples. The vacA m2 allele showed a distinct ASC response in gastritis versus ulcer patients and was associated with increased GSDMD expression in ulcerative cases. Along with the babB gene, this allele appears to play a critical role in the interaction between H. pylori virulence and host pyroptotic responses. A statistically significant negative association was identified between the presence of the H. pylori alpA gene and Gasdermin D expression (odds ratio = 0, p < 0.01), suggesting that Gasdermin D was absent in all alpA-positive samples. Conclusion: This study provides novel insights into the interrelation between the virulence factors of H. pylori and pyroptosis in gastritis and ulcer diseases. Our findings demonstrate that H. pylori infection significantly alters the expression levels of pyroptosis markers, including ASC, NLRP3, caspase-1, GSDMD, IL-18, and IL-1β, in gastric tissues. Notably, the vacA m2 allele was associated with a differential response in ASC expression among patients with gastritis and ulcers, correlating with increased GSDMD levels in ulcerative conditions. The presence of the H. pylori alpA gene is markedly associated with the lack of Gasdermin D activation, indicating a possible suppressive function or immune evasion tactic. These results underscore the critical role of H. pylori virulence determinants in modulating pyroptosis and suggest that understanding this relationship may pave the way for developing targeted therapeutic strategies to mitigate H. pylori-associated pathologies. Full article

Chronic periodontitis, driven by the keystone pathogen Porphyromonas gingivalis, has been increasingly associated with Alzheimer’s disease (AD) and AD-related dementias (ADRDs). However, the mechanisms through which P. gingivalis-lipopolysaccharide (LPS)-induced release of neuroinflammatory proteins contribute to the pathogenesis of AD and ADRD remain inadequately understood. Caspase-4, a critical mediator of neuroinflammation, plays a pivotal role in these processes following exposure to P. gingivalis-LPS. In this study, we investigated the mechanistic role of caspase-4 in P. gingivalis-LPS-induced IL-1β production, neuroinflammation, oxidative stress, and mitochondrial alterations in human neuronal and microglial cell lines. Silencing of caspase-4 significantly attenuated IL-1β secretion by inhibiting the activation of the caspase-4-NLRP3-caspase-1-gasdermin D inflammasome pathway, confirming its role in neuroinflammation. Moreover, caspase-4 silencing reduced the activation of amyloid precursor protein and presenilin-1, as well as the secretion of amyloid-β peptides, suggesting a role for caspase-4 in amyloidogenesis. Caspase-4 inhibition also restored the expression of key neuroinflammatory markers, such as total tau, VEGF, TGF, and IL-6, highlighting its central role in regulating neuroinflammatory processes. Furthermore, caspase-4 modulated oxidative stress by regulating reactive oxygen species production and reducing oxidative stress markers like inducible nitric oxide synthase and 4-hydroxynonenal. Additionally, caspase-4 influenced mitochondrial membrane potential, mitochondrial biogenesis, fission, fusion, mitochondrial respiration, and ATP production, all of which were impaired by P. gingivalis-LPS but restored with caspase-4 inhibition. These findings provide novel insights into the role of caspase-4 in P. gingivalis-LPS-induced neuroinflammation, oxidative stress, and mitochondrial dysfunction, demonstrating caspase-4 as a potential therapeutic target for neurodegenerative conditions associated with AD and related dementias. Full article

Background: Growing evidence suggests that the prevalence of sarcopenic obesity (SOB) is on the rise across the globe. However, the key molecular mechanisms behind this disease have not been clarified. Methods: In this experiment, we fed zebrafish a high-fat diet (HFD) for 16 weeks to induce sarcopenic obesity. Results: After a dietary trial, HFD zebrafish exhibited an obese phenotype with skeletal muscle atrophy and decreased swimming capacity. We demonstrated that mitochondrial content and function were abnormal in SOB zebrafish skeletal muscle. These results may be associated with the impairment of mitophagy regulated by the PTEN-induced putative kinase 1 (PINK1)/Parkin (PRKN) pathway. In addition, we also found that NOD-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD) signaling was activated with the upregulation of NLRP3, GSDMD-NT, and mature-IL1β, which indicated that pyroptosis was induced in SOB zebrafish skeletal muscle. Conclusions: Our study identified that impaired mitophagy and pyroptosis were associated with the pathogenesis of SOB. These results could potentially offer novel therapeutic objectives for the treatment of sarcopenic obesity. Full article

Extensive research has been conducted on mesenchymal stem cells (MSCs) regarding their ability to modify the immune response and reduce tissue damage. Many researchers have found that the regulatory capacity of MSCs primarily comes from their secretome. As a result, there has been much interest in utilizing “cell-free” therapies as alternatives to stem cell treatments. In this study, the secretome from adipose mesenchymal stem cells (ADSC-secretome) was extracted and injected into minipigs with established liver injury models. Blood and liver tissue samples were obtained prior to the procedure, as well as on days 1, 3, and 7 after surgery. It was found that ADSC-secretome effectively suppressed the synthesis of the NOD-like receptor protein 3 (NLRP3) inflammasome, leading to a downregulation of gasdermin-D (GSDMD) expression, and demonstrated a more prominent anti-pyroptosis effect compared to ADSCs. Furthermore, ADSC-secretome inhibited the high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) inflammatory pathway. In summary, both ADSC-secretome and ADSCs inhibited pyroptosis in right hemihepatic ischemia–reperfusion combined with left hemihepatectomy injury, and ADSC-secretome exhibited a stronger therapeutic effect. ADSC-secretome exerted these therapeutic effects through the inhibition of the HMGB1/TLR4/NF-κB inflammatory pathway. In the future, “cell-free” therapy is expected to replace cell-based methods. Full article

Polycystic ovary syndrome (PCOS), a common and multifactorial endocrine disorder in reproductive-aged women, is strongly associated with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), and also affects up to one in four women with type 1 diabetes mellitus (T1DM). The current study explored the potential of Plantago ovata (P. ovata) seed ethanol extract (POEE) to modulate oxidative stress (OS), inflammatory responses, metabolic profiles, and hormonal levels in rat Streptozotocin (STZ)-induced DM and Letrozole (LET)-induced PCOS. Phytochemical analysis measured total phenolic content (TPC) and total flavonoid content (TFC) using HPLC-DAD-ESI MS for compound identification. POEE’s antioxidant activity was evaluated in vitro through DPPH, H₂O₂, FRAP, and NO scavenging assays. Rats received POEE, metformin, or Trolox (TX) for 10 days. PCOS confirmation was achieved via ultrasound and histopathology. Serum levels of OS markers (TOS, TAC, OSI, MDA, AOPP, 8-OHdG, NO, 3-NT, AGEs, and SH), inflammatory markers (NF-κB, IL-1β, IL-18, Gasdermin D, and IL-10), metabolic parameters (fasting blood glucose, lipid profile, and liver enzymes), and hormone levels (LH, FSH, estrogen, testosterone, and insulin) were assessed. Additionally, the Triglyceride–Glucose index (TyG) and HOMA-IR were calculated. POEE had a medium content of polyphenols and a good in vitro antioxidant effect. In vivo, POEE administration in diabetic rats led to a reduction in OS markers and an increase in antioxidant levels, alongside decreases in inflammatory cytokines, blood glucose levels, and transaminase activity and improvements in lipid profile. In the PCOS model, POEE treatment effectively reduced total OS and lowered levels of LH, FSH, and testosterone, while elevating estrogen concentrations and reducing insulin resistance. These therapeutic effects were dose-dependent, with higher doses producing more pronounced outcomes, comparable to those observed with metformin and TX treatment. Full article

Polycystic ovary syndrome (PCOS) and diabetes mellitus (DM) are prevalent endocrine disorders with overlapping pathophysiological mechanisms. Type 2 diabetes mellitus (T2DM) is commonly associated with PCOS, with both conditions strongly linked to insulin resistance (IR), while recent studies have also reported an increased prevalence of PCOS among women with type 1 diabetes mellitus (T1DM). This study evaluated the potential of Lythrum salicaria L. ethanol extract (LSEE) to mitigate oxidative stress (OS), inflammation, and metabolic and hormonal imbalances in separate experimental models of Streptozotocin (STZ)-induced DM and Letrozole (LET)-induced PCOS. LSEE underwent phytochemical analysis to quantify total phenolic and flavonoid content and HPLC-MS for polyphenols identification. In vitro, antioxidant capacity was investigated through FRAP, DPPH, NO, and H₂O₂ scavenging assays. Subsequently, in vivo, studies utilized STZ-induced DM and LET-induced PCOS rat models, with 10-day treatments of LSEE, metformin, or trolox (TX) administered by gavage. Dysregulation of hormonal profiles, ultrasound, and histological examinations confirmed PCOS development. At the end of the treatment period, serum samples were collected to assess OS markers (TOS, OSI, MDA, AOPP, 8-OHdG, NO, 3-NT, AGEs, TAR, SH) in both models. Inflammatory markers were also measured (IL-1β, NF-κB, IL-18, and Gasdermin D in DM and IL-1β, NF-κB, IL-18, and IL-10 in PCOS). Additionally, metabolic markers (glucose, lipids, TG-glucose index, liver enzymes) were assessed in DM rats, and hormones (LH, FSH, estrogen, testosterone, insulin, HOMA-IR) were determined in PCOS rats. LSEE demonstrated a high polyphenolic content and notable in vitro antioxidant activity. In vivo, it effectively reduced OS by lowering oxidant levels and enhancing antioxidant defenses, reduced inflammatory markers and blood glucose levels, and improved lipid profiles along with the TyG index and liver injury markers in diabetic rats. In PCOS rats, LSEE lowered the total oxidants, increased antioxidants, reduced LH, FSH, testosterone, and insulin, and increased estrogen levels. The effects exhibited a dose-dependent pattern, with higher doses producing more pronounced benefits comparable to those observed with metformin and TX. In conclusion, LSEE may be a promising complementary treatment for DM and PCOS. Full article

Cell death and inflammation are key innate immune responses, but excessive activation can cause tissue damage. The NLRP3 inflammasome is a promising target for reducing inflammation and promoting recovery. Immunometabolism regulates NLRP3 responses in neurological and inflammatory diseases through cyclic nucleotide signaling. Targeting phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, offer a novel approach to mitigate inflammation. While 14 PDE inhibitors are FDA-approved, PDE10A’s role in NLRP3 inflammasome activation remains unclear. This study investigates the effects of PDE10A inhibition on inflammasome-driven inflammation using two PDE10A inhibitors, MP-10 and TP-10, in macrophage and animal models of sepsis and traumatic nerve injury. Our results show that PDE10A inhibition reduces inflammasome activation by preventing ASC speck formation and by lowering levels of cleaved caspase-1, gasdermin D, and IL-1β, which are key mediators of pyroptosis. In the sepsis model, MP-10 significantly reduced inflammation, decreased plasma IL-1β, alleviated thrombocytopenia, and improved organ damage markers. In the nerve injury model, PDE10A inhibition enhanced motor function recovery and reduced muscle atrophy-related gene expression. These findings suggest that PDE10A inhibition could be a promising therapeutic approach for inflammatory and neuromuscular injuries. Given MP-10’s established safety in human trials, Phase 2 clinical studies for sepsis and nerve injury are highly promising. Full article

Artemisia alba Turra is a plant used in folk medicine. Due to its significant polymorphism, there are different chemotypes. This study aimed to characterize the specific chemotypes and evaluate the anti-inflammatory, antioxidant, and antiproliferative potential of an ethanol extract of A. alba Turra aerial parts prepared from plants harvested from the “Alexandru Borza” Botanical Garden, Cluj-Napoca, Romania. The extract phytochemical analysis performed by measuring total polyphenol content (3.4 ± 0.21 mgGAE/g d.w.), total polyphenolic flavonoids (147.12 ± 10.09 mg QE/100 g d.w.), and HPLC-ESI MS polyphenol profiles indicated that in the A. alba Tura extract from the hydroxycinnamic acids chlorogenic acid, caffeoyl tartaric acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid had and from the flavonols, isorhamnetin-rutinoside and rutin had the highest concentration. The extract exhibited good in vitro and in vivo antioxidant activity by reducing oxidants without significant effects on antioxidants. The anti-inflammatory effect tested on rat turpentine oil-induced inflammation was indicated by the reduction in NLRP3 inflammasome markers, NfkB-p65, IL-1β, IL-18, caspase-1, and gasdermin D. The extract had in vitro antiproliferative activity against ovarian tumor cell lines at concentrations from 12.5 to 50 μg/mL, and this mechanism was linked to MDR and NF-κB modulation. A. alba Turra had no liver toxicity and reduced kidney injury associated with inflammation. These findings indicated that this specific Romanian chemotype of A. alba Turra has antioxidant, anti-inflammatory, and antiproliferative properties with potential applications as tumor microenvironment-targeted therapy. Full article

Traumatic brain injury (TBI) pathology is significantly mediated by an inflammatory response involving inflammasome activation, resulting in the release of interleukin (IL)-1β and pyroptotic cell death through gasdermin-D (GSDMD) cleavage. Inflammasome components are transported through extracellular vesicles (EVs) to mediate systemic inflammation in peripheral organs, including the gut. The purpose of this study was to determine the protective effect of GSDMD knockout (KO) on TBI-induced inflammasome activation, EV signaling, and gut function. GSDMD-KO and C57BL6 (WT) mice were subjected to the controlled cortical impact model of TBI. Cytokine expression was assessed with electrochemiluminescent immunoassay and immunoblotting of the cerebral cortex and gut. EVs were examined for pathology-associated markers using flow cytometry, and gut permeability was determined. GSDMD-KO attenuated IL-1β and IL-6 expression in the cerebral cortex and reduced IL-1β and IL-18 in the gut 3 days post-injury. GSDMD-KO mice had decreased neuronal- and gut-derived EVs compared to WT mice post-TBI. GSDMD-KO EVs also had decreased IL-1β and different surface marker expression post-TBI. GSDMD-KO mice had decreased gut permeability after TBI. These data demonstrate that GSDMD ablation improves post-TBI inflammation and gut pathology, suggesting that GSDMD may serve as a potential therapeutic target for the improvement of TBI-associated pathologies. Full article

Male infertility is intricately linked to dysregulated cell death pathways, including ferroptosis, cuproptosis, pyroptosis, and autophagy. Ferroptosis, driven by iron-dependent lipid peroxidation through the Fenton reaction and inactivation of the GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions of oxidative stress, environmental toxin exposure, or metabolic disorders. Similarly, cuproptosis—characterized by mitochondrial dysfunction and disulfide stress due to copper overload—exacerbates germ cell apoptosis via FDX1 activation and NADPH depletion. Pyroptosis, mediated by the NLRP3 inflammasome and gasdermin D, amplifies testicular inflammation and germ cell loss via IL-1β/IL-18 release, particularly in response to environmental insults. Autophagy maintains testicular homeostasis by clearing damaged organelles and proteins; however, its dysregulation impairs sperm maturation and compromises blood–testis barrier integrity. These pathways intersect through shared regulators; reactive oxygen species and mTOR modulate the autophagy–pyroptosis balance, while Nrf2 and FDX1 bridge ferroptosis–cuproptosis crosstalk. Therapeutic interventions targeting these mechanisms have shown promise in preclinical models. However, challenges persist, including the tissue-specific roles of gasdermin isoforms, off-target effects of pharmacological inhibitors, and transgenerational epigenetic impacts of environmental toxins. This review synthesizes current molecular insights into the cell death pathways implicated in male infertility, emphasizing their interplay and translational potential for restoring spermatogenic function. Full article

Infection with influenza A virus (IAV) may trigger excessive inflammatory responses, leading to severe viral pneumonia and accelerating disease progression. Therefore, controlling these excessive inflammatory responses is crucial for the prevention and treatment of pneumonia caused by IAV. Berberine (BBR), an isoquinoline alkaloid extracted from traditional Chinese medicine, possesses extensive pharmacological activities. However, its immunoregulatory effects and molecular mechanisms in the context of IAV infection require further investigation. This study explored the impact of BBR on macrophage pyroptosis and inflammatory responses induced by IAV infection. Our findings revealed that BBR effectively inhibits the release of IL-1β and TNF-α induced by IAV infection and suppresses gasdermin D (GSDMD)-mediated pyroptosis in a dose-dependent manner. Further research indicates that BBR alleviates macrophage pyroptosis and inflammatory responses in IAV-infected cells by reducing the release of mitochondrial reactive oxygen species (mtROS), inhibiting mitochondrial antiviral signaling protein (MAVS) expression and blocking the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Experiments using siRNA to knockdown MAVS further confirmed the pivotal role of MAVS in BBR’s inhibition of IAV-induced macrophage pyroptosis. This study provides a scientific basis for the application of BBR as an anti-inflammatory drug in the treatment of inflammatory diseases caused by IAV infection and directs future research endeavors. Full article

The yeast Saccharomyces cerevisiae is the paradigm of a eukaryotic model organism. In virtue of a substantial degree of functional conservation, it has been extensively exploited to understand multiple aspects of the genetic, molecular, and cellular biology of human disease. Many aspects of cell signaling in cancer, aging, or metabolic diseases have been tackled in yeast. Here, we review the strategies undertaken throughout the years for the development of humanized yeast models to study regulated cell death (RCD) pathways in general, and specifically, those related to innate immunity and inflammation, with an emphasis on pyroptosis and necroptosis. Such pathways involve the assembly of distinct modular signaling complexes such as the inflammasome and the necrosome. Like other supramolecular organizing centers (SMOCs), such intricate molecular arrangements trigger the activity of enzymes, like caspases or protein kinases, culminating in the activation of lytic pore-forming final effectors, respectively, Gasdermin D (GSDMD) in pyroptosis and MLKL in necroptosis. Even though pathways related to those governing innate immunity and inflammation in mammals are missing in fungi, the heterologous expression of their components in the S. cerevisiae model provides a “cellular test tube” to readily study their properties and interactions, thus constituting a valuable tool for finding novel therapies. Full article