Search Results (4,959)

The Influenza A Virus (IAV) is known to hijack cellular proteins during its replication. IAV infection increases the expression of Heat-shock-protein family A (Hsp70) member 5 (HSPA5) in human cells, but its specific function in the viral life cycle remains unclear. This study aims to elucidate the function of HSPA5 in IAV replication, by implementing HSPA5 knockdown (KD) in A549 cells and assessing its impact on IAV’s viral protein translation, genomic RNA transcription, and the host cellular proteome. HSPA5 KD significantly reduced progeny virus release, although viral RNA levels were unaffected. Interestingly, levels of viral structural proteins increased in HSPA5 KD cells after infection. Treatment with HSPA5 inhibitor also suppressed IAV replication, confirming its role as a host dependency factor. Proteomic profiling revealed 116 proteins altered in wild-type cells and 223 in HSPA5 KD cells, with 32 uniquely dysregulated in wild-type and 139 unique to HSPA5 KD cells. In HSPA5 knockdown cells, the altered proteins were linked to pathways such as EIF2, EGF, PEDF, CNTF, IL-13, and G-protein receptor signaling, as well as to cellular processes like lymphocyte activation and regulation of immune and blood cell death, which were not affected in wild-type cells after IAV infection. Overall, this study suggests that HSPA5 contributes to late stages of IAV replication, likely assembly or maturation, and represents a promising target for antiviral drug development. Full article

Biosynthesis of ribose-5-phosphate (R5P) underlies all biosynthetic processes associated with biomass growth. Actively dividing cells continuously require building blocks for genome replication, synthesis of ribosomes and other derivatives containing R5P as a carbohydrate backbone. The main source of R5P in the cell is the pentose phosphate pathway (PPP), which is an anabolic sensor designed to coordinate the level of pentose phosphates and reduced NADPH required for anabolic processes. This review is devoted to a comparative analysis of R5P biosynthesis pathways among different domains of microorganisms, the features of PPP regulation in bacterial cells depending on physiological conditions, as well as genetic modifications of PPP and their effect on cell viability. We emphasize that ribose metabolism is a factor in the consolidation of cellular homeostasis under conditions of intensive biomass growth and the discrepancy between the processes of ribose synthesis and consumption is marked by spontaneous cell death. Full article

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disorder caused by right heart failure leading to premature death. The TGFBR2 and BMPR-II receptors, which are members of the TGF-β receptor family, are considered promising targets for developing novel drugs in PAH. Lupeol and ψ-taraxasterol, naturally occurring triterpene molecules with proven anti-inflammatory, anti-cancer, and cardioprotective activities, hold considerable potential in the treatment of PAH. Hence, the present study aimed to evaluate the impacts of lupeol and ψ-taraxasterol isolated from Cirsium sintenisii Freyn on the TGF-β and BMP pathways, aiming to determine their therapeutic values in PAH. The effects of the compounds were extensively investigated using both in silico and wet lab experiments, including reporter assays, RT-PCR/QPCR, Western blots, and cell proliferations assays. Both lupeol and ψ-taraxasterol demonstrated interactions with the majority of components of these signaling pathways, including the TGFBR2 and BMPR-II receptors, suggesting that both compounds were capable of modulating the BMP and TGF-β pathways. Data derived from reporter assays, RT-PCR/QPCR, and Western blots demonstrated that lupeol and ψ-taraxasterol inhibited the TGF-β signaling pathway by reducing the phosphorylation of the SMAD3 protein and the expression of pai-1 transcripts. Additionally, ψ-taraxasterol enhanced BMP signaling via regulating the phosphorylation of SMAD1/5 proteins and upregulated the expression of id-1 transcripts. Finally, lupeol and ψ-taraxasterol inhibited abnormal proliferation of mutant-type (bmpr2^R899X+/-) PAMSCs stimulated with the TGF-β1 ligand with no discernible effects on wild-type cells. This is the first comprehensive report outlining the potential therapeutic effects of lupeol and ψ-taraxasterol in PAH, which may have immediate experimental and clinical applications not only in PAH but also other BMP- and TGF-β-associated disorders. Full article

Cancer cells can sustain survival independently of exogenous growth factors. To investigate their adaptation to serum deprivation, we analyzed transcriptomic responses in two cancer cell lines. Transcriptome analysis revealed upregulation of mRNAs encoding cholesterol biosynthesis enzymes. This was a critical adaptive response, as a pharmacological inhibition of the pathway with statin triggered a robust apoptotic cell death accompanied by generation of a mitochondrial reactive oxygen species. The mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, is known to be engaged in controlling lipid biosynthesis. We detected the high polysomal and preribosomal peaks not only in serum-containing medium but also under serum deprivation, indicating a high rate of protein synthesis and ribosomal biogenesis independent of serum. In addition, the inhibition of mTOR kinase activity substantially reduced polysome abundance, with a more pronounced effect in serum-deprived cancer cells. Notably, the mTOR kinase inhibition also prevented the upregulation of the cholesterol synthesis enzyme that established a direct link between mTOR activity, protein synthesis, and cholesterol biosynthesis. Together, our results show that cancer cells adapt to serum withdrawal by activating the cholesterol synthesis pathway through mTOR-dependent regulation of gene expression and protein synthesis, underscoring a critical mechanism of survival under serum withdrawal. Full article

Cancer progression in skeletal muscle (SkM) is very rare, and mechanisms remain unclear. This study assessed the potential of SkM (myocyte)-derived EVs (C2C12-EVs) as anti-cancer agents. Using murine in vitro models, we showed that following treatment with C2C12-EVs, lung carcinoma cells failed to colonise SkM cells, and that C2C12-EVs selectively exerted apoptosis on cancer cells. Uptake of C2C12-EVs by carcinoma cells caused changes in lysosomal function and mitochondrial membrane properties inducing cell death with elevated caspase 3 and 9. The C2C12-EVs also inhibited cell proliferation, affecting cell cycle arrest at S phase and inhibited cell migration. Proteomic analysis of C2C12-EV cargoes highlighted functional enrichment pathways involved in lysozyme function, HIF-1 and PI3K-Akt signalling, regulation of actin cytoskeleton, pyruvate metabolism, platelet activation, and protein processing in ER. Decorin, a muscle cell-specific cytokine released from myocytes in response to stress, was significantly enriched in C2C12-EVs and may contribute to C2C12-EVs’ inhibitory activity on cancer cells. C2C12-EVs may suppress cancer and potentially be used as therapeutic agents for cancer metastasis. Full article

The nuclear membrane has emerged as a dynamic regulatory platform coordinating genome organization, mechanotransduction, and regulated cell death (RCD). Beyond its barrier function, the nuclear skeleton—comprising lamins, actin–myosin isoforms, nuclear matrix proteins, and the LINC complex—supports nuclear integrity and gene regulation. Recent evidence shows that type II membrane-bound bZIP transcription factors such as cAMP-responsive element-binding protein 3 (CREB3) and CREB3L1 localize to the inner nuclear membrane (INM), linking chromatin tethering with stress signaling. Their stress-induced cleavage by S1P/S2P disrupts chromatin anchoring and, in some contexts, triggers karyoptosis, a novel form of RCD defined by nuclear rupture. These findings position the nuclear envelope (NE) as a mechanosensitive signaling hub with direct implications for disease and therapy. In this review, we provide a comprehensive discussion on how type II membrane-bound bZIP transcription factors and chromatin acting as a nucleoskeleton cooperate to regulate nuclear membrane integrity. Full article

Pseudomonas aeruginosa (P. aeruginosa) is responsible for the high prevalence of various nosocomial infections, and it is challenging to completely eradicate P. aeruginosa infection in clinics. One of P. aeruginosa’s main pathogenic mechanisms is to trigger multiple forms of programmed cell death (PCD), such as apoptosis, pyroptosis, necroptosis, ferroptosis, and PANoptosis, among which PANoptosis is a newly discovered PCD pathway mediated by PANoptosome complexes and their key upstream regulators. Compared with other well-studied PCD pathways, advances in P. aeruginosa-induced PANoptosis have yet to be thoroughly reviewed. This review highlights research advances in this pathway, providing mechanistic insights by summarizing the upregulation and/or activation of PANoptosome sensor proteins and their key upstream regulators during P. aeruginosa infection. We also offer perspectives on the mechanistic links between P. aeruginosa cytotoxicity and other forms of PCD. Additionally, pharmacological compounds that may be used to target P. aeruginosa-induced PCD, particularly PANoptosis, are discussed, and future research and therapeutic directions are proposed. Our work helps bridge the knowledge gap, paving the way for further understanding of P. aeruginosa-induced PCD and the development of novel therapeutics against P. aeruginosa infection. Full article

Cancer remains a persistent global health challenge, continuously driving the search for novel and effective therapeutic strategies. In the case of breast cancer, treatment decisions are primarily guided by factors such as the disease stage, histological grade, molecular receptor status, and the presence of genetic mutations. Understanding these parameters is crucial for tailoring interventions and improving clinical outcomes. To enhance prognostic and diagnostic accuracy, attention has increasingly turned to identifying molecular targets that play key roles in breast cancer development. Currently, standard treatments include surgery, chemotherapy, and radiotherapy. However, these approaches are often associated with significant side effects and a diminished quality of life. As a result, many breast cancer patients are turning to complementary therapies—including phytotherapy, nutritional interventions, and dietary supplements—to support conventional treatment, alleviate adverse effects, and improve overall well-being. Within the vast realm of medicinal flora, anticancer plants represent a compelling area of study, serving as a rich reservoir of bioactive compounds. These compounds have demonstrated significant promise in the ongoing battle against cancer. Often highlighted in traditional medicinal practices, these plants harbor a wide array of phytochemicals, such as alkaloids, flavonoids, polyphenols, and terpenoids. These phytochemicals manifest diverse biological activities, notably exhibiting pronounced anticancer properties. The exploration of these natural compounds has opened new avenues for developing innovative and targeted therapeutic strategies in cancer treatment. They achieve definitive chemotherapeutic and chemopreventive roles by integrating with specific molecular signals. Their multiple biological functions include antimutagenic, antiproliferative, antimetastatic, anti-angiogenesis, anti-inflammatory, antioxidant, and immunomodulatory properties, which collectively enable them to control cancer progression and intervene at various stages of cancer cell development. Moreover, these compounds are involved in regulating the cell cycle and microRNA, ultimately leading to cancer cell death by promoting apoptosis and autophagy, often mediated through ROS signaling. Thus, based on a large theoretical revision, we conclude that high-quality evidence is necessary in order to advise these products concerning their efficacy and safety. Also, clinical evidence should be supported by a comprehensive individual diagnosis and adequate research protocols in order to evaluate whether the benefits of these plant-produced interventions can outweigh their harms. Full article

The heart’s relentless contractile activity depends critically on mitochondrial function to meet its extraordinary bioenergetic demands. Mitochondria, through oxidative phosphorylation, not only supply ATP but also regulate metabolism, calcium homeostasis, and apoptotic signaling, ensuring cardiomyocyte viability and cardiac function. Mitochondrial dysfunction is a hallmark of cardiomyopathies and heart failure, characterized by impaired oxidative phosphorylation, excessive production of reactive oxygen species (ROS), dysregulated calcium handling, and disturbances in mitochondrial dynamics and mitophagy. These defects culminate in energetic insufficiency, cellular injury, and cardiomyocyte death, driving heart disease progression. Diverse cardiomyopathy phenotypes exhibit distinct mitochondrial pathologies, from acute ischemia-induced mitochondrial collapse to chronic remodeling seen in dilated, hypertrophic, restrictive, and primary mitochondrial cardiomyopathies. Mitochondria also orchestrate cell death and inflammatory pathways that worsen cardiac dysfunction. Therapeutic strategies targeting mitochondrial dysfunction, including antioxidants, modulators of mitochondrial biogenesis, metabolic therapies, and innovative approaches such as mitochondrial transplantation, show promise but face challenges in clinical translation. Advances in biomarker discovery and personalized medicine approaches hold promise for optimizing mitochondrial-targeted therapies. Unlike previous reviews that examined these pathways or interventions individually, this work summarizes insights into mechanisms with emerging therapeutic strategies, such as SGLT2 inhibition in HFpEF, NAD⁺ repletion, mitochondrial transplantation, and biomarker-driven precision medicine, into a unified synthesis. This framework underscores the novel contribution of linking basic mitochondrial biology to translational and clinical opportunities in cardiomyopathy and heart failure. This review synthesizes the current understanding of mitochondrial biology in cardiac health and disease, delineates the molecular mechanisms underpinning mitochondrial dysfunction in cardiomyopathy and heart failure, and explores emerging therapeutic avenues aimed at restoring mitochondrial integrity and improving clinical outcomes in cardiac patients. Full article

Chronic hepatitis B virus (HBV) infection is a major health problem that leads to approximately one million deaths every year worldwide. Mother-to-child transmission (MTCT) is the major cause of chronic HBV infection. HBV e antigen (HBeAg) is a secretory viral protein and modulates the immunological landscape of the newborn to promote HBV persistence. HBeAg actively reprograms innate and adaptive immunity. Mechanistically, HBeAg regulates macrophage polarization, suppresses dendritic cell and natural killer (NK) cell activities, impairs T cell and B cell functions, and promotes the expansion of myeloid-derived suppressor cells (MDSCs). These multifaceted effects contribute to immune tolerance and persistent HBV infection in the offspring of carrier mothers. Clinically, HBeAg status is a critical determinant for MTCT risk stratification and intervention, particularly in resource-limited settings. Despite advances in neonatal immunoprophylaxis and maternal antiviral therapy, residual transmission of HBV persists. Emerging approaches targeting HBeAg directly or restoring antiviral immunity offer promising avenues for breaking immune tolerance and achieving HBV elimination. This review summarizes current understanding of HBeAg-mediated immune modulation and highlights strategies that are being used to disrupt MTCT and treat HBV patients. Full article

A nonlocal transport–reaction system is proposed to model the coupled dynamics of stem and differentiated cell populations, structured by a continuous damage variable. The framework incorporates bidirectional transitions via differentiation and dedifferentiation, with nonlocal birth operators encoding damage redistribution upon division and Hill-type feedback regulation dependent on total populations. Global well-posedness of solutions in $C([0,\infty );L^1([0,\infty )\times L^1\left([0,\infty )\right))$ is established by combining the contraction mapping principle for local existence with a priori $L^1$ bounds for global existence, ensuring uniqueness and nonnegativity. Integration yields balance laws for total populations, reducing to a finite-dimensional autonomous ordinary differential equation (ODE) system under constant death rates. Linearization reveals a bifurcation threshold separating extinction, homeostasis, and unbounded growth. Under compensatory feedback, Dulac’s criterion precludes periodic orbits, and the Poincaré–Bendixson theorem confines bounded trajectories to equilibria or heteroclinics. Uniqueness implies global asymptotic stability. A scaling invariance for steady states under uniform feedback rescaling is identified. The analysis extends structured population theory to feedback-regulated compartments with nonlocal operators and reversible dedifferentiation, providing explicit stability criteria and linking an infinite-dimensional structured model to tractable low-dimensional reductions. Full article

Background: Hepatocellular carcinoma (HCC) continues to be a major cause of cancer associated deaths worldwide, highlighting the need for new prognostic biomarkers and treatment strategies. Triaptosis, a recently characterized mode of regulated cell death, has shown potential as a therapeutic target in various malignancies, including HCC. Nevertheless, how long non-coding RNAs (lncRNAs) regulate triaptosis, as well as their function in HCC, is still not well understood. Methods: This study integrates bioinformatics and functional validation to delineate the interplay between lncRNAs and triaptosis in HCC progression. Results: Firstly, we confirm that pharmacologically inducing triaptosis, a process centrally mediated by ROS accumulation, with menadione sodium bisulfite (MSB) can inhibit HCC growth both in vitro and in vivo. Furthermore, single-cell RNA sequencing identifies a specific elevation of the triaptosis-related gene MTM1 in malignant hepatocytes. Through systematic bioinformatics analysis of TCGA data, we develop a 5-lncRNA prognostic signature (LINC01134, HPN-AS1, DDX11-AS1, AC009283.1, AC009005.1) with superior predictive power over conventional clinical parameters. Strikingly, functional studies reveal that LINC01134 acts as a crucial oncogenic driver and its depletion suppresses proliferation, migration, and invasion while sensitizing cells to triaptosis via MTM1-mediated PI(3)P catabolism. Conclusions: Collectively, our study confirms that triaptosis is a therapeutically targetable signaling in HCC and proposes LINC01134 as a biomarker and therapeutic target, offering new insights into lncRNA-mediated regulation of cell death for precision oncology. Full article

RASopathies are a heterogeneous group of genetic syndromes caused by germline mutations in genes encoding proteins of the RAS/MAPK pathway, which are essential in the regulation of cell proliferation, differentiation and survival. Although characterized by common phenotypic manifestations such as craniofacial dysmorphism, congenital heart defects, and growth retardation, an aspect of great clinical relevance is the increased risk of sudden cardiac death, especially in relation to hypertrophic cardiomyopathy (HCM) and ventricular arrhythmias. Pathogenic variants in genes such as RAF1, RIT1, PTPN11, BRAF and SHOC2 have been associated with phenotypes with increased incidence of HCM, sometimes with early onset and a rapidly evolving course. The literature highlights the importance of early identification of patients at risk; however, specific surveillance protocols and follow-up strategies are defined in expert guidelines. This literature review aims to provide an updated overview of the main RASopathies with cardiac involvement, highlighting the genotype-phenotype correlations, the pathogenic mechanisms underlying sudden cardiac death, and current diagnosis, monitoring, and prevention strategies. The aim is to promote greater clinical awareness and encourage a multidisciplinary approach aimed at reducing mortality in these rare genetic conditions. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have achieved striking clinical efficacy in the subset of CRCs with mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H), the vast majority of patients—those with proficient mismatch repair/microsatellite-stable (pMMR/MSS) tumors—derive little benefit from current immunotherapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal accumulation of lipid peroxides, has emerged as a promising antitumor mechanism that can interact with and modulate antitumor immunity. Concurrently, the gut microbiota exerts powerful control over host metabolism and immune tone through microbial community structure and metabolite production; accumulating evidence indicates that microbiota-derived factors can either sensitize tumors to ferroptosis (for example, via short-chain fatty acids) or confer resistance (for example, indole-3-acrylic acid produced by Peptostreptococcus anaerobius acting through the AHR→ALDH1A3→FSP1/CoQ axis). In this review we synthesize mechanistic data linking microbial ecology, iron and lipid metabolism, and immune regulation to ferroptotic vulnerability in CRC. We discuss translational strategies to exploit this “microbiota–ferroptosis” axis—including precision microbiome modulation, dietary interventions, pharmacologic ferroptosis inducers, and tumor-targeted delivery systems—and we outline biomarker frameworks and trial designs to evaluate combinations with ICIs. We also highlight major challenges, such as interindividual microbiome variability, potential collateral harm to ferroptosis-sensitive immune cells, adaptive antioxidant compensation (e.g., NRF2/FSP1 activation), and safety/regulatory issues for live biotherapeutics. In summary, this review highlights that targeting the microbiota-ferroptosis axis may represent a rational and potentially transformative approach to reprogramming the tumor microenvironment and overcoming immune checkpoint resistance in pMMR/MSS colorectal cancer; however, further research is essential to validate this concept and address existing challenges. Full article

Purpose: Cisplatin chemotherapy is complicated by acute kidney injury (cis-AKI), driven by regulated cell death pathways, including apoptosis and pyroptosis. However, the temporal relationship between apoptosis and pyroptosis in cis-AKI remains unclear. This study investigated the roles of these pathways and evaluated the renoprotective effect of the hydrogen sulfide (H₂S) donor GYY4137. Method: Cis-AKI was modeled in mice and HK2 cells, divided into control, cisplatin, and cisplatin + GYY groups. Kidney function parameters, histopathology, and cell death were evaluated. Markers of apoptosis and pyroptosis, along with the H₂S-producing enzyme, were analyzed. Results: Renal impairment progressed from BUN elevation to increased Scr, coupled with aggravated renal tissue damage. Apoptotic signaling peaked at 24 h, evidenced by a raised Bax/Bcl-2 ratio and caspase-3 cleavage. Pyroptosis pathways, via both NLRP3/caspase-1/GSDMD and caspase-3/GSDME axes, were activated later at 72 h, with concurrent rises in IL-1β and IL-18. GYY4137 treatment significantly ameliorated renal dysfunction, reducing serum creatinine and BUN levels by 22.64% and 22.5%, respectively. It suppressed both the early apoptotic and delayed pyroptosis cascades without reversing CBS downregulation. Conclusions: GYY4137 mitigated both apoptosis and pyroptosis, offering a promising multi-targeted therapy for cis-AKI. Full article