American journal of physiology. Cell physiology最新文献

Kidney fibrosis is characterized by excessive deposition of extracellular matrix, which is ultimately disrupting normal renal architecture. Despite its clinical relevance, no targeted anti-fibrotic therapies are currently available. Myofibroblasts, primarily derived from pericytes and resident fibroblasts, are key effectors of fibrosis due to their high extracellular matrix production. Here, we tested the hypothesis that ferroptosis induction would enable the targeted elimination of activated kidney fibroblasts. We found that kidney fibroblasts exhibit marked sensitivity to ferroptotic cell death upon exposure to the ferroptosis inducer RAS-selective lethal 3 (RSL3), an effect further amplified by TGF-β stimulation. In tissue slice cultures of murine fibrotic kidneys, RSL3 eliminated myofibroblasts without causing overt damage to other cell types. Extending these findings in vivo, we applied a post-ischemia/reperfusion model of kidney fibrosis and demonstrated that repeated low-dose systemic administration of RSL3 significantly reduced the activated fibroblast population without inducing appreciable injury to parenchymal cells. These results provide proof-of-principle that the ferroptosis susceptibility of activated fibroblasts may offer a potential strategy for the selective depletion of profibrotic effector cells in kidney fibrosis.

Previous studies have implicated the α7 nicotinic acetylcholine receptor (α7nAChR) in cardioprotection via its anti-inflammatory effects, yet the underlying mechanisms remain poorly understood. Here, we investigated the impact of α7nAChR deficiency on cardiac injury induced by a 7-day isoproterenol (ISO) treatment in littermate wild-type (WT) and α7nAChR-knockout (α7-KO) mice. ISO administration in WT mice led to a marked upregulation of α7nAChR expression in cardiac tissue and isolated cardiomyocytes, suggesting a compensatory response to adrenergic stress. To investigate this hypothesis, we assessed ISO-induced structural and inflammatory changes in both genotypes. ISO-treated WT mice developed isolated cardiac hypertrophy with minimal inflammation or fibrosis. In contrast, α7-KO mice subjected to ISO treatment displayed exacerbated hypertrophy and fibrosis. These alterations were accompanied by marked leukocyte accumulation, supporting the anti-inflammatory role of α7nAChR. To explore this further, we characterized the inflammatory profile using flow cytometry. FACS-analyzed hearts from α7- KO/ISO mice exhibited increased monocyte infiltration and a marked expansion of the CCR2⁺ population compared to WT/ISO. This phenotype was associated with greater cardiomyocyte death. In vitro, isolated ventricular myocytes lacking α7nAChR were intrinsically more susceptible to ISO-induced cytotoxicity, indicating that α7nAChR exerts a cell-autonomous protective role beyond its anti-inflammatory function. Our findings establish α7nAChR as a key determinant of cardiac resilience to adrenergic insult and underscore its potential as a therapeutic target for mitigating myocardial injury.

Chaperone-Mediated Autophagy (CMA) is a key lysosomal proteolytic pathway essential for cellular homeostasis and metabolism, with dysfunction linked to various human diseases. While extensively studied in humans and mice, CMA was only recently identified in fish, paving the way for novel and evolutionary research perspectives. Here, we demonstrate a role for CMA in regulating feed intake (FI) in rainbow trout (Oncorhynchus mykiss), a major aquaculture species and a widely used model in numerous research fields, including physiology, evolutionary genetics, toxicology, immunology, and nutrition. Specifically, we observed that feed deprivation induces an increase in the CMA activation score - a reliable proxy for CMA activity - in the hypothalamus, a central brain region involved in the regulation of feeding behavior. To probe its functional relevance, we intracerebroventricularly (ICV) injected the CMA activator CA77.1 and found a significant reduction in FI levels, suggesting a regulatory role for CMA in appetite. Further analysis suggested that CMA may regulate FI partly through changes in hypothalamic free amino acid availability, with ribosomal protein degradation potentially contributing to this mechanism. Through this mechanism, CMA may play a critical role in the precise regulation of satiety and represent a promising target for therapeutic strategies aimed at treating metabolic disorders, as well as for nutritional interventions to improve feed efficiency and promote more sustainable growth practices in aquaculture.

Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive fibroblast-to-myofibroblast transition (FMT) and extracellular matrix (ECM) deposition, largely driven by transforming growth factor-beta 1 (TGFβ1). Existing therapies offer limited efficacy, particularly in advanced disease. Circadian rhythms have recently emerged as key modulators of lung inflammation and fibrosis. In this study, we developed an in vitro model of chronic fibrotic signaling using adenovirus-mediated TGFβ1 overexpression (Ad-TGFβ1) or human recombinant protein TGFβ1 in primary human lung fibroblasts. Using this model, we investigated the antifibrotic potential of STL1267, a next-generation Rev-erbα agonist with improved potency, specificity, and pharmacokinetic properties. RNA sequencing and pathway analysis revealed that STL1267 significantly reversed Ad-TGFβ1-induced expression of genes associated with ECM remodeling, collagen biosynthesis, and immune suppression. STL1267 also upregulated pathways related to IL-10, IL-4, and IL-13 signaling, which are known to counteract fibrotic responses. Quantitative PCR and immunoblotting confirmed STL1267's ability to downregulate key pro-fibrotic markers, including COL1A1, αSMA, FN1, and FAP, at both gene and protein levels. Comparative studies with other Rev-erbα agonists (GSK4112, SR9009), Saracatinib, and FDA-approved antifibrotic drugs (Pirfenidone, Nintedanib) demonstrated superior efficacy of STL1267 in inhibiting both preventive and post-fibrotic induction models. Moreover, lentiviral overexpression of Rev-erbα suppressed TGFβ1-induced αSMA expression, supporting a direct antifibrotic role. These findings highlight Rev-erbα as a key regulator of myofibroblast differentiation and support both STL1267 and GSK4112 as promising candidates for circadian-based antifibrotic therapy. Future in vivo studies are warranted to evaluate its translational potential in idiopathic pulmonary fibrosis.

This study investigated the efficacy of two natural compounds-celastrol, a heat shock protein (HSP) inducer, and Cblin peptide, a ubiquitination inhibitor-in counteracting muscle atrophy under real microgravity conditions. Both agents independently attenuated microgravity-induced reductions in myotube thickness, myosin heavy chain protein levels, and atrogene expression. Celastrol primarily enhanced HSP expression, whereas Cblin peptide inhibited insulin receptor substrate-1 degradation, thereby promoting insulin-like growth factor-1 signaling. Despite their distinct molecular actions, no synergistic or additive effects were observed when combined. These findings highlight the potential of celastrol and Cblin peptide as functional ingredients for mitigating muscle atrophy, particularly in the context of space travel. Notably, Cblin peptide is abundant in glycinin-rich soybean protein, and celastrol is derived from the root of Tripterygium wilfordii (Taiwan vine). Future applications may include incorporating these plant-derived compounds into space foods to improve the quality of life for astronauts in space.NEW & NOTEWORTHY This study evaluated the effects of celastrol and the Cblin peptide in mitigating muscle atrophy under microgravity conditions. Both compounds alleviated myotube atrophy through distinct mechanisms, though no synergistic effect was observed. Celastrol upregulated heat shock protein (HSP) expression, whereas Cblin prevented IRS-1 degradation, thereby enhancing IGF-1 signaling. Sourced from Tripterygium wilfordii and soybean protein, respectively, these agents may serve as functional space foods to help counteract muscle atrophy and support astronauts' health during spaceflight.

Colorectal cancer is a complex disease shaped by genetic changes and cross talk among tumor cells, stromal factors, and infiltrating cellular elements within the tumor environment. In this review, we explore an integrative network of genes and their encoded proteins that play significant roles in colorectal cancer progression. Among the most clinically relevant and frequently implicated factors in digestive system cancer is the prominent protumorigenic serine protease inhibitor SERPINE1 (also known as plasminogen activator inhibitor-1 or PAI-1). This SERPIN impacts critical pathways that regulate extracellular matrix remodeling, neoplastic and immune cell migration, tumor cell survival, metastasis, and drug resistance, and plays a major role in shaping the neoplastic inflammatory microenvironment. As a result of this multifaceted function, PAI-1 correlates with high-risk scores and poor patient outcomes in various malignancies including colorectal cancer. Recent bioinformatic approaches provide new insights on how PAI-1 contributes to tumor progression and patient prognosis. This review provides a unified framework for understanding this disease at the molecular level and highlights promising targets for future therapies and diagnosis.

Autophagy is a catabolic process that enables cellular metabolic adaptation in response to nutrient deprivation. It facilitates the degradation of proteins and cellular components within lysosomes to generate essential metabolites. The glucose transporter 1 (GLUT1) is among the proteins that can undergo autophagy-mediated degradation in response to metabolic stimuli. GLUT1 is essential for cellular glucose supply in several tissues. Notably, GLUT1 facilitates glucose transport across the blood-brain barrier, creating a concentration gradient from the bloodstream into the brain's interstitial fluid. The presence of GLUT1, at the plasma membrane, is the first step in initiating glucose uptake and driving glycolysis inside the cell. Glycolysis can be initiated in response to several stimuli, including glucose availability, autophagy inhibition, and growth factor accessibility. In this review, we highlight recently described mechanisms that govern the subcellular distribution of GLUT1 with a focus on autophagy-mediated trafficking. Understanding how autophagy coordinates GLUT1 sorting in response to metabolic demands may uncover novel therapeutic targets for metabolic disorders characterized by dysregulated GLUT1 trafficking.

Frailty in patients with chronic kidney disease (CKD) greatly exacerbates disease comorbidities and increases probability of death. Prior research underscores molecular alterations in skeletal muscle physiology that may underly frailty and poor intervention response in this patient population. CKD can negatively affect satellite cell abundance and function, reducing skeletal muscle injury resilience and adaptive capacity. Pathogenic drivers of compromised satellite cell abundance and activity in patients with CKD remain largely unknown. To address this gap in knowledge, we isolated primary myogenic progenitor cells (MPCs) from patients with CKD and control participants. We also sought to define cell-extrinsic and cell-intrinsic processes that may underlie myogenic deficits. We performed RNA sequencing on MPCs from control participants cultured in control serum, MPCs from control participants cultured in CKD serum, and MPCs from participants with CKD cultured in control serum. We identified zinc mishandling as a shared pathway between control cells treated with CKD serum and CKD cells treated with control serum. Consistent with these observations, we found zinc deficiency and attenuated myogenesis in MPCs from patients with CKD. Finally, we showed that zinc supplementation partially restores the myogenic capacity of MPCs from patients with CKD. Together, these data highlight the importance of zinc metabolism in myogenesis and identify a novel mechanism whereby CKD pathogenesis impedes MPC differentiation.NEW & NOTEWORTHY Satellite cell abundance and function are negatively affected by chronic kidney disease (CKD). Using primary myogenic progenitor cells (MPCs) cultured from patients with late-stage CKD and matched controls, we expose cells to CKD or control serum and identify metallothionein-induced zinc deficiency as both a cell-autonomous and nonautonomous consequence of CKD on MPCs. We find zinc deficiency likely attenuates myogenesis through an AKT-FOXO1 signaling cascade, which can be partially rescued by supplementation of exogenous zinc.

Cancer cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting and systemic inflammation, primarily observed in patients with advanced-stage cancer. Cachexia severely impacts patients' quality of life and even increases mortality rates; however, effective therapeutic interventions remain elusive. To identify key mediators of muscle atrophy, we integrated >100 bulk and single-cell transcriptomic datasets from diverse murine cachexia models, including colorectal, lung, and pancreatic cancer. This analysis identified leucine-rich α-2-glycoprotein 1 (Lrg1), as consistently upregulated in skeletal muscle endothelial cells across cachexia models and progressively increased during disease progression. Functional studies demonstrated that recombinant Lrg1 induced myotube atrophy in vitro, accompanied by reduced fusion index, shortened myotube length, and increased expression of the atrogenes such as MAFbx and MuRF1. Neutralization of Lrg1 or pharmacological inhibition of Stat3 prevented these effects. Our findings nominate Lrg1 as a candidate biomarker and potential therapeutic target for preventing skeletal muscle wasting in cancer cachexia.NEW & NOTEWORTHY This study reports the first omics-based characterization of the CT-26 cancer cachexia model and shows transcriptomic concordance with other models. Integrative bulk and single-cell analyses identified Lrg1 as a gene highly expressed in endothelial cells and associated with muscle wasting. Functional assays indicated that extracellular Lrg1 activates Stat3 and induces myotube atrophy, whereas its neutralization or Stat3 inhibition prevented these effects. Lrg1 may therefore serve as a biomarker and therapeutic target in cancer cachexia.

Persistent necroinflammation is a continuous feedback loop between the regulated necrotic cell death and the sustained immune system activation. It has been increasingly recognized as a key driver of chronic tissue remodeling and fibrosis. Necrosis, unlike apoptosis, is a lytic and immunogenic form of cell death that releases danger-associated molecular patterns (DAMPs) and alarmins, which activate inflammatory pathways including the NOD-like receptor protein 3 (NLRP3) inflammasome. This sustained inflammatory environment promotes pathological remodeling and impairs tissue regeneration. This review elucidates the mechanistic framework of necroinflammation involving key molecular players such as receptor-interacting protein kinases (RIPK) 1, RIPK3, mixed lineage kinase domain-like protein (MLKL), NLRP3, calcium/calmodulin-dependent protein kinase II (CaMKII), gasdermin (GSDM), glutathione peroxidase-4 (GPX-4), acyl-CoA synthetase long-chain family member 4 (ACSL4), ferroptosis suppressor protein 1 (FSP1), and their role in fibrotic pathologies across kidneys, heart, liver, lungs, and brain. We emphasize how these signaling pathways further augment transforming growth factor-beta (TGF-β) signaling, thereby contributing to tissue fibrosis in chronic disease conditions. We also highlight recent advances in targeting these necroinflammatory mediators, especially inhibitors of these pathways, as promising antifibrotic therapeutic strategies. We emphasize the urgent need for further research to deepen our understanding of the temporal and spatial dynamics of necroinflammatory signaling and to develop organ-specific, targeted interventions against fibrosis. This will provide a robust foundation for translational research to exploit these pathways in clinical settings to mitigate chronic inflammatory diseases and their fibrotic consequences across multiple organ systems.