Experimental Cell Research[JOURNAL]
Sun
200 papers
Early-Life Cardiovascular Programming by Maternal Protein Restriction: Electrophysiological, Structural, and Molecular Alterations in Female Rats.
Gomes LC, Fioretto MN, Lemos LS … +13 more , Barata LA, Maciel FA, Ribeiro IT, de Abreu ALS, Portela LMF, Bravo IL, Stoppa EG, Willmann RG, Silva MTE, Lima CAH, Miranda JRA, Scarano WR, Justulin LA
Exp Cell Res · 2026 Jul · PMID 42402324 · Publisher ↗
Maternal malnutrition is a major risk factor for adverse health outcomes in offspring, including cardiovascular disorders. According to the Developmental Origins of Health and Disease (DOHaD) concept, adverse conditions...
Maternal malnutrition is a major risk factor for adverse health outcomes in offspring, including cardiovascular disorders. According to the Developmental Origins of Health and Disease (DOHaD) concept, adverse conditions during critical developmental windows can induce long-lasting physiological adaptations that increase disease susceptibility later in life. Among the experimental models used to investigate these mechanisms, maternal protein restriction (MPR) has been associated with metabolic, cardiovascular, and hypertensive phenotypes in offspring, some of which emerge early in life. Therefore, this study evaluated the effects of MPR on the cardiovascular morphophysiology of female offspring at postnatal day 21 (PND21). Pregnant rats were allocated to either a Control group (CTR), receiving a normoprotein diet (17% protein), or a Gestational and Lactational Low-Protein group (GLLP), receiving a low-protein diet (6% protein) throughout gestation and lactation. At PND21, female offspring underwent electrocardiographic assessment and were subsequently euthanized for morphological, molecular, and oxidative stress analyses. Female offspring from the GLLP group exhibited reduced body weight and body length, whereas absolute heart weight was preserved, resulting in increased relative heart weight and suggesting disproportionate somatic growth. Electrocardiographic analysis revealed a shortened P-R interval and decreased heart rate, indicating early alterations in cardiac electrical activity. Morphologically, cardiomyocyte architecture was preserved; however, reduced nuclear width and increased collagen and elastin deposition were observed, indicating early extracellular matrix remodeling without significant changes in reticular fibers. At the molecular level, GLLP offspring exhibited reduced PRDX3 expression, accompanied by decreased catalase (CAT) activity, reduced glutathione (GSH) levels, and lower lipid peroxidation (TBARS), suggesting alterations in redox regulation and antioxidant homeostasis during early cardiac development. Collectively, these findings demonstrate that MPR induces early structural, molecular, oxidative, and electrophysiological alterations in the hearts of female offspring. These adaptations may represent early programming events that increase susceptibility to cardiovascular dysfunction later in life, reinforcing the importance of maternal nutrition in shaping cardiovascular health across generations.
The AP2α/PDHA1 signaling pathway promotes lung cancer progression by mediating aerobic glycolysis and inhibiting cuproptosis.
Zheng Z, Pan Q, Lu W … +6 more , Ji Z, Tian Y, Song N, Zhang J, Dong L, Wang J
Exp Cell Res · 2026 Jul · PMID 42392558 · Publisher ↗
Lung cancer poses a severe global health burden with limited effective therapeutic strategies, and dysregulated aerobic glycolysis and cuproptosis are closely linked to its progression. This study aimed to explore the ro...
Lung cancer poses a severe global health burden with limited effective therapeutic strategies, and dysregulated aerobic glycolysis and cuproptosis are closely linked to its progression. This study aimed to explore the role and underlying mechanism of the AP2α/PDHA1 signaling axis in lung cancer. In this research, lung cancer cell lines with stably altered AP2α and PDHA1 expression were constructed via lentivirus and shRNA transfection; rescue experiments were performed using the glycolysis inhibitor 2-deoxyglucose (2-DG) and copper chelator tetrathiomolybdate (TTM), and nude mouse xenograft models were established for in vivo verification. The results showed that AP2α was highly expressed in lung cancer, while PDHA1 was lowly expressed in lung cancer. High AP2α and low PDHA1 expression predicted poorer overall survival in lung cancer patients. Moreover, AP2α- and PDHA1-correlated genes were enriched in ATP-related biological processes, which were closely associated with aerobic glycolysis. Downregulation of AP2α suppressed cell viability, migration and invasion while inducing apoptosis, reduced aerobic glycolysis, elevated intracellular copper content and regulated key cuproptosis-related markers. Moreover, AP2α directly bound to the PDHA1 promoter. Further rescue assays confirmed that PDHA1 mediated the oncogenic effects of AP2α, and 2-DG could reverse the phenotypic changes caused by PDHA1 knockdown. In vivo experiments also validated that the AP2α/PDHA1 axis facilitated tumor growth via modulating glycolytic metabolism. Collectively, the AP2α/PDHA1 pathway may accelerate lung cancer progression by promoting aerobic glycolysis and restraining cuproptosis. This finding reveals a novel molecular mechanism of lung cancer development and provides promising targets for combined antitumor therapy.
Distributed transcription activity in DLX proteins defies conventional mapping of a transcription activation domain.
Samifanni R, Bendall AJ
Exp Cell Res · 2026 Jun · PMID 42379337 · Publisher ↗
The DNA binding domains of transcription factors are structurally well-defined and their presence in novel genome sequence can be reliably detected via sequence homology. In contrast, regions of transcription factors tha...
The DNA binding domains of transcription factors are structurally well-defined and their presence in novel genome sequence can be reliably detected via sequence homology. In contrast, regions of transcription factors that stimulate or repress mRNA synthesis by RNA polymerase II are more enigmatic and difficult to identify with bioinformatic tools. Experimental discovery of transactivation (or repression) domains typically makes use of a reporter gene transcription assay in one or more cell types and the progressive removal of protein sequence from the transcription factor under study. By and large, this reveals one or more minimal subdomains that are required for most of the transcription activity for the wild type protein. In applying this approach to the experimental identification of minimal transactivation domains of the chicken DLX5 and DLX6 paralogues, we find no obvious subdomain organization but, instead, show redundant transactivation activity that is distributed throughout each protein. We also reveal that DLX domains can cooperate in trans in homo- or heterotypic reactions with DLX domains that are DNA-bound via the homeodomain.
Extracellular release of cytotoxic aggregates from HSV-1-replicating SH-SY5Y cells: involvement of alpha-synuclein and poly-ubiquitin conjugates.
Kurohashi M, Ikeda Y, Tsutsumi M … +12 more , Kanemaki S, Ito K, Sugimoto-Ishizuka M, Yamaguchi T, Yamamoto Y, Kokubo T, Iwaisako Y, Ikeda M, Ishimaru H, Suga K, Nakaso K, Fujimuro M
Exp Cell Res · 2026 Jun · PMID 42379336 · Publisher ↗
Herpes simplex virus 1 (HSV-1) is a neurotropic enveloped DNA virus that latently infects sensory ganglia cell bodies. HSV-1 causes cold sores, keratitis, meningitis, and encephalitis. During the HSV-1-replicating phase...
Herpes simplex virus 1 (HSV-1) is a neurotropic enveloped DNA virus that latently infects sensory ganglia cell bodies. HSV-1 causes cold sores, keratitis, meningitis, and encephalitis. During the HSV-1-replicating phase (lytic phase), viral proteins and genomes are produced in the host cell and assemble into virions. Mature virions egress from the cell, leading to cell lysis. Here, we show that HSV-1-replicating neuroblastoma cells generate cytotoxic aggregates that are detected in the extracellular medium. We initially examined the intracellular and extracellular levels of polyubiquitin conjugates in SH-SY5Y cells undergoing HSV-1 replication. The dynamics of ubiquitination were altered within cells during the lytic phase. The accumulation of poly-ubiquitin conjugates and HSV-1 membrane proteins (gB and gD) was mainly detected at the juxtanuclear cytoplasm in HSV-1-replicating cells. Moreover, poly-ubiquitin conjugates, HSP90, gB, gD, alpha-synuclein, and cytotoxic molecules were detected in the culture supernatant. Co-immunoprecipitation assays revealed that polyubiquitin conjugates in the supernatant contained aggregated gD and alpha-synuclein. Furthermore, poly-ubiquitin conjugates and alpha-synuclein in the culture supernatant contributed to its cytotoxic effects. Our results indicate that HSV-1-replicating SH-SY5Y cells produce not only virions but also cytotoxic protein aggregates containing poly-ubiquitin conjugates and alpha-synuclein. These findings may provide insight into mechanisms underlying virus-induced protein aggregation and cytotoxicity, which may be relevant to neurodegenerative processes.
MiR-1281 downregulates LMX1B to inhibit gastric cancer development.
Gao S, Xiong J, Jiao X … +4 more , Lang X, Lang W, Zhai S, Qu J
Exp Cell Res · 2026 Jun · PMID 42372902 · Publisher ↗
Gastric cancer (GC) is a prevalent and life-threatening malignancy worldwide, with its complex pathogenesis remaining incompletely understood. Identifying novel molecular mechanisms underlying gastric cancer development...
Gastric cancer (GC) is a prevalent and life-threatening malignancy worldwide, with its complex pathogenesis remaining incompletely understood. Identifying novel molecular mechanisms underlying gastric cancer development is crucial for improving diagnosis and treatment strategies. In this study, we investigated the role of miR-1281 and its target gene LMX1B in gastric cancer progression. We employed a series of experimental techniques, including real-time quantitative polymerase chain reaction (RT-qPCR) to measure the expression levels of miR-1281 in gastric cancer cell lines and clinical tissue samples. Luciferase reporter assays were performed to validate the direct binding between miR - 1281 and the 3'-untranslated region (3'-UTR) of LMX1B mRNA. Functional assays such as cell proliferation, invasion and migration assays were carried out to evaluate the effects of miR-1281 and LMX1B on gastric cancer cell behaviors. The results showed that miR-1281 was significantly downregulated in gastric cancer tissues and cell lines compared with normal counterparts. Overexpression of miR-1281 remarkably inhibited gastric cancer cell proliferation, invasion and migration. Mechanistically, we demonstrated that miR-1281 directly targeted the 3'-UTR of LMX1B mRNA, leading to decreased LMX1B expression. Conversely, knockdown of LMX1B phenocopied the effects of miR-1281 overexpression, while restoration of LMX1B expression reversed the inhibitory effects of miR-1281 on gastric cancer cells. In addition, clinical correlation analysis revealed that low miR-1281 expression was associated with poor prognosis in gastric cancer patients, while high LMX1B expression showed an opposite correlation. In conclusion, our findings suggest that miR-1281 functions as a tumor suppressor in gastric cancer by downregulating LMX1B expression. The miR - 1281/LMX1B axis may serve as a potential therapeutic target and prognostic biomarker for gastric cancer, providing new insights into the molecular mechanisms of gastric cancer development and offering novel strategies for its treatment.
Corrigendum to "Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells" [Exp. Cell Res., 326, 1, 1 August 2014, Pages 78-89].
Xiong X, Wang Y, Liu C … +4 more , Lu Q, Liu T, Rao H, Luo S
Exp Cell Res · 2026 Jun · PMID 42366130 · Publisher ↗
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Neutrophilic differentiation of promyelocytic HL-60 cells is associated with increased expression of terminal galactose residues on the cell surface.
Timoshenko AV, Kay SC
Exp Cell Res · 2026 Aug · PMID 42364919 · Publisher ↗
An important hallmark of cancer cells is altered glycosylation of cell surface molecules in comparison with normal or differentiated cells. Terminal galactose residues represent important elements of cellular glycocalyx,...
An important hallmark of cancer cells is altered glycosylation of cell surface molecules in comparison with normal or differentiated cells. Terminal galactose residues represent important elements of cellular glycocalyx, but their regulation and functions remain not fully elucidated. Here, we used lectin-induced aggregation assay to analyze changes in the expression of galactose residues on the surface of live human leukemia HL-60 cells in association with their neutrophilic differentiation induced by all-trans retinoic acid (ATRA). We found that live HL-60 in suspension expressed multiple types of glycans on the cell surface recognized by plant lectins with different glycan-binding specificity. Detailed analysis of cell aggregation responses induced by the galactose-binding Ricinus communis agglutinin (RCA) demonstrated that this activity was enhanced by a sialyltransferase inhibitor P-3FAX-Neu5Ac and suppressed by an inhibitor of N-glycosylation tunicamycin. Following the ATRA-induced differentiation (1 μM ATRA, 3 days), RCA-induced aggregation was elevated, implying the increase in the level of terminal galactose residues on the cell surface. Bioinformatics analysis of available GEO datasets showed that this change might be associated with the metabolic reprogramming of sialyltransferases and neuraminidases, both controlling the availability of galactose-terminated glycans in cells. Collectively, these findings demonstrate that ATRA-induced neutrophilic differentiation of promyelocytic leukemia HL-60 cells is accompanied by elevated cell surface galactosylation, suggesting new directions for future investigations into the cell biological mechanisms of cancer differentiation therapy.
SAHH-mediated homocysteine dysregulation drives diabetic retinopathy progression through ferroptosis-dependent mechanisms.
Li J, Liu G
Exp Cell Res · 2026 Jun · PMID 42336231 · Publisher ↗
OBJECTIVE: Homocysteine (Hcy) metabolic dysregulation has been implicated in the progression of diabetic retinopathy (DR), but the underlying molecular mechanisms remain incompletely understood. This study aims to identi...
OBJECTIVE: Homocysteine (Hcy) metabolic dysregulation has been implicated in the progression of diabetic retinopathy (DR), but the underlying molecular mechanisms remain incompletely understood. This study aims to identify key factors mediating the role of Hcy in DR and explore the molecular mechanisms by which S-adenosylhomocysteine hydrolase (SAHH)-mediated Hcy metabolic dysregulation contributes to DR pathogenesis. METHODS: Human retinal microvascular endothelial cells (RMECs) were cultured under high-glucose conditions. Levels of Hcy, inflammatory factors, expression of glial fibrillary acidic protein (GFAP), as well as cell migration, invasion, tube formation, and ferroptosis-related markers were detected using ELISA, qPCR, Western blot, and immunofluorescence techniques. A rat model of type 1 diabetes mellitus (T1DM) and an Hcy gavage model were established, and retinal pathological changes were evaluated by HE staining, Doppler ultrasound, and Evans blue staining. SAHH gene silencing was achieved using siRNA and AAV-shSAHH, followed by transcriptome sequencing to identify downstream signaling pathways. RESULTS: In vitro, high glucose combined with Hcy treatment increased intracellular Hcy levels, upregulated inflammatory factors and GFAP expression, inhibited cell proliferation, and promoted cell migration, invasion, iron accumulation, and oxidative stress. In vivo, similar pathological changes were observed in a DR rat model, and these were exacerbated by Hcy gavage. Conversely, SAHH silencing via siRNA in cultured cells reduced Hcy content and inflammation, while increasing cell proliferation, downregulating GFAP, impairing migration, invasion, and tube formation, and decreasing intracellular iron accumulation and oxidative stress. Transcriptome sequencing combined with molecular validation revealed that the SAHH-Hcy axis is associated with ferroptosis in DR, potentially by downregulating SLC7A11/GPX4 signaling, disrupting cellular iron ion transport and GSH-dependent antioxidant homeostasis, which further triggers oxidative stress and iron overload, and is closely associated with the occurrence and development of retinal lesions. CONCLUSION: SAHH-mediated Hcy dysmetabolism acts as a key driver in DR by suppressing the SLC7A11/GPX4 antioxidant axis, impairing GSH synthesis, inducing iron overload and lipid peroxidation, and ultimately triggering ferroptosis.
FAM105A regulates the Hippo/YAP signaling pathway via deubiquitination to promote gastric cancer cell proliferation and migration.
Bo S, You Y, Bai L … +8 more , Liu S, Wang J, Jiang T, Tian S, Yan F, Cheng Y, Gao Y, Wang Y
Exp Cell Res · 2026 Jun · PMID 42331176 · Publisher ↗
BACKGROUND: Gastric cancer (GC) is one of the leading causes of global cancer mortality, underscoring an urgent need for novel therapeutic targets. Dysregulation of ubiquitination and deubiquitination plays a critical ro...
BACKGROUND: Gastric cancer (GC) is one of the leading causes of global cancer mortality, underscoring an urgent need for novel therapeutic targets. Dysregulation of ubiquitination and deubiquitination plays a critical role in tumorigenesis. The deubiquitinating enzyme FAM105A, belonging to the OTULIN subfamily, has not yet been characterized in cancer. Preliminary bioinformatics analysis indicated that FAM105A is upregulated in gastric adenocarcinoma and positively correlates with the expression of CTGF, a downstream target of the Hippo/YAP signaling pathway, which is frequently dysregulated in GC. This study aimed to elucidate the role and mechanism of FAM105A in GC progression. METHODS: Bioinformatics databases were used to analyze the expression of FAM105A and its clinical significance, which was further validated in clinical samples via immunohistochemistry (IHC) and Western blot (WB). In vitro and in vivo functional assays were conducted using stable FAM105A-knockdown and FAM105A-overexpressing GC cell lines. The interaction between FAM105A and YAP was investigated using co-immunoprecipitation (Co-IP), immunofluorescence, ubiquitination assays, and proximity ligation assay (PLA). The functional dependency on the Hippo pathway was assessed using the YAP inhibitor Verteporfin (VP). Domain mapping was performed by constructing truncated mutants of both FAM105A and YAP. RESULTS: FAM105A was significantly overexpressed in GC tissues, and its high expression correlated with advanced TNM stage and poor prognosis. Functionally, FAM105A promoted GC cell proliferation, migration, and inhibited apoptosis in vitro. In vivo evaluation using xenograft models demonstrated that FAM105A-overexpressing xenografts exhibited significantly larger tumor volumes compared to controls, while FAM105A-knockdown tumors showed reduced growth. FAM105A knockdown significantly decreased final tumor weight, whereas overexpression increased tumor mass. Immunohistochemical analysis revealed that knockdown tumors exhibited consistently reduced Ki-67 immunopositivity, while overexpression samples showed enhanced proliferation signatures. Mechanistically, Co-IP experiments further confirmed that FAM105A binds to YAP via its OTU domain, whereas full-length YAP, but not its truncation variants, efficiently interacts with FAM105A. FAM105A deubiquitinates and stabilizes YAP protein, promotes its nuclear translocation, and thereby activates the Hippo/YAP signaling pathway. The oncogenic effects of FAM105A overexpression were effectively reversed by the YAP inhibitor VP. CONCLUSION: This study provides comprehensive in vitro and in vivo evidence demonstrating that the deubiquitinating enzyme FAM105A functions as an oncogene in GC by stabilizing YAP and activating the Hippo/YAP pathway, thereby promoting tumor growth. FAM105A represents a promising prognostic biomarker and a potential therapeutic target for gastric cancer.
LncRNA Gm13561 interacts with the splicing factor Hnrnpa1 to safeguard podocytes from apoptosis and oxeiptosis in diabetic nephropathy.
Wu Y, Liu Q, Zheng W … +5 more , Liu H, Wu K, Cha H, Li Y, Sun Y
Exp Cell Res · 2026 Aug · PMID 42320723 · Publisher ↗
Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus, without suitable therapies, ultimately leading to end-stage renal disease. Podocyte loss serves as an initial insult d...
Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus, without suitable therapies, ultimately leading to end-stage renal disease. Podocyte loss serves as an initial insult during DN progression, yet the endogenous protective mechanisms remain elusive. Our single-nucleus RNA sequencing data revealed a large group of differentially expressed lncRNAs in renal tissues of DN. In this study, we found that Gm13561 was a podocyte-specific lncRNA predominantly localized in the nucleus and significantly downregulated in both DN mouse renal tissues and high-glucose-induced mouse podocytes. Gain- and loss-of-function studies demonstrated that overexpression of Gm13561 attenuated high-glucose-induced podocyte apoptosis, ROS accumulation, and oxeiptosis, while knockdown of Gm13561 aggravated these phenotypes under normal glucose conditions. Mechanistically, RNA pull-down coupled with mass spectrometry was performed and identified that Gm13561 interacts with the splicing factor Hnrnpa1. RNA immunoprecipitation assay further validated their binding association. Intriguingly, Hnrnpa1 knockdown abolished the protective effects of Gm13561 against apoptosis and oxeiptosis, and vice versa. Furthermore, RNA sequencing revealed that Gm13561 and Hnrnpa1 co-regulated alternative splicing of 446 overlapping genes, with 25 genes enriched in ROS-related and apoptotic pathways. These results together suggested a novel regulatory axis between Gm13561 and Hnrnpa1 that safeguards podocytes from apoptosis and oxeiptosis via modulating alternative splicing, and may serve as a potential therapeutic target for DN.
MG53-mediated membrane repair attenuates pulmonary fibrosis by antagonizing TGF-β1-driven epithelial mesenchymal transition.
Miao J, Wang H, Feng X … +3 more , Liao L, Deng M, Hou G
Exp Cell Res · 2026 Aug · PMID 42320722 · Publisher ↗
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive disease with limited options for therapy. Mitsugumin 53 (MG53), a key factor involved in cell membrane repair, emerges as a protector in diverse...
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive disease with limited options for therapy. Mitsugumin 53 (MG53), a key factor involved in cell membrane repair, emerges as a protector in diverse disease models and cell injury. Although its role in pulmonary fibrosis is not well understood, this study focuses on exploring the function of MG53 in IPF and evaluating the therapeutic potential of recombinant MG53 protein. METHODS: Circulating MG53 levels were quantified in IPF patients and healthy controls. A pulmonary fibrosis model was induced in C57BL/6J mice using bleomycin (BLM), and the mice were then treated with either recombinant human MG53(rhMG53) or saline. In vitro, MLE-12 cells were subjected to TGF-β1 stimulation with or without rhMG53 to explore the affected mechanisms, with a focus on the TGF-β1/Smad signaling pathway and epithelial-mesenchymal transition (EMT). RESULTS: Circulating MG53 levels were significantly decreased in IPF patients and positively correlated with lung function parameters. Similarly, MG53 expression was decreased in the BLM-exposed mice lungs. Treatment with rhMG53 improved survival, attenuated weight loss, and enhanced pulmonary function in BLM-injured mice. Mechanistically, rhMG53 decreased TGF-β1 levels in bronchoalveolar lavage fluid and inhibited Smad2/3 phosphorylation both in vivo and in TGF-β1-stimulated MLE-12 cells. rhMG53 administration did not cause any signs of systemic toxicity. CONCLUSION: MG53 deficiency is associated with IPF severity, and supplementation with rhMG53 mitigates BLM-induced pulmonary fibrosis by preventing TGF-β1/Smad signaling and EMT. These findings highlight MG53 as a potential protein-based therapy and biomarker of pulmonary fibrosis.
SLC39A1 sustains mitochondrial integrity in alveolar epithelium during acute lung injury.
Wang S, Wang Z, Zhang J … +4 more , Tan M, Liu C, Mao L, Zou Z
Exp Cell Res · 2026 Aug · PMID 42314858 · Publisher ↗
Acute respiratory distress syndrome (ARDS) is a devastating lung condition in which injury to the alveolar epithelium and loss of mitochondrial fitness are central. The zinc transporter SLC39A1 is known to engage with mi...
Acute respiratory distress syndrome (ARDS) is a devastating lung condition in which injury to the alveolar epithelium and loss of mitochondrial fitness are central. The zinc transporter SLC39A1 is known to engage with mitochondria and modulate intraorganellar zinc levels. How this interaction translates into functional organelle protection, however, has not been resolved. Using an in vitro model of LPS-induced alveolar epithelial injury, we combined high-resolution imaging, biochemical assays, and mitochondrial functional analyses to investigate this relationship. These findings were extended in vivo using a murine model of LPS-induced lung injury. We found that inflammatory stress selectively recruits SLC39A1 to mitochondria. Functional studies demonstrated that SLC39A1 overexpression preserves mitochondrial integrity by maintaining ultrastructure, membrane potential, and ATP synthesis while mitigating oxidative stress. This cytoprotective role of SLC39A1 was further substantiated in an in vivo model of acute lung injury. Conversely, SLC39A1 depletion exacerbates LPS-induced damage. Mechanistically, we show that SLC39A1 is responsible for stress-triggered zinc accumulation within mitochondria. This zinc flux correlates with enhanced PINK1 protein stability, linking it to a PINK1-associated quality control mechanism. Our study thus reveals an organelle-specific defense mechanism in which inflammation-induced translocation of SLC39A1 to mitochondria facilitates zinc delivery, thereby engaging a PINK1-mediated quality control program that promotes cell survival. These insights extend our understanding of cellular adaptation in ARDS and nominate zinc transport as a potential target for mitochondrial therapy.
An asynchronous production line of meiotic prophase I in the mouse fetal ovary.
Jin Z, Liu C, Liu G … +6 more , Feng G, Li J, Wu Y, Jia H, Keefe DL, Liu L
Exp Cell Res · 2026 Aug · PMID 42297203 · Publisher ↗
The initiation of meiosis in the female germline of mammals is a gradual process, but there is currently no clear quantitative framework for determining the precise timing of its onset. Here, we attempt to standardize th...
The initiation of meiosis in the female germline of mammals is a gradual process, but there is currently no clear quantitative framework for determining the precise timing of its onset. Here, we attempt to standardize the description of meiotic entry timing through a systematic, quantitative analysis of meiotic entry and progression in the mouse fetal ovary. Using dynamic expression profiling of key regulators Stra8, Sycp1, and Sycp3 alongside proliferation markers, we demonstrate that germ cells enter meiosis asynchronously and continuously between embryonic days E12.5 and E16.5. During this extended period, mitotic proliferation persists, indicating that germ cells are progressively recruited into the meiotic pathway rather than halting division simultaneously. Homologous chromosome synapsis, marked by Sycp1/Sycp3 co-localization, initiates at E14.5 and is completed prenatally by E18.5. Using stage-composition data, we constructed a continuous-time Markov chain model to infer a population-level meiotic stage clock. This model estimates approximately conserved population-level effective intervals from the modeled early-prophase L compartment to pachytene-stage synapsis (∼72 h) and to the late-prophase/dictyate-associated D-state transition (∼91 h) across modeled cohort-start times. Our findings refine the conventional view by quantitatively defining the extended window of meiotic entry and subsequent progression through prophase I.
NADPH oxidase-dependent reactive oxygen species upregulate K3.1 to promote atrial fibroblast activation.
Wu J, Zhu Y, Wu Y … +8 more , Liu X, Jiang W, Wang Y, Wang Z, Li M, Liu L, Zhao J, Zhao L
Exp Cell Res · 2026 Aug · PMID 42297202 · Publisher ↗
Atrial fibroblast activation is a central cellular event driving atrial fibrotic remodeling, which plays a critical role in the initiation and maintenance of atrial fibrillation (AF). Our previous studies have identified...
Atrial fibroblast activation is a central cellular event driving atrial fibrotic remodeling, which plays a critical role in the initiation and maintenance of atrial fibrillation (AF). Our previous studies have identified the intermediate-conductance Ca-activated potassium channel K3.1 as a key mediator of reactive atrial fibrosis. However, the upstream mechanisms regulating its expression under pro-fibrotic stimulation remain incompletely defined. The present study aimed to investigate whether NADPH oxidase (NOX)-derived reactive oxygen species (ROS) regulate K3.1 expression and function in atrial fibroblasts. Primary rat atrial fibroblasts were stimulated with angiotensin II (Ang II). Ang II markedly increased intracellular ROS generation through AT1 receptor-dependent activation of NOX. Pharmacological inhibition with Diphenyleneiodonium (DPI) or CRISPR-mediated deletion of NOX2 or NOX4 significantly suppressed Ang II-induced upregulation of K3.1 expression and channel activity. Exposure to hydrogen peroxide (HO) alone was sufficient to enhance K3.1 expression and TRAM-34-sensitive currents. Functionally, pharmacological blockade or genetic deletion of K3.1 markedly attenuated ROS-induced fibroblast proliferation, migration, and myofibroblast differentiation. Mechanistically, ROS activated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of either pathway suppressed K3.1 promoter activity and expression. Collectively, these findings identify a NOX-ROS-JNK/ERK-K3.1 signaling axis that drives atrial fibroblast activation and may represent a potential therapeutic target in oxidative stress-associated atrial remodeling.
Septins regulate kinase-inhibitor induced micron-scale vacuolation.
Sharma K, Sharma H, Insan J … +4 more , Ansari F, Roy A, Dhamija S, Menon MB
Exp Cell Res · 2026 Aug · PMID 42276196 · Publisher ↗
Several kinase inhibitors including pyridinyl imidazole class p38 MAPK inhibitors and specific PIKFYVE inhibitors have been shown to induce endosomal swelling and micron-scale vacuolation, by inhibiting a PIKFYVE-depende...
Several kinase inhibitors including pyridinyl imidazole class p38 MAPK inhibitors and specific PIKFYVE inhibitors have been shown to induce endosomal swelling and micron-scale vacuolation, by inhibiting a PIKFYVE-dependent pathway. We performed a screen to identify small molecule modulators of micron-scale vacuolation and identified septin inhibitor Forchlorfenuron (FCF) as an inhibitor of vacuolation. FCF inhibited vacuolation induced by SB202190, PIKFYVE inhibitors and VE-821. shRNA-mediated depletion of SEPT9 suppressed kinase inhibitor-induced vacuolation, while SEPT7 knockdown did not affect vacuolation. Similar results were obtained when experiments were performed using penfluridol as another modulator of septin cytoskeleton. The kinase-inhibitor induced vesicles, identified as swollen RAB7+ late endosomes colocalized with CD63 and FCF treatment led to the loss of these RAB7-labelled micron-scale vacuoles. FCF not only abrogates vacuole formation but also suppresses resolution of vacuoles upon SB202190 withdrawal. However, septin filaments do not colocalize with the vacuoles. Unlike bafilomycin, which inhibits vacuolation with parallel blockade of autophagic proteolysis, FCF mediated suppression of vacuoles doesn't involve accumulation of autophagy markers. The role of septins in micron scale vacuolation may be linked to their role in endosome maturation and septins may contribute towards the cell-type specificity of micron-scale vacuolation.
Molecular mechanism of MAFB transcriptional activation of PPARD in regulating adipose browning and protecting against vascular endothelial cell injury.
Hu X, Li H, Zhang Q … +5 more , Zhang Y, Lv Z, Zou T, Tang R, Zhang X
Exp Cell Res · 2026 Aug · PMID 42264121 · Publisher ↗
BACKGROUND: Adipose browning in perivascular adipose tissue (PVAT) confers vascular protection, yet its molecular regulation remains poorly defined. The transcription factor MAFB has been implicated in this process, but...
BACKGROUND: Adipose browning in perivascular adipose tissue (PVAT) confers vascular protection, yet its molecular regulation remains poorly defined. The transcription factor MAFB has been implicated in this process, but its downstream targets are unclear. METHODS: Bioinformatics analyses were performed to identify browning-related targets of MAFB, highlighting PPARD as a candidate. 3T3-L1 adipocytes were used to investigate MAFB's role in browning. ChIP and luciferase assays assessed MAFB binding and transcriptional activation. Functional consequences were examined via PPARD knockdown and HCAECs co-culture. RESULTS: MAFB overexpression enhanced UCP1, PPARGC1α, PRDM16, and CIDEA expression, mitochondrial content, oxygen consumption, and adiponectin secretion, while reducing ASC1 in adipocytes. MAFB directly bound to and activated the PPARD promoter. PPARD knockdown diminished MAFB-induced browning. Conditioned medium from brown adipocytes protected HCAECs and primary mouse vascular endothelial cellsmore effectively than white adipocyte medium. Modulating the MAFB-PPARD axis in adipocytes significantly influences endothelial cell viability, apoptosis, and inflammatory responses. CONCLUSION: MAFB promotes adipocyte browning via direct transcriptional activation of PPARD, contributing to endothelial protection. The MAFB-PPARD axis may offer a novel therapeutic target for vascular and metabolic diseases.
Vactosertib reverses ABCG2-mediated multidrug resistance through dual inhibition of drug efflux and transporter expression.
Li Z, Dong XD, Zhang B … +4 more , Li YD, Chen X, Yang H, Chen ZS
Exp Cell Res · 2026 Aug · PMID 42264120 · Publisher ↗
ATP-binding cassette (ABC) transporter ABCG2 is a key mediator of multidrug resistance (MDR) in cancer. Its overexpression limits the intracellular retention and cytotoxicity of chemotherapeutic agents. Identifying clini...
ATP-binding cassette (ABC) transporter ABCG2 is a key mediator of multidrug resistance (MDR) in cancer. Its overexpression limits the intracellular retention and cytotoxicity of chemotherapeutic agents. Identifying clinically relevant modulators capable of suppressing ABCG2 activity remains an important therapeutic objective. In this study, we examined whether selective ALK4/5 inhibitor vactosertib can reverse ABCG2-associated MDR. At non-cytotoxic concentrations, vactosertib significantly reduced the IC values of multiple ABCG2 substrates in both wild-type and R482-variant mutant ABCG2-overexpressing cell models, indicating that it restored drug sensitivity. Similar re-sensitizing effects of mitoxantrone were also observed in colony formation and multicellular tumor spheroid assays. Accumulation and efflux assays showed that vactosertib increased intracellular mitoxantrone accumulation by suppressing ABCG2-mediated efflux, which meet the result of docking simulations and ATPase assays. In addition to functional inhibition, vactosertib reduced the expression levels in both ABCG2 mRNA and protein without altering membrane localization, suggesting transcriptional downregulation. As a result, these findings indicate that vactosertib reverses ABCG2-mediated MDR through dual effects on inhibiting ABCG2 function and downregulating and the expression of ABCG2, supporting its potency as a chemo sensitizing agent in ABCG2-mediated MDR cancer models.
Functional analysis of uPAR alternatively spliced isoforms.
Kulíšková P, Zapletal O, Ballonová L … +3 more , Kocourková A, Souček P, Freiberger T
Exp Cell Res · 2026 Aug · PMID 42264119 · Publisher ↗
The urokinase-type plasminogen activator receptor (uPAR) plays an essential role in cellular adhesion, migration, and differentiation. Alternative splicing of the PLAUR gene generates several isoforms, including ΔE5 and...
The urokinase-type plasminogen activator receptor (uPAR) plays an essential role in cellular adhesion, migration, and differentiation. Alternative splicing of the PLAUR gene generates several isoforms, including ΔE5 and ΔE6, whose biological functions remain unclear. This study examined the localization and functional properties of these variants in comparison with membrane-bound uPAR (muPAR). Although ΔE5 and ΔE6 retain an intact GPI-anchor sequence, both isoforms were intracellularly retained and failed to localize to the cell membrane, unlike muPAR. In PMA-induced differentiation assays, only muPAR-expressing cells maintained adhesion after stimulation, whereas ΔE5, ΔE6, and PLAUR cells did not. All cell lines expressed the macrophage differentiation marker SR-A I, indicating preserved differentiation capacity. Functional analyses showed that only muPAR-expressing cells adhered to vitronectin and interacted with α5β1 integrin. Neither ΔE5 nor ΔE6 bound vitronectin, even after PMA or uPA stimulation, nor did they interact with α5β1 integrin. Functionally, both variants closely resembled uPAR-deficient cells. These results demonstrate that exons 5 and 6 are critical for proper uPAR localization and function. Dysregulated PLAUR splicing may therefore contribute to pathological processes, and modulation of uPAR splicing could represent a potential therapeutic approach.
Overexpression of scavenger receptor class B member 2 leads to different response of ovarian adenocarcinoma cells to chemotherapy.
Harvanik P, Solárová Z, Danková K … +5 more , Bober P, Majerová P, Michalková R, Bhide M, Solár P
Exp Cell Res · 2026 Aug · PMID 42248503 · Publisher ↗
AIMS: Scavenger Receptor Class B Member 2 (SCARB2) is an integral lysosomal membrane protein essential for lysosomal integrity and autophagy regulation. The aim of this study was to investigate the functional impact of S...
AIMS: Scavenger Receptor Class B Member 2 (SCARB2) is an integral lysosomal membrane protein essential for lysosomal integrity and autophagy regulation. The aim of this study was to investigate the functional impact of SCARB2 overexpression on chemotherapy response, reactive oxygen species (ROS) production and proteomic composition of human ovarian adenocarcinoma cells A2780. METHODS: To induce SCARB2 overexpression, A2780 cells were transfected using a PiggyBac vector system. Two clones with the highest SCARB2 expression (L and V) were selected for further analyses. Differences in chemosensitivity were assessed using the MTS assay. Proteomic analysis was used to identify differentially expressed proteins and enriched pathways. We also performed flow cytometry to investigate changes in ROS production and lysosomal activity. Lysosomal distribution was assessed using LAMP1 immunofluorescence staining followed by confocal microscopy, and total cholesterol levels were determined using an enzymatic colorimetric assay. RESULTS: Both clones showed increased sensitivity to cisplatin compared to the control group. In contrast, clone V showed resistance to doxorubicin and no significant differences were observed for gemcitabine, except for a transient sensitizing effect when low concentrations used. Elevated ROS levels were detected in untreated clones, and after doxorubicin exposition. Proteomic analysis showed significant changes in lysosome-associated proteins, with consistent enrichment of the lysosomal pathway across all experimental comparisons. Immunofluorescence analysis of LAMP1 and LysoTracker staining demonstrated altered lysosomal distribution and activity in SCARB2-overexpressing clones. In addition, both SCARB2-overexpressing clones exhibited significantly reduced total cholesterol levels compared with control cells. CONCLUSIONS: This study broadens our understanding of SCARB2 in ovarian cancer. SCARB2 overexpression induces extensive lysosomal reprogramming in A2780 ovarian cancer cells and modulates chemotherapy response.
Forsythiaside A attenuates sepsis-induced acute lung injury by suppressing EGR1/GLS2-mediated ferroptosis-associated lipid peroxidation.
Chang X, Li L, Xu W … +2 more , Shi Q, Yu D
Exp Cell Res · 2026 Aug · PMID 42235787 · Publisher ↗
Sepsis-associated acute lung injury (ALI) is a life-threatening condition with limited targeted therapies. Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in the pathogenesis of ALI. Fors...
Sepsis-associated acute lung injury (ALI) is a life-threatening condition with limited targeted therapies. Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in the pathogenesis of ALI. Forsythiaside A (FTA), a natural compound derived from Forsythia suspensa, exhibits anti-inflammatory and antioxidant properties, yet its role in regulating ferroptosis during sepsis-induced ALI remains unclear. Here, we investigated whether FTA protects against ALI by suppressing the early growth response protein 1/glutaminase 2 (EGR1/GLS2) axis, a pathway that contributes to ferroptosis. In a cecal ligation and puncture (CLP)-induced septic mouse model, FTA treatment significantly improved survival, attenuated lung histopathological injury, reduced pulmonary edema, and suppressed inflammatory cytokine levels. RNA sequencing and gene set enrichment analysis (GSEA) revealed ferroptosis as a major pathway affected by FTA. Mechanistically, FTA inhibited the upregulation of EGR1 and its downstream target GLS2, leading to decreased glutamate/α-ketoglutarate flux, reduced lipid peroxidation, and enhanced glutathione peroxidase 4 (GPX4) activity. In LPS-stimulated MLE-12 lung epithelial cells, FTA similarly suppressed the EGR1/GLS2 axis, mitigated lipid reactive oxygen species (ROS) accumulation, and preserved mitochondrial membrane potential. Overexpression of EGR1 reversed the protective effects of FTA in vitro, while the ferroptosis inducer Erastin partially abolished FTA-mediated lung protection in vivo. Collectively, our findings suggest that FTA alleviates sepsis-associated ALI, an effect that may involve inhibition of ferroptosis and suppression of the EGR1/GLS2 axis. FTA thus merits further investigation as a potential therapeutic agent for septic lung injury.
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