Life Sciences[JOURNAL]
Sun
200 papers
The death code in nanomessengers: Mechanisms and advances in the regulation of programmed cell death by exosomes.
Zhang L, Su L, Zhao J … +3 more , Xu J, Xu K, Chi H
Life Sci · 2026 Aug · PMID 42128274 · Publisher ↗
The process of cellular demise is fundamental for sustaining physiological balance and influencing disease outcomes. Recently, exosomes have emerged as critical nanoscale messengers in intercellular signaling, with versa...
The process of cellular demise is fundamental for sustaining physiological balance and influencing disease outcomes. Recently, exosomes have emerged as critical nanoscale messengers in intercellular signaling, with versatile functions in orchestrating distinct patterns of programmed cell death. This article provides a comprehensive overview of exosome-mediated regulation of multiple cell death subtypes-including apoptosis, ferroptosis, necroptosis, entosis, SLFN11-related death, and ammonia-triggered death-and highlights their multifaceted contributions to immune modulation, cancer development, and tissue regeneration. This article integrates Ongoing studies on the functions of exosomes in various cell death modes from the perspectives of signaling pathways, epigenetic regulation, and metabolic pathways. It focuses on the molecular mechanisms by which exosomes, through bioactive cargos such as miRNA, lncRNA, circRNA, and proteins, influence key signaling axes, including PI3K/AKT, Fas/FasL, p53, SLC7A11/GPX4, RIPK1/RIPK3/MLKL, Keap1/Nrf2, STAT6, and TAM receptors. Notably, exosomes demonstrate powerful specificity and systemic regulatory potential, particularly in the regulation of iron homeostasis, lipid peroxidation, immune polarization, and entosis. As a "nano delivery system" for intracellular and extracellular signals, exosomes not only regulate cell death modalities but also offer new strategic possibilities for disease intervention. In the future, exosome-mediated cell death regulation is expected to be used in the development of precision therapeutic tools, improving the intervention efficiency in tumors, immune diseases, and metabolic disorders. In summary, a thorough insight of the mechanisms by which exosomes regulate cell death is crucial for elucidating the fundamental basis of disease development and for translational medical applications.
TBX5-GATA4 interaction aggravates pulmonary artery smooth muscle proliferation and pathogenesis of pulmonary arterial hypertension through transcriptional co-activating CDK18.
Zhou WY, Wu XL, Wang SY … +4 more , Zhang XY, Zhang H, Chen SL, Wang F
Life Sci · 2026 Aug · PMID 42128273 · Publisher ↗
AIMS: Hypoxia-induced pulmonary arterial hypertension, a frequent complication of chronic respiratory diseases, is recognized as a severe and lethal clinical syndrome. Currently, there are no established pharmacological...
AIMS: Hypoxia-induced pulmonary arterial hypertension, a frequent complication of chronic respiratory diseases, is recognized as a severe and lethal clinical syndrome. Currently, there are no established pharmacological treatment, highlighting the need to identify targets and mechanism regarding it. MATERIALS AND METHODS: RNA-seq followed by comprehensive in vitro and in vivo validation was used to examine changes in TBX5 expression in pulmonary arterial smooth muscle cells under hypoxic conditions. The effects of TBX5 knockdown on cell proliferation, pulmonary arterial pressure, and vascular remodeling were assessed, and downstream RNA-seq together with rescue experiments was performed to explore the underlying regulatory mechanisms. KEY FINDINGS: A marked increase in TBX5 expression was observed in pulmonary arterial smooth muscle cells in response to hypoxia. Knockdown of TBX5 significantly reduced cell proliferation, decreased pulmonary arterial pressure, and slowed vascular remodeling in experimental mouse models. Moreover, GATA4 was found to enhance TBX5 expression and promote cell proliferation. Mechanically, GATA4 and TBX5 formed a transcriptional co-activator complex that targets CDK18, thereby driving the initiation and progression of hypoxia-induced pulmonary arterial hypertension. SIGNIFICANCE: This study will clarify the role and mechanism of TBX5 in promoting hypoxia-induced pulmonary arterial hypertension, provide a theoretical basis for improving the mechanism of hypoxia-induced pulmonary arterial hypertension, thus providing new potential targets for PAH.
MOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction.
Li SH, Chen SQ, Lu T … +5 more , Wang JH, Wang JX, Wu YX, Pang QF, Chen D
Life Sci · 2026 Aug · PMID 42128272 · Publisher ↗
AIMS: Hyperoxia-induced oxidative stress is a primary cause of neonatal injury. Neonatal heart shows a particular susceptibility to hyperoxic toxicity, yet mechanisms and effective therapeutic strategies remain limited....
AIMS: Hyperoxia-induced oxidative stress is a primary cause of neonatal injury. Neonatal heart shows a particular susceptibility to hyperoxic toxicity, yet mechanisms and effective therapeutic strategies remain limited. Oxeiptosis is a ROS-specific programmed cell death. Mitochondrial-derived peptide MOTS-c possesses well-known anti-oxidative effect. This study investigated the cardio-protective role of MOTS-c in hyperoxia exposed neonatal mice and its mechanism. MAIN METHODS: Neonatal mice exposed hyperoxia (85% O) were used to establish the hyperoxic cardiac injury model. Additionally, the rat cardiomyocyte cell line H9C2 were subjected to hyperoxic conditions as an in vitro model. Serum MOTS-c content was measured using enzyme-linked immunosorbent assay. Hematoxylin and eosin staining, Real-time PCR, Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to evaluate the effects of MOTS-c on hyperoxia-induced cardiac insufficiency. KEY FINDINGS: We found that hyperoxia exposure in neonatal mice led to significant cardiac hypertrophy, fibrosis, and dysfunction, concomitant with decreased serum MOTS-c content. Administration of MOTS-c markedly ameliorated these pathological changes and restored cardiac function. In vitro and in vivo experiments revealed that hyperoxia triggers oxidative stress and oxeiptosis via activating KEAP1-PGAM5-AIFM1 axis, and MOTS-c inhibited oxeiptosis. Mechanistically, MOTS-c could potentially interact with KEAP1, thereby maintaining the KEAP1-PGAM5 interaction, and inhibiting the downstream nuclear translocation of AIFM1. Notably, KEAP1 overexpression abrogated the protective effects of MOTS-c, confirming KEAP1 as a critical target of MOTS-c in hyperoxia-induced cardiac injury. SIGNIFICANCE: MOTS-c attenuates hyperoxic cardiac injury by inhibiting KEAP1-mediated oxeiptosis, highlighting its potential as a novel therapeutic agent for neonatal cardiomyopathy.
Proteotoxicity and tubular epithelial cell fate in acute kidney injury: Molecular insights and treatment strategies.
Yerra VG, Gavara A, Paudel KR … +1 more , Jeengar MK
Life Sci · 2026 Aug · PMID 42114736 · Publisher ↗
Acute kidney injury (AKI) is the most frequent renal complication, characterized by a rapid and severe loss of kidney function. Given its high incidence and strong propensity to progress into chronic kidney disease (CKD)...
Acute kidney injury (AKI) is the most frequent renal complication, characterized by a rapid and severe loss of kidney function. Given its high incidence and strong propensity to progress into chronic kidney disease (CKD), a deeper insight into its molecular pathology is critical for the development of more effective therapies. In this review, we offer a novel conceptual framework illustrating how diverse AKI triggers induce oxidative stress-driven protein damage, which can exceed the capacity of endogenous protein quality control systems, ultimately promoting proteotoxic stress and renal tubular epithelial cells (RTECs) demise. Importantly, we emphasize the central role of proteotoxicity in shaping the core features of unresolved AKI such as tubular cast formation, impaired proliferation and differentiation of surviving RTECs, mitochondrial and metabolic dysfunction in RTECs. Through this discussion on the relevance of proteotoxicity to the major molecular mechanisms underlying AKI, we highlight its central role in regulating renal tubular epithelial cell fate-balancing survival and death under AKI conditions-and propose that sustained proteotoxic stress may serve as a critical link driving the transition from AKI to CKD. We further outline experimental approaches to identify RTEC proteins susceptible to aggregation during AKI and discussed emerging therapeutic strategies aimed at enhancing their clearance. By delineating key mechanisms linking RTEC proteotoxic stress to cell survival and repair, we aim to spotlight this underexplored dimension of AKI biology, inspiring future research and therapeutic innovation to alleviate AKI burden and hinder AKI-to-CKD progression.
Tumor cell-intrinsic TET3 restrains type I interferon signaling and anti-tumor immunity.
Liu L, Zhao W, Shang T … +8 more , Xu B, Wang M, Li X, Min J, Xu W, Shen H, Tan L, Shi YG
Sci China Life Sci · 2026 Apr · PMID 42113451 · Publisher ↗
The ten-eleven translocation (TET) family genes, which encode 5-methylcytosine (5mC) dioxygenases, play a "double-edged sword" role in tumor initiation and progression. However, the functional role and molecular mechanis...
The ten-eleven translocation (TET) family genes, which encode 5-methylcytosine (5mC) dioxygenases, play a "double-edged sword" role in tumor initiation and progression. However, the functional role and molecular mechanism of tumor cell-intrinsic TET3 in anti-tumor immunity remain incompletely understood. Here, we uncover that TET3 mRNA expression was aberrantly elevated in multiple cancer types and correlated with poor overall survival. Transcriptomic analysis reveals that TET3 depletion upregulated the expression of innate immune response genes, including numerous interferon-stimulated genes (ISGs), in cancer cells. The expression levels of dsRNA sensors (i.e., MDA5 and RIG-I) were increased in TET3 KO or KD cells, while the biogenesis of endogenous dsRNA was not affected. Mechanistically, TET3 regulates type I interferon signaling by inhibiting STAT1 activation. Importantly, depletion of TET3 in B16F10 melanoma cells significantly curbed the synergistic tumor growth, accompanied by increased tumor-infiltrating CD4 T cells, CD8 T cells, and dendritic cells. Notably, analysis of the TCGA dataset also shows that TET3 expression levels were negatively correlated with tumor-infiltrating cytotoxic CD8 T cells and MHC-I expression across multiple cancer types. Taken together, our findings identify TET3 as a new negative regulator of the type I interferon signaling in cancer cells. We envisage that targeting the tumor cell-intrinsic TET3 could reduce tumor immune evasion and promote anti-tumor immunity.
Human MAITregs possess diverse TCR repertoires and are functionally supported by glycolysis.
Tang M, Li X, Yang X … +12 more , Zhao C, Zhang Y, Chen S, Ye Z, Hou L, Chen Y, Lv R, Zhao H, Cheng X, Wang H, Bai L, Fu S
Sci China Life Sci · 2026 Apr · PMID 42113450 · Publisher ↗
Mucosal-associated invariant T (MAIT) regulatory cells (MAITregs) represent a specialized subset with immunosuppressive functions, yet their properties and molecular basis are largely unknown. We demonstrate that MAITreg...
Mucosal-associated invariant T (MAIT) regulatory cells (MAITregs) represent a specialized subset with immunosuppressive functions, yet their properties and molecular basis are largely unknown. We demonstrate that MAITregs, while sharing T cell receptor (TCR) repertoires with conventional MAIT cells, undergo selective clonal expansion during in vitro generation, leading to biased V(D)J profiles and restricted CDR3 diversity. Moreover, integrated transcriptomics revealed that MAITregs preferred glycolysis, which was supported by chromatin remodeling at glycolytic gene loci. Functionally, glycolysis in MAITregs favored their IL-10 production but inhibited Th1 cytokines, whereas oxidative phosphorylation (OXPHOS) promoted their Th1/Th17 cytokines. Our study defines MAITregs as a clonally expanded population whose regulatory potency is strictly governed by cellular metabolism.
A T4SS effector directly disarms competing antibacterial T6SSs by hijacking their conserved spike component.
Xiong D, Liao J, Zhang Z … +12 more , Giraud JF, Li X, Cheng D, Wang B, Wang L, Shao X, Lin L, Zheng J, Li X, Liu F, Cascales E, Qian G
Sci China Life Sci · 2026 Jun · PMID 42113449 · Publisher ↗
Interspecies competition plays a crucial role in shaping microbial community dynamics and influencing host-associated outcomes. However, the mechanisms by which microbes directly neutralize the antimicrobial systems of t...
Interspecies competition plays a crucial role in shaping microbial community dynamics and influencing host-associated outcomes. However, the mechanisms by which microbes directly neutralize the antimicrobial systems of their rivals remain largely unexplored. Here, we demonstrate that a bacterial effector protein, translocated via the widely distributed type IV secretion system (T4SS), directly disarms the antibacterial type VI secretion system (T6SS) of a competitor. Specifically, we show that Lysobacter enzymogenes, a ubiquitous soil bacterium, uses its bacterial-killing T4SS (T4SS) to deliver a non-lethal effector, LqqE1, into the cytoplasm of Pseudomonas putida, a competitor equipped with a functional antibacterial K1-T6SS. LqqE1 targets and hijacks VgrG1, a conserved structural component of the K1-T6SS's spike in P. putida, through direct binding. We propose that the binding of LqqE1 to VgrG1 disrupts the native loading of the K1-T6SS nuclease effector Tke2 onto VgrG1. As a result, the translocated LqqE1 abolishes the secretion of the inner-tube protein Hcp via K1-T6SS, effectively interfering with the antibacterial function of P. putida. Structural and phylogenetic analyses reveal that LqqE1 homologs are widespread among bacteria that encode T4SS, with several representative members exhibiting similar K1-T6SS-disabling functions. These findings uncover a novel interbacterial warfare strategy in which a T4SS effector sabotages a competitor's T6SS by subverting its core structural architecture. Our results provide new insights into the molecular arms race between two distinct and widespread antibacterial contact-dependent secretion systems, enhancing our understanding of the diversity in microbial community competition.
Applications of omics-based phenotyping technologies in animal genetic breeding.
Li Y, Yin Y, He Q
Sci China Life Sci · 2026 Apr · PMID 42113448 · Publisher ↗
Traditional selective breeding relies on observable phenotypic traits. Recent advances in omics technologies (e.g., genomics, transcriptomics, proteomics, and metabolomics) have revolutionized phenotyping in animal genet...
Traditional selective breeding relies on observable phenotypic traits. Recent advances in omics technologies (e.g., genomics, transcriptomics, proteomics, and metabolomics) have revolutionized phenotyping in animal genetic breeding by providing deeper insights into complex traits and improving the efficiency of breeding programs. This review summarizes the applications of omics-based phenotyping technologies to improve the phenotypic traits, such as meat, egg, milk and wool quality, as well as yield, disease resistance and stress tolerance. Integrative multi-omics data enable the identification of key candidate genes, biomarkers and regulatory networks, thereby allowing earlier and more precise selection in breeding programs. The adoption of omics-driven strategies is accelerating the genetic enhancement of the economically important traits, offering a comprehensive framework to improve animal productivity and health. Nevertheless, significant challenges remain, including constructing species and traits-specific omics databases, establishing robust correlations between omics-derived phenotypes and traditional traits, and translating omics discoveries into practical breeding solutions.
Proteomic comparison of human neural cell-derived extracellular vesicles and parental cells from Alzheimer's disease and cognitively normal individuals.
Xin JY, Liu J, Dong HM … +19 more , Yu HL, Xiao ZS, Hu JN, Jiang Q, Zhu YP, Feng L, Feng Y, Jia YJ, Yuan ZY, Yu ZY, Shi AY, Zeng GH, Wang J, Wang WY, Cheng L, Vella LJ, Li FZ, Masters CL, Wang YJ
Sci China Life Sci · 2026 Apr · PMID 42113447 · Publisher ↗
Circulating brain-derived extracellular vesicles (BDEVs) have emerged as promising biomarkers for neurodegenerative diseases, including Alzheimer's disease (AD). However, it remains unclear to what extent extracellular v...
Circulating brain-derived extracellular vesicles (BDEVs) have emerged as promising biomarkers for neurodegenerative diseases, including Alzheimer's disease (AD). However, it remains unclear to what extent extracellular vesicles (EVs) proteomes reflect the molecular states and disease-associated alterations of their parent brain cell types. Here, using a multi-line human induced pluripotent stem cell (hiPSC) platform derived from three AD and three cognitively normal (CN) donors, we generated neurons, astrocytes, microglia, and oligodendrocytes, and performed paired proteomic profiling of each cell type and its secreted EVs. We systematically compared protein profiles to evaluate cell-EV similarity, disease-associated features, and concordance with proteomic datasets from human AD brain tissue. Across all four lineages, EV proteomes showed extensive overlap with parent cells (>97% overlap; Jaccard index: 0.69-0.80) while also displaying lineage-specific functional biases. Under AD versus CN comparisons, EVs exhibited larger effect sizes and retained a higher number of differentially expressed proteins (DEPs) when applying the same fold-change criteria, yielding clearer AD-CN separation than their parent cells. Importantly, EV DEPs showed higher concordance with human AD brain proteomic signatures (EVs: 2,134 DEPs; cells: 816 DEPs). Finally, amyloid precursor protein (APP)-derived peptides, including amyloid-β (Aβ), were preferentially enriched in neuron- and oligodendrocyte-derived EVs, and AD EVs showed elevated Aβ42, p-Tau217 and p-Tau181 relative to CN EVs. Together, these data indicate that cell type-resolved EV proteomes largely recapitulate parent cell identity while sensitively capturing AD-relevant molecular alterations, supporting EV-based strategies for early diagnosis and monitoring of AD and potentially other neurodegenerative disorders.
CircClint1/miR-378b/NPDC1 axis: A novel therapeutic target and biomarker for myocardial infarction.
Zhang X, Zhu X, Dang Z … +12 more , Chen M, Tian J, Guo X, Guo R, Han C, Shen N, Li X, Liu J, Wu X, Yang Y, Chang H, Jin Z
Life Sci · 2026 Aug · PMID 42107693 · Publisher ↗
Myocardial infarction (MI) remains a leading cause of global morbidity, often progressing to irreversible ischemic cardiomyopathy due to the limitations of current pharmacological interventions in arresting adverse remod...
Myocardial infarction (MI) remains a leading cause of global morbidity, often progressing to irreversible ischemic cardiomyopathy due to the limitations of current pharmacological interventions in arresting adverse remodeling. Here, we combined whole-transcriptome sequencing with bioinformatic prioritization in a murine MI model to identify circClint1 as a pivotal, upregulated mediator within the infarcted microenvironment. Mechanistically, luciferase reporter assays and RNA pull-down confirmed that circClint1 functions as a competitive endogenous RNA (ceRNA) for miR-378b, thereby sequestering the miRNA and preventing the targeted degradation of its downstream effector, NPDC1. Notably, both in vivo Western blot and immunofluorescence revealed that ischemic stress triggers a dramatic and spatiotemporal accumulation of NPDC1 protein, particularly within the cytoplasm of peri-infarct cardiomyocytes. Functionally, we established an AAV9-mediated myocardial-specific overexpression model to evaluate the pathological consequences of sustained NPDC1 elevation. Our results demonstrated that NPDC1 accumulation significantly exacerbates post-infarction damage by promoting TUNEL-positive cardiomyocyte apoptosis, intensifying fibrotic remodeling, and impairing the myocardial microcirculation. Conversely, siRNA-mediated genetic silencing of NPDC1 in HL-1 cardiomyocytes effectively attenuated hypoxia-induced oxidative stress, preserved mitochondrial membrane potential, and improved cell viability. Collectively, this study provides definitive evidence that the circClint1/miR-378b/NPDC1 axis is a master detrimental driver of post-MI progression. By elucidating the multi-dimensional role of NPDC1 in coordinating cell death and impaired revascularization, our findings identify this axis as a promising therapeutic target for mitigating myocardial injury and improving long-term cardiovascular outcomes.
Salvianolic acid A inhibits tumor cell proliferation and induces chromosomal abnormalities by blocking the citrullinating enzyme PADs.
Chen J, Wang T, Gao B … +3 more , Ke X, Zhou X, Qu Y
Life Sci · 2026 Aug · PMID 42107692 · Publisher ↗
AIMS: Citrullination, a post-translational modification catalyzed by peptidylarginine deiminases (PADs), is closely linked to cancer progression. Despite PADs' clinical importance, effective inhibitors are urgently neede...
AIMS: Citrullination, a post-translational modification catalyzed by peptidylarginine deiminases (PADs), is closely linked to cancer progression. Despite PADs' clinical importance, effective inhibitors are urgently needed. We aimed to identify a novel PAD inhibitor, salvianolic acid A (SAA), and to characterize the mechanism by which SAA inhibits PAD activity and exerts anti-tumor effects. MATERIALS AND METHODS: Citrullination of histone H3 (CitH3), drug affinity responsive target stability (DARTS) assays, in vitro enzymatic activity, and molecular docking were used to investigate SAA's direct interaction with PAD family members. PAD oligomerization was evaluated by disuccinimidyl suberate (DSS) cross-linking, native PAGE, and proximity ligation assay (PLA). PAD-histone H3 interaction was assessed by co-immunoprecipitation and PLA. Cellular effects were evaluated in colorectal cancer cell lines and mouse intestinal organoids using CCK-8, Transwell, EdU, and karyotype analyses. KEY FINDINGS: SAA was identified as a reversible pan-PAD inhibitor that binds directly to PAD1, PAD2, PAD3, and PAD4. Unlike traditional covalent inhibitors, SAA promotes PAD oligomerization and enhances PAD-histone H3 interaction while inhibiting histone H3 citrullination. SAA significantly inhibited cancer cell proliferation, migration, and organoid growth, and induced numerical chromosomal abnormalities in a PAD2/4-dependent manner. SIGNIFICANCE: These findings establish PADs as functional targets of SAA and reveal a novel mechanism for PAD inhibition, positioning SAA as a promising chemical probe for treating citrullination-related diseases.
Chronic intranasal URB597 treatment reverts short-term memory deficits in a rat model of metabolic syndrome.
Di Cesare B, Mancini GF, Parente M … +9 more , Pisa E, Romanelli L, Zwergel C, Mai A, Morena M, Pallottini V, Scuderi C, Macrì S, Campolongo P
Life Sci · 2026 Aug · PMID 42107691 · Publisher ↗
AIMS: Metabolic syndrome (MetS) is characterized by several metabolic alterations that may increase the risk of memory alterations. While metabolic consequences of MetS are well documented, its memory impact remains unde...
AIMS: Metabolic syndrome (MetS) is characterized by several metabolic alterations that may increase the risk of memory alterations. While metabolic consequences of MetS are well documented, its memory impact remains underexplored. This study aimed at investigating the progression of MetS-associated impairments and evaluating the therapeutic potential of URB597, a fatty-acid amide hydrolase inhibitor, that increases the N-acylethanolamine levels. MATERIALS AND METHODS: In Experiment 1, male Sprague-Dawley rats were fed a control (CTRL), high-fat (HF), high-carbohydrate (HC), or combined HF/HC diet for 12 weeks to identify the most effective model of MetS-induced metabolic and memory changes. In Experiment 2, rats received intranasal URB597 (0.1 mg/kg) for 10 weeks following the HF/HC diet to assess its therapeutic impact. Body weight, body mass index (BMI), and triglycerides were measured; memory function was assessed using the Object Recognition, Morris Water Maze, and Y-maze tasks. KEY FINDINGS: Results from Experiment 1 showed that the HF/HC diet induced metabolic dysfunctions and impairments in both recognition and long-term spatial memory, while short-term spatial memory remained intact. In Experiment 2, the prolonged diet reproduced the same metabolic and memory deficits observed in Experiment 1, and URB597 treatment reversed recognition memory impairments but did not improve spatial memory performance, suggesting a domain-specific vulnerability to MetS and to the treatment response. SIGNIFICANCE: These findings highlight memory deficits associated with MetS and point to N-acylethanolamine signaling as a potential modulatory pathway, with URB597 serving as a pharmacological tool to investigate its therapeutic relevance.
Hypoxia-induced endothelial exosomal MSTRG.12883.2 enhances ox-LDL- induced phenotypic switching of vascular smooth muscle cells.
Yin R, Zhang G, Ruan P … +3 more , Qu L, Shen Z, Zhi K
Life Sci · 2026 Aug · PMID 42107690 · Publisher ↗
AIMS: Plaque regions in atherosclerosis (AS) exhibit sustained moderate hypoxia, which may impair endothelial function and influence vascular smooth muscle cell (VSMC) behavior. This study aims to investigate hypoxia-res...
AIMS: Plaque regions in atherosclerosis (AS) exhibit sustained moderate hypoxia, which may impair endothelial function and influence vascular smooth muscle cell (VSMC) behavior. This study aims to investigate hypoxia-responsive endothelial-derived long noncoding RNAs (lncRNAs), and their role in enhancing oxidized low-density lipoprotein(ox-LDL)-induced phenotypic switching of VSMCs. MATERIALS AND METHODS: Differentially expressed lncRNAs in endothelial cells (ECs) under hypoxia were selected for analysis and validated by qRT-PCR. Luciferase and ChIP-PCR assays were performed to assess HIF-2α-mediated transcriptional regulation of MSTRG.12883.2. Bioinformatic analysis, luciferase and RIP assays were conducted to examine the interaction between MSTRG.12883.2 and the miR-632/KLF4 axis. Exosomes were isolated and characterized, and exosome-dependent transfer of MSTRG.12883.2 from ECs to VSMCs was demonstrated. Phenotypic switching of VSMCs was evaluated using functional assays (CCK-8 and migration assays) and molecular analyses (ELISA and Western blotting). KEY FINDINGS: MSTRG.12883.2 was identified as a hypoxia-induced, endothelial-enriched lncRNA transcriptionally regulated by HIF-2α. Preferentially enriched in exosomes, it is transferred from ECs to VSMCs. Mechanistically, MSTRG.12883.2 acts as a competing endogenous RNA that sponges miR-632, thereby relieving KLF4 repression and facilitating the ox-LDL-induced transition of VSMCs from a contractile to a synthetic phenotype. SIGNIFICANCE: We reveal that the unique plaque microenvironment triggers the expression of endothelial-derived MSTRG.12883.2, leading to its exosomal transfer to VSMCs. This hypoxia-responsive axis serves as a key driver of plaque destabilization and vascular remodeling. Together, these findings highlight a critical layer of endothelial-VSMC communication in AS and position MSTRG.12883.2 as a potent diagnostic and therapeutic target.
Sensory nerve desensitisation exerts differential effects on the severity of acute pancreatitis in rodent models.
Joó ER, Kiss L, Fűr GM … +10 more , Balla Z, Kormányos ES, Kui B, Hegyi P, Maléth J, Pallagi P, Venglovecz V, Pintér E, Helyes Z, Rakonczay Z
Life Sci · 2026 Aug · PMID 42107689 · Publisher ↗
Acute pancreatitis (AP) is a common gastroenterological disorder characterized by severe abdominal pain and inflammation. Despite its high mortality rate, the pathomechanism of AP remains incompletely understood, althoug...
Acute pancreatitis (AP) is a common gastroenterological disorder characterized by severe abdominal pain and inflammation. Despite its high mortality rate, the pathomechanism of AP remains incompletely understood, although neurogenic inflammation - where nerve-derived mediators trigger or amplify inflammatory responses - also appears to contribute to its pathogenesis. The aim of this study was to further investigate the role of neurogenic inflammation in AP and the impact of sensory nerve desensitisation on disease severity. Sensory afferent neurons were ablated using resiniferatoxin (RTX) prior to AP induction in four distinct rat and mouse models. Additionally, TRPV1 knock-out mice were employed to assess the contribution of this ion channel to AP development. Our findings reveal that RTX-induced sensory nerve desensitisation exacerbates the severity of necrotising AP induced by L-ornithine (L-Orn) and sodium taurocholate (NaTc) in rats, as evidenced by increased tissue damage, leukocyte infiltration or serum amylase activity. Conversely, in the cerulein (Cer)-induced oedematous AP rat model, RTX treatment significantly reduced leukocyte infiltration without affecting tissue oedema. In mice, RTX administration worsened the severity of Cer-induced AP, while TRPV1 gene deletion led to a modest reduction in disease severity. These results suggest that the impact of sensory nerve disruption on AP varies depending on the model and type of AP. The study underscores the important role of sensory neurons and TRPV1 ion channels in the pathogenesis and progression of AP, highlighting the potential for targeted therapies that modulate neurogenic inflammation.
Role of cystathionine β-synthase in modulating NO and H₂S signaling under metabolic stress in obesity-driven endothelial dysfunction.
Esposito E, Indolfi C, Pirozzi C … +9 more , Correale M, Bello I, Casale V, Panza E, Mattace Raso G, Meli R, Sorrentino R, Mitidieri E, d'Emmanuele di Villa Bianca R
Life Sci · 2026 Aug · PMID 42107688 · Publisher ↗
Cystathionine β-synthase (CBS), a hydrogen sulfide (H₂S)-producing enzyme, plays a role in maintaining vascular homeostasis through its dual function of generating H₂S and nitric oxide (NO) within the endothelium. Here,...
Cystathionine β-synthase (CBS), a hydrogen sulfide (H₂S)-producing enzyme, plays a role in maintaining vascular homeostasis through its dual function of generating H₂S and nitric oxide (NO) within the endothelium. Here, we investigated the role of the CBS/H₂S/NO axis under metabolic stress, using both an in vitro model of lipid overload and an in vivo model of high-fat diet (HFD)-induced obesity. Bovine aortic endothelial cells (BAEC) exposed to sodium palmitate (NaP) exhibited impaired NO signaling, accompanied by increased oxidative stress, as evidenced by elevated reactive oxygen species production and upregulation of Nox4 expression, along with activation of the unfolded protein response, an index of endoplasmic reticulum stress. In parallel, a downregulation of CBS expression and H₂S levels was found. Similarly to NaP, CBS silencing was associated with an impairment in NO signaling, supporting its role in endothelial function. The exogenous source of HS reversed NaP-induced damage in BAEC. Extending these findings in vivo, HFD-fed mice developed metabolic dysfunction in terms of HOMA, insulin resistance, and hyperlipidaemia. This was associated with disrupted NO signaling and increased H₂S levels in the aorta. The rise in HS serves as a protective response to oxidative stress induced by HFD. Collectively, these findings demonstrated a crucial role for endothelial CBS in modulating the interplay between H₂S and NO in metabolic stress associated with obesity. Targeting CBS to enhance both H₂S and NO bioavailability can represent a novel therapeutic approach in obesity-related endothelial dysfunction.
Ameliorative impact of aprepitant on cisplatin testicular toxicity: Dual regulation of PI3K/AKT pro-survival signaling and Bax/cytochrome c/caspase-3 apoptotic signaling.
Mohamed TB, Khalifa YMMA, Attya ME … +2 more , Azouz AA, Sharkawi SMZ
Life Sci · 2026 Aug · PMID 42107687 · Publisher ↗
AIM: Cisplatin is a powerful antineoplastic agent utilized for the management of several cancers. Due to its significant deleterious impact on the testis, manifested as long-term infertility and irreversible azoospermia...
AIM: Cisplatin is a powerful antineoplastic agent utilized for the management of several cancers. Due to its significant deleterious impact on the testis, manifested as long-term infertility and irreversible azoospermia in 50% of individuals, its clinical application is markedly restricted. Therefore, this study focused on the investigation of aprepitant's potential effectiveness against cisplatin-induced testicular injury due to its previously reported efficacy in modulation of inflammatory, pro-survival, and apoptotic signaling. MAIN METHODS: In a 10-day experimental protocol, male Wistar rats were assigned to five groups: normal control, aprepitant (20 mg/kg), cisplatin (10 mg/kg, 5 day-only), aprepitant (10 mg/kg) + cisplatin, and aprepitant (20 mg/kg) + cisplatin, then sacrificed on day 11. Sperm quality and testosterone level were evaluated, along with biochemical, immunohistochemical, and histopathological analysis of the testicular tissue. KEY FINDINGS: Cisplatin administration notably diminished sperm viability, count, morphology, and increased abnormalities, alongside the decline in serum testosterone level. Furthermore, cisplatin upregulated nuclear factor-kappa B p65 (NF-κB p65), while downregulating phosphorylated-phosphatidylinositol-3-kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) protein expressions in testicular tissue sections. That in turn enhanced the transcription of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines, aggravated oxidant/antioxidant imbalance, triggered apoptosis via Bax/cytochrome c/caspase-3 intrinsic pathway, while suppressing the antiapoptotic Bcl-2 protein. In contrast, aprepitant treatment guarded against these alterations in a dose-dependent manner. SIGNIFICANCE: Aprepitant exhibits efficient protection against cisplatin-induced testicular toxicity that could be attributed to its inhibitory influence on Bax/cytochrome c/cleaved caspase-3 apoptotic signaling, with simultaneous enhancement of PI3K/AKT pro-survival signaling.
Corrigendum to "Quercetin ameliorated remote myocardial injury induced by renal ischemia/reperfusion in rats: Role of Rho-kinase and hydrogen sulfide" [Life Sci. Volume 287 (2021) 120144].
El-Sayed SS, Shahin RM, Fahmy A … +1 more , Elshazly SM
Life Sci · 2026 Jul · PMID 42106278 · Publisher ↗
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Inhalation of hydrogen gas reduces exacerbations of acute aortic dissection in mice.
Iketani M, Kawata M, Ito M … +3 more , Ohsawa I, Takayama K, Aokage T
Life Sci · 2026 Jul · PMID 42105975 · Publisher ↗
AIMS: Acute aortic dissection (AAD) is a life-threatening condition in which vascular inflammation contributes to disease progression and complications such as aortic rupture. Current treatment is centered on hemodynamic...
AIMS: Acute aortic dissection (AAD) is a life-threatening condition in which vascular inflammation contributes to disease progression and complications such as aortic rupture. Current treatment is centered on hemodynamic control, and anti-inflammatory options remain limited. We investigated whether inhaled molecular hydrogen (H) gas attenuates AAD severity in a murine model. MATERIALS AND METHODS: AAD was induced in male C57BL/6J mice by β-aminopropionitrile pretreatment followed by continuous angiotensin II infusion. Mice were exposed to 2% H gas or control gas for 24 h, and effects on AAD severity and inflammation were examined. KEY FINDINGS: H inhalation improved 24-h survival and spontaneous locomotor activity, while systolic blood pressure was not altered. H also reduced aortic rupture frequency and suppressed false lumen enlargement. In plasma, H inhalation significantly reduced IL-6 and G-CSF levels, while MMP-9 and CXCL1 showed downward trends. In the aortic wall, H reduced MMP-9 and CXCL1 expression, including within Ly-6B.2-positive regions, whereas CXCL1 expression within SMA-positive regions was unchanged. In addition, the number of Ly-6B.2-positive cells in the aortic wall was decreased and positively correlated with false lumen area. In bone marrow, the reduction in CD11bLy-6G neutrophils observed in AAD mice was significantly attenuated by H inhalation. H also attenuated oxidative stress-related changes in the aortic wall. SIGNIFICANCE: These findings indicate that 2% H gas inhalation reduces acute AAD exacerbation without affecting blood pressure, likely through modulation of inflammatory mediators and neutrophil-associated acute inflammation. H inhalation may represent a safe adjunctive strategy to limit AAD progression and rupture.
Immunometabolic mechanisms and therapeutic perspectives in aortic dissection.
Ma Y, Tang H, Bian L … +1 more , Liu J
Life Sci · 2026 Jul · PMID 42105414 · Publisher ↗
Aortic dissection (AD) is a life-threatening cardiovascular disease with high morbidity and mortality. Its pathogenesis involves tearing of the aortic intima, degradation of the extracellular matrix (ECM), phenotypic tra...
Aortic dissection (AD) is a life-threatening cardiovascular disease with high morbidity and mortality. Its pathogenesis involves tearing of the aortic intima, degradation of the extracellular matrix (ECM), phenotypic transformation of vascular smooth muscle cells (VSMCs), and excessive inflammatory activation. However, effective therapeutic strategies to prevent AD progression are still lacking. Recent studies have revealed that immunometabolic mechanisms play a crucial role in the initiation and progression of AD. Inflammatory responses, particularly macrophage activation and secretion of matrix metalloproteinases (MMPs), accelerate aortic wall destruction. Meanwhile, metabolic disorders such as diabetes mellitus and dyslipidemia further increase the risk of AD by impairing VSMC function and promoting oxidative stress. Metabolic reprogramming of immune and vascular cells regulates inflammatory activation, oxidative stress, phenotypic switching, and extracellular matrix remodeling, thereby creating a self-amplifying immunometabolic network that increases aortic wall fragility and susceptibility to dissection. This review summarizes current advances in understanding the interplay between immune regulation and metabolic processes in AD. By elucidating the immunometabolic mechanisms underlying AD, we aim to provide new insights into its pathogenesis and identify potential molecular targets for the prevention, diagnosis, and treatment of this devastating disease.
Angiopoietin-2-mediated integrin α5β1 and FAK signaling contributes to pulmonary arterial hypertension pathogenesis.
Chen S, Yin J, Kan Z … +7 more , Li X, Yang M, Chen H, Chen H, Li S, Huang W, Yu X
Life Sci · 2026 Aug · PMID 42103072 · Publisher ↗
Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling and right heart failure, in which endothelial dysfunction plays a central role. Angiopoietin-2 (ANGPT2) has b...
Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling and right heart failure, in which endothelial dysfunction plays a central role. Angiopoietin-2 (ANGPT2) has been implicated in endothelial injury and vascular remodeling in multiple diseases; however, its role in hypoxic PAH remains incompletely understood. This study investigated the role and underlying mechanisms of ANGPT2 in PAH, with a particular focus on endothelial integrity, permeability, and vascular remodeling. Gene expression profiling was performed using lung tissues from patients with PAH, and ANGPT2 expression was further evaluated in plasma and lung tissues. Its functional role was examined in hypoxia-induced and Sugen/hypoxia (SuHx)-induced animal models of PAH. The effects of ANGPT2 inhibition by AAV-shANGPT2 delivery on hemodynamics, right ventricular function, and vascular remodeling were assessed. In vitro, pulmonary artery endothelial cells (PAECs) were used to evaluate the effects of ANGPT2 on proliferation, migration, and extracellular matrix remodeling. ANGPT2 expression was significantly increased in patients with PAH and in experimental models, and its levels correlated with indices of disease severity. Inhibition of ANGPT2 attenuated pulmonary hypertension, reduced right ventricular hypertrophy, and ameliorated pulmonary vascular remodeling, including collagen deposition and small-vessel muscularization. In PAECs, ANGPT2 inhibition restored impaired migration and tube formation and attenuated hypoxia-induced cell cycle progression. Mechanistically, ANGPT2 regulated integrin expression and activated focal adhesion kinase (FAK) signaling, thereby influencing endothelial adhesion, migration, and extracellular matrix remodeling. Collectively, these findings identify ANGPT2 as an important mediator of pulmonary vascular remodeling in experimental PAH and support ANGPT2 inhibition as a potential therapeutic approach warranting further preclinical investigation.
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