Search Results (23)

Bladder cancer (BC) is one of the most common urinary tract malignancies. In recent years, increasing attention has been paid to the role of pyroptosis—an inflammatory form of programmed cell death—in cancer development. Gasdermin B (GSDM B), a member of the gasdermin protein family, is involved in the regulation of inflammatory processes and the immune response, and its expression may be associated with cancer development and progression. The aim of the study was to assess GSDM B concentrations in the serum of patients with bladder cancer and to determine its potential diagnostic value in comparison with the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). This study included patients with bladder cancer hospitalized at the Department of Urology, Medical University of Białystok, and a healthy control group. GSDM B concentrations were determined by Enzyme-Linked Immunosorbent Assay (ELISA), while CEA and CA19-9 concentrations were determined by chemiluminescent microparticle immunoassay (CMIA). Concentrations in the serum of patients with bladder cancer were significantly higher than in the control group. A positive correlation was found between GSDM B and CEA and CA19-9 concentrations, as well as the age of the subjects. Receiver-operating characteristic (ROC) analysis demonstrated moderate but significant diagnostic value of GSDM B in differentiating patients with BC from healthy controls. No significant differences in GSDM B concentrations were observed between low- and high-grade tumors. These findings suggest that GSDM B may serve as a potential diagnostic marker for bladder cancer, particularly when used as part of a multimarker panel. Full article

Background/Objectives: Sepsis is a life-threatening condition characterized by an uncontrolled immune response due to systemic infections. It is responsible for millions of deaths worldwide. Although inflammasomes play an important role in host defense, they have a detrimental role in sepsis induced by LPS or Gram-negative bacteria. We aimed to revise the molecular mechanisms of inflammasome activation in sepsis by LPS and Gram-negative bacteria other than cytokine release as treatments blocking TNF-α and IL-1 cytokines have been ineffective even though cytokine storm is associated with lethality. Results: Studies with knockout mice deficient in inflammasome-derived cytokines have shown contrasting results on the role of these proinflammatory cytokines in the lethality of LPS- and Gram-negative-induced sepsis. However, DAMPs released after non-canonical inflammasome activation such as extracellular DNA, histones, HMGB1, and tissue factor result in disseminated-intravascular coagulation (DIC) and mortality in mice. Blocking these products in preclinical studies with animal models showed improved clinical scores and survival after LPS-induced sepsis or polymicrobial sepsis induced by Cecal Ligation and Puncture. Conclusions: Even though immunomodulatory drugs have shown inconclusive results as therapies for sepsis, blocking DAMPs associated with DIC may be considered for clinical trials in the future, especially in patients presenting biomarkers of coagulopathies. Full article

This paper proposes a novel joint precoding and artificial noise design framework for generalized spatial directional modulation (AN-GSDM) in unmanned aerial vehicle (UAV) communications, aimed at enhancing the physical-layer security of downlink UAV communication systems. The key innovation lies in the dynamic co-optimization of multi-beam control and artificial noise (AN) power allocation under mobility constraints, enabling real-time adaptation to varying channel conditions. This approach jointly optimizes the precoding matrix and power-control factor, facilitating the effective management of multi-beams and AN to maximize the secrecy rate. The secrecy rate expression is derived, and the corresponding joint optimization problem is formulated. Due to the non-convex nature of the problem and the lack of a closed-form solution, an alternating iterative algorithm is proposed. This algorithm alternates between optimizing the precoding matrix using gradient descent and deriving a suboptimal closed-form solution for the power-control factor. Simulation results confirm that the proposed algorithm significantly enhances security by maximizing the secrecy rate, reducing eavesdroppers’ achievable rate to near zero, while simultaneously maintaining legitimate user’s rate. The approach not only strengthens security but also preserves system effectiveness, demonstrating robust convergence properties. This makes it a practical and promising solution for secure UAV communication. Full article

Pyroptosis is an inflammatory programmed cell death recently identified as a crucial cellular process in various diseases, including cancers. Unlike other forms of cell death, canonical pyroptosis involves the specific cleavage of gasdermin by caspase-1, resulting in cell membrane damage and the release of the pro-inflammatory cytokines IL-1β and IL-18. Initially observed in innate immune cells responding to external pathogens or internal death signals, pyroptotic cell death has now been observed in numerous cell types. Recent studies have extensively explored different ways to trigger pyroptotic cell death in solid tumors, presenting a promising avenue for cancer treatment. This review outlines the mechanisms of both canonical and noncanonical pyroptosis pertinent to cancer and primarily focuses on various biomolecules that can induce pyroptosis in malignancies. This strategy aims not only to eliminate cancer cells but also to promote an improved tumor immune microenvironment. Furthermore, emerging research indicates that targeting pyroptotic pathways may improve the effectiveness of existing cancer treatments, making them more potent against resistant tumor types, offering new hope for overcoming treatment resistance in aggressive malignancies. Full article

Background: Traditional methods of bladder cancer (BC) diagnosis include clinical examination, imaging, urine tests, cystoscopy, and biopsy. Due to the complexity of detection, diagnostic markers of bladder cancer measured in blood are still being sought. The pathogenesis of BC is complex and depends on many factors. However, the available literature data suggest that gasdermin D (GSDM D) has an influence in the pathogenesis of cancers. This study is the first that assesses the significance and diagnostic utility of serum GSDM D in bladder cancer. Methods: A total of 80 serum samples were obtained and analysed from healthy volunteers (C) and bladder cancer patients. The cancer patients were further classified into two groups, low-grade (LG) and high-grade (HG) bladder cancer, according to the TNM classification. The serum levels of GSDM D, CEA, and CA19-9 were assessed following the manufacturer’s instructions using immunoassay techniques. Results: The concentrations of GSDM D were nearly twice as high in the serum of BC patients compared to controls. Additionally, the median of GSDM D concentration was notably elevated in LG and HG bladder cancer than in C. In the total study group, the GSDM D concentration correlated with CRP and CEA levels. The diagnostic sensitivity of GSDM D was higher than that of CEA, but slightly lower in comparison to CA19-9. Moreover, the negative predictive value of GSDM D was the highest among all tested markers. The highest positive predictive value and diagnostic accuracy were observed for CEA, while the accuracy of GSDM D was comparable. GSDM D had an AUC value of 0.741, which was similar to the AUC value of CEA. Conclusions: GSDM D in serum appears to be a valuable diagnostic biomarker, especially when its measurement is used in conjunction with other markers such as CEA. Its high sensitivity makes it effective for the early detection of bladder cancer. Full article

Background: Pyroptosis, an inflammatory cell death, is involved in the progression of atherosclerosis. Pyroptosis in endothelial cells (ECs) and its underlying mechanisms in atherosclerosis are poorly understood. Here, we investigated the role of a caspase-4/5-NF-κB pathway in pyroptosis in palmitic acid (PA)-stimulated ECs and EVs as players in pyroptosis. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured in an endothelial cell medium, treated with Ox-LDL, PA, caspase-4/5 inhibitor, NF-κB inhibitor, and sEV release inhibitor for 24 h, respectively. The cytotoxicity of PA was determined using an MTT assay, cell migration using a scratch-wound-healing assay, cell morphology using bright field microscopy, and lipid deposition using oil red O staining. The mRNA and protein expression of GSDM-D, CASP4, CASP5, NF-κB, NLRP3, IL-1β, and IL-18 were determined with RT-PCR and Western blot. Immunofluorescence was used to determine NLRP3 and ICAM-1 expressions. Extracellular vesicles (EVs) were isolated using an exosome isolation kit and were characterized by Western blot and scanning electron microscopy. Results: PA stimulation significantly changed the morphology of the HUVECs characterized by cell swelling, plasma membrane rupture, and increased LDH release, which are features of pyroptosis. PA significantly increased lipid accumulation and reduced cell migration. PA also triggered inflammation and endothelial dysfunction, as evidenced by NLRP3 activation, upregulation of ICAM-1 (endothelial activation marker), and pyroptotic markers (NLRP3, GSDM-D, IL-1β, IL-18). Inhibition of caspase-4/5 (Ac-FLTD-CMK) and NF-κB (trifluoroacetate salt (TFA)) resulted in a significant reduction in LDH release and expression of caspase-4/5, NF-κB, and gasdermin D (GSDM-D) in PA-treated HUVECs. Furthermore, GW4869, an exosome release inhibitor, markedly reduced LDH release in PA-stimulated HUVECs. EVs derived from PA-treated HUVECs exacerbated pyroptosis, as indicated by significantly increased LDH release and augmented expression of GSDM-D, NF-κB. Conclusions: The present study revealed that inflammatory, non-canonical caspase-4/5-NF-κB signaling may be one of the crucial mechanistic pathways associated with pyroptosis in ECs, and pyroptotic EVs facilitated pyroptosis in normal ECs during atherosclerosis. Full article

Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) inflammasomes are multiprotein signaling platforms that control the inflammatory response and coordinate antimicrobial defense. In the present study, the distribution of NLR, Caspase-1, and gasdermin (GSDM) homologues and their structural characteristics and evolutionary relationships were systematically analyzed in metazoa according to the genomes of species. In invertebrates, there were only NLRC and/or NLRD presented from sponge to amphioxus, and according to the evolutionary tree, NLR from sponge located in the most primitive position. Caspase-1 existed in some metazoan phyla (Brachiopoda, Ectoprocta, Arthropoda, Mollusca, Annelia, Nematoda, Platyelminthes, Coelenterate, and Porifera) and its activation sites were relatively conserved. The amino acid sequences and three-dimensional structures of N-terminal CARD/Death domain of NLR and Caspase-1 were similar in species from sponge to human. NLR and Caspase-1 co-existed in species of Brachiopoda, Mollusca, Annelia, Coelenterate, and Porifera. There was only GSDME or PJVK found in some phyla of invertebrates and their cleavage sites were conserved (DxxD). And it was predicted that the NLR inflammasome in inducing pyroptosis could occur in species of Brachiopoda, Mollusca, Annelia, and Coelenterate. These studies indicated that NLR inflammasome emerged early in sponges of metazoa, and NLR inflammasome in inducing pyroptosis first appeared in Coelenterate, suggesting that inflammasome and its mediated pyroptosis had existed in the early stage of metazoa, but they had been lost in many species during evolution. Full article

In this paper, for the sake of enhancing the security of wireless transmission, we proposed a novel system based on spatial and direction modulation (SDM) combined with generalized spatial modulation (GSM) which is aided by covert information mapping (CIM), termed as the CIM-GSDM system. In such a system, the legitimated user is equipped with distributed receivers so as to demodulate the conveyed signal by exploiting its indices while disturbing eavesdroppers for information security. More specifically, part of the information is modulated into the indices of the legitimated distributed receiver subsets with the aid of the mapped covert information and the interference matrix, while another part of the message is arranged by conventional amplitude-phase modulation. The proposed system can reap the benefits from both GSM and CIM to make eavesdropper suffer great mixture. Furthermore, the detection scheme and theoretical analysis of error performance are discussed as well. The simulation results exhibit that the bit error rate (BER) performance of legitimate user is much better than that of the eavesdropper while the proposed scheme improves the security compared to the original CIM-SDM system at the same spectral efficiency. Full article

Pyroptosis, known as one typical mode of programmed cell death, is generally characterized by the cleaved gasdermin family (GSDMs) forming pores in the cell membrane and inducing cell rupture, and the activation of aspartate-specific proteases (caspases) has also been found during this process. Diabetic Kidney Disease (DKD) is caused by the complication of diabetes in the kidney, and the most important kidney’s function, Glomerular Filtration Rate (GFR), happens to drop to less than 90% of its usual and even lead to kidney failure in severe cases. The persistent inflammatory state induced by high blood glucose implies the key pathology of DKD, and growing evidence shows that pyroptosis serves as a significant contributor to this chronic immune-mediated inflammatory disorder. Currently, the expanded discovery of GSDMs, pyroptosis, and its association with innate immunity has been more attractive, and overwhelming research is needed to sort out the implication of pyroptosis in DKD pathology. In this review, we comb both classical studies and newly founds on pyroptosis, prick off the novel awakening of pyroptosis in DKD, and center on the significance of pyroptosis in DKD treatment, aiming to provide new research targets and treatment strategies on DKD. Full article

Hypoxia-induced neuronal death is a major cause of neurodegenerative diseases. Pyroptosis is a type of inflammatory programmed cell death mediated by elevated intracellular levels of reactive oxygen species (ROS). Therefore, we hypothesized that hypoxia-induced ROS may trigger pyroptosis via caspase-dependent gasdermin (GSDM) activation in neuronal cells. To test this, we exposed SH-SY5Y neuronal cells to cobalt chloride (CoCl₂) to trigger hypoxia and then evaluated the cellular and molecular responses to hypoxic conditions. Our data revealed that CoCl₂ induced cell growth inhibition and the expression of hypoxia-inducible factor-1α in SH-SY5Y cells. Exposure to CoCl₂ elicits excessive accumulation of cytosolic and mitochondrial ROS in SH-SY5Y cells. CoCl₂-induced hypoxia not only activated the intrinsic (caspases-3, -7, and -9) apoptotic pathway but also induced caspase-3/GSDME-dependent and NLRP3/caspase-1/GSDMD-mediated pyroptosis in SH-SY5Y cells. Importantly, inhibition of caspase-3 and -1 using selective inhibitors ameliorated pyroptotic cell death and downregulated GSDM protein expression. Additionally, treatment with a ROS scavenger significantly suppressed caspase- and pyroptosis-related proteins in CoCl₂-treated SH-SY5Y cells. Our findings indicate that hypoxia-mediated ROS production plays an important role in the activation of both apoptosis and pyroptosis in SH-SY5Y neuronal cells, thus providing a potential therapeutic strategy for hypoxia-related neurological diseases. Full article

This manuscript explores the role of pyroptosis, an inflammatory programmed cell death, in the pathogenesis of two chronic dermatoses, psoriasis and hidradenitis suppurativa (HS). The diseases, though clinically diverse, share common pathogenetic pathways involving the unbalanced interaction between the adaptive and innate immune systems. This review focuses on the molecular changes in psoriatic and HS skin, emphasizing the activation of dendritic cells, secretion of interleukins (IL-17, IL-22, and TNF-α), and the involvement of inflammasomes, particularly NLRP3. This manuscript discusses the role of caspases, especially caspase-1, in driving pyroptosis and highlights the family of gasdermins (GSDMs) as key players in the formation of pores leading to cell rupture and the release of proinflammatory signals. This study delves into the potential therapeutic implications of targeting pyroptosis in psoriasis and HS, examining existing medications like biologics and Janus kinase inhibitors. It also reviews the current limitations and challenges in developing therapies that selectively target pyroptosis. Additionally, the manuscript explores the role of pyroptosis in various inflammatory disorders associated with psoriasis and HS, such as inflammatory bowel disease, diabetes mellitus, and cardiovascular disorders. The review concludes by emphasizing the need for further research to fully elucidate the pathomechanisms of these dermatoses and develop effective, targeted therapies. Full article

The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of a similar intensity and duration failed to induce pathology. The repetitive spOHT induced the rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, and Gasdermin D (GSDMD), and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinogram (PERG) amplitude and a significant loss of RGCs 7 days post-injury. The inactivation of inflammasome complexes in Nlrp1^−/−, Casp1^−/−, and GsdmD^−/− knockout animals significantly suppressed the spOHT-induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death. Full article

Fatty liver disease (FLD) is a clinical and pathological syndrome characterized by excessive fat deposition and even steatosis in hepatocytes. It has been proven that liver inflammation induced by fat and its derivatives are involved in the pathogenesis of FLD, while the precise mechanism still remains poorly understood. Pyroptosis is programmed inflammatory cell death driving cell swelling and membrane rupture. Pyroptosis is initiated by the activation of inflammasomes and caspases, which further cleaves and activates various gasdermins, leading to pores forming on the cell membrane and the release of pro-inflammatory factors such as interleukin (IL)-1β and IL-18. Recent studies demonstrate that pyroptosis occurs in hepatocytes, and inhibiting pyroptosis could effectively reduce fat deposition in the liver and could ameliorate inflammation from FLD, attracting our prime focus on the role of pyroptosis in FLD. In this manuscript, we reviewed the current understanding of pyroptosis in FLD development, aiming to provide new insights and potential research targets for the clinical diagnosis and intervention of FLD. Full article

Glaesserella parasuis (G. parasuis), an important pathogenic bacterium, cause Glässer’s disease, and has resulted in tremendous economic losses to the global swine industry. G. parasuis infection causes typical acute systemic inflammation. However, the molecular details of how the host modulates the acute inflammatory response induced by G. parasuis are largely unknown. In this study, we found that G. parasuis LZ and LPS both enhanced the mortality of PAM cells, and at the same time, the level of ATP was enhanced. LPS treatment significantly increased the expressions of IL-1β, P2X7R, NLRP3, NF-κB, p-NF-κB, and GSDMD, leading to pyroptosis. Furthermore, these proteins’ expression was enhanced following extracellular ATP further stimulation. When reduced the production of P2X7R, NF-κB-NLRP3-GSDMS inflammasome signaling pathway was inhibited, and the mortality of cells was reduced. MCC950 treatment repressed the formation of inflammasome and reduced mortality. Further exploration found that the knockdown of TLR4 significantly reduced ATP content and cell mortality, and inhibited the expression of p-NF-κB and NLRP3. These findings suggested upregulation of TLR4-dependent ATP production is critical for G. parasuis LPS-mediated inflammation, provided new insights into the molecular pathways underlying the inflammatory response induced by G. parasuis, and offered a fresh perspective on therapeutic strategies. Full article

Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and subsequent revision surgery, however, the precise molecular mechanism underlying PPO remains unclear. Aseptic inflammation triggered by metal particles, resulting in the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts may be the decisive factor. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by gasdermins (GSDMs) family, among which GSDMD is the best characterized. Recent evidence indicates that activation of NLRP3 inflammasomes and pyroptosis play a pivotal role in the pathological process of PPO. Here, we review the pathological process of PPO, the molecular mechanism of pyroptosis and the interventions to inhibit the inflammation and pyroptosis of different cells during the PPO. Conclusively, this review provides theoretical support for the search for new strategies and new targets for the treatment of PPO by inhibiting pyroptosis and inflammation. Full article