J. Cell. Physiol. [JOURNAL]
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200 papers
PBMCs Mitochondrial Respiration and Its Relation to Immunity, Fitness, and Metabolic Risk in the Healthy Elderly.
Gebhardt K, Hebecker A, Sommer N … +6 more , Ringseis R, Eder K, Huber M, Raifer H, Krüger K, Weyh C
J Cell Physiol · 2025 Sep · PMID 41014054 · Full text
Mitochondrial function plays a central role in regulating immunological and metabolic processes, particularly during successful aging. This cross-sectional study aimed to investigate associations between mitochondrial re...
Mitochondrial function plays a central role in regulating immunological and metabolic processes, particularly during successful aging. This cross-sectional study aimed to investigate associations between mitochondrial respiration of peripheral blood mononuclear cells (PBMCs; MR) and key markers of immune function, systemic inflammation, and metabolic health in a cohort of healthy older adults. Sixteen healthy, physically active participants aged > 55 years (male: n = 9; female: n = 7; age: 64 ± 3.7 years; BMI: 24.3 ± 2.9; VO: 31.1 ± 8.8 mL/min/kg) were recruited. Participants were tested for their maximal oxygen uptake (VO) as well as cardiovascular and metabolic risk factors. Venous fasting blood samples were collected. For further analysis, MR was measured using the Oroboros O2k-Oxygraph. T cell subsets were analyzed by flow cytometry, serum cytokines by LUMINEX assays, and gene expression by qPCR analysis. We found positive associations between basal and maximal MR and the percentage of CD4 T cells, with a notable link to naïve CD4 T cells (p < 0.05). Maximal MR was negatively associated with proportion of effector memory CD4 T cells (p < 0.05). Basal MR showed negative associations with pro-inflammatory serum cytokine tumor necrosis factor alpha (TNF-α), while maximal MR was positively associated with interleukin 8 (IL-8), intercellular adhesion molecule 1 (ICAM-1), and vascular endothelial growth factor (VEGF) (p < 0.05). Intracellular signaling markers, including mRNA level of signal transducer and activator of transcription 3 (STAT3), also showed positive associations with maximal MR (p < 0.05). No correlations were found for variables such as cardiorespiratory fitness, IL-6, and IL-10. In conclusion, PBMC mitochondrial bioenergetics are linked to T cell subpopulations and systemic inflammation in healthy older adults. Higher mitochondrial respiration reflecting better mitochondrial function favors a more naïve CD4 T cell distribution. In contrast, lower mitochondrial function was observed in individuals with a more pro-inflammatory profile, suggesting a potential relationship between immune status and mitochondrial bioenergetics in older adults.
Mitochondrial Ca in Cancer Growth and Metabolism.
Weissenrieder JS, Kevin Foskett J
J Cell Physiol · 2025 Sep · PMID 40985275 · Full text
Cancer is a leading cause of death in developed countries, despite many breakthroughs in targeted small molecule and immunotherapeutic interventions. A deeper understanding of the characteristics and processes that under...
Cancer is a leading cause of death in developed countries, despite many breakthroughs in targeted small molecule and immunotherapeutic interventions. A deeper understanding of the characteristics and processes that underlie malignancy will enable us to develop more effective therapeutic options to improve patient outcomes. One particular area of interest is in cancer cell metabolism. Even as early as the 1920s, Otto Warburg recognized dysregulated metabolism in cancerous cells. Altered metabolism may provide targetable nutrient dependencies for further clinical development, either by nutrient restriction or pathway inhibition. More recently, researchers have observed an increasingly strong linkage between altered mitochondrial Ca homeostasis and tumor cell metabolism, with strong implications for therapeutic targeting. In this review, we summarize the literature surrounding mitochondrial Ca homeostasis, metabolism, and cancer, as well as providing a discussion of the potential for mitochondrial Ca modulation as an anticancer therapeutic modality.
Intermediate Conductance Calcium-Dependent Potassium Channel (K3.1) Interacting Proteins Using Turboid-Based Proximity Labeling Technology: Insights Into Interactome and Related Signaling Pathways in Pancreatic Tumors.
Carpanese V, Sadeghi S, Todesca LM … +2 more , Szabò I, Checchetto V
J Cell Physiol · 2025 Sep · PMID 40952239 · Full text
K3.1 ion channel is a calcium-activated potassium channel expressed in various tissues, showing dual localization to the plasma membrane and to mitochondria. This channel is highly expressed in numerous cancers and has b...
K3.1 ion channel is a calcium-activated potassium channel expressed in various tissues, showing dual localization to the plasma membrane and to mitochondria. This channel is highly expressed in numerous cancers and has been implicated in the regulation of proliferation and migration. The molecular details of the signaling pathways linked to regulation exerted by K3.1 in cancer cells are, however, not fully elucidated yet. Therefore, we determined the interactome of K3.1 using proximity labeling in intact KPC pancreatic cancer cells that mirror the aggressive metastatic behavior of human pancreatic cancer. The results highlight several novel interactors, including those residing in intracellular membranes. The K3.1 channel proxisome and related pathways are discussed in light of our current knowledge about K3.1 and pancreatic cancer, available in public databases.
Mast Cell Immunometabolism in Type 2 Diabetes and Alzheimer's Disease.
Caslin HL, Kapadia M, Clemons TA
J Cell Physiol · 2025 Sep · PMID 40948440 · Publisher ↗
Type 2 diabetes (T2D) and Alzheimer's Disease (AD) have seemingly different pathologies and symptoms. However, T2D is a risk factor for AD, and recent evidence suggests there are many mechanistic similarities between the...
Type 2 diabetes (T2D) and Alzheimer's Disease (AD) have seemingly different pathologies and symptoms. However, T2D is a risk factor for AD, and recent evidence suggests there are many mechanistic similarities between the etiologies of each disease including inflammation. Mast cells are tissue resident, sentinel immune cells that reside in the pancreas, adipose tissue, and brain, increase in T2D and AD, and have generally been shown to worsen T2D and AD. However, there are limited studies of local or temporal mast cell deletion, and different phenotypic and polarization states seemingly influence the role of mast cells in the progression of disease. As there are metabolic similarities between T2D and AD including insulin resistance and lipid influx into the brain, we discuss the impact of glucose, insulin, amylin, and different lipid species on the activation and polarization of mast cells, which generally reduce IgE-mediated degranulation and promote lipid droplet formation and arachidonic acid metabolism. Altogether, this review provides a framework for understanding a shared mechanism of immunometabolic regulation of T2D and AD and provides rationale for future work in this area.
The Age-Associated Long Noncoding RNA lnc81 Regulates Ovarian Granulosa Cell Proliferation and Apoptosis Through TEAD2-CCN1/2 Pathway in Mice.
Ma Z, Luo R, Xue Y … +8 more , Zheng L, Zhou C, Fang S, Hu N, Wang H, Cheng X, Luo T, Hu L
J Cell Physiol · 2025 Sep · PMID 40928008 · Publisher ↗
Ovarian granulosa cells (GCs) are pivotal for follicular homeostasis, and their dysregulated apoptosis drives age-related ovarian aging. The Hippo signaling pathway, modulated by long noncoding RNAs (lncRNAs), is implica...
Ovarian granulosa cells (GCs) are pivotal for follicular homeostasis, and their dysregulated apoptosis drives age-related ovarian aging. The Hippo signaling pathway, modulated by long noncoding RNAs (lncRNAs), is implicated in regulating GCs proliferation and ovarian aging. TEAD2 (Transcriptional Enhanced Associate Domain 2), a key downstream transcription factor of the Hippo signaling pathway, plays a critical role in regulating cell proliferation, apoptosis, and embryonic stem cell self-renewal. However, the precise molecular mechanisms by which lncRNAs influence the Hippo pathway in GCs are not fully understood. Through comprehensive RNA-seq analysis of ovarian tissues across three distinct age groups (3-, 11-, and 17-month-old mice), we identified lnc81 as a senescence-associated lncRNA that physically interacts with TEAD2. RNA immunoprecipitation (RIP) assays demonstrated direct binding between lnc81 and TEAD2, while subcellular fractionation coupled with qRT-PCR revealed predominant nuclear localization of lnc81 in granulosa cells (GCs). Importantly, lnc81 expression exhibited a progressive, age-dependent elevation during ovarian aging. Functional characterization showed that lnc81 knockdown in GCs significantly: (i) Inhibited cellular proliferation (as evidenced by decreased Pcna expression). (ii) Promoted apoptosis (indicated by increased BAX/BCL-2 ratio and elevated TUNEL-positive cells). Mechanistically, while lnc81 depletion upregulated CCN1/CCN2 protein levels, it did not affect TEAD2 expression, suggesting that lnc81 regulates TEAD2 transcriptional activity rather than modulating its protein stability. Our findings highlight lnc81 as a nuclear lncRNA that interacts with TEAD2 to amplify CCN1/CCN2 signaling, thereby promoting GC apoptosis and ovarian aging. This mechanistic insight positions lnc81 as a potential biomarker for age-related ovarian decline and a candidate target for therapeutic intervention.
RETRACTION: Novel Oral Transforming Growth Factor-β Signaling Inhibitor Potently Inhibits Postsurgical Adhesion Band Formation.
J Cell Physiol · 2025 Sep · PMID 40919829 · Publisher ↗
A. Soleimani, F. Asgharzadeh, F. Rahmani, et al. "Novel Oral Transforming Growth Factor-β Signaling Inhibitor Potently Inhibits Postsurgical Adhesion Band Formation." Journal of Cellular Physiology 235, no. 5 (2019): 134...
A. Soleimani, F. Asgharzadeh, F. Rahmani, et al. "Novel Oral Transforming Growth Factor-β Signaling Inhibitor Potently Inhibits Postsurgical Adhesion Band Formation." Journal of Cellular Physiology 235, no. 5 (2019): 1349-1357, https://doi.org/10.1002/jcp.29053. The above article, published online on 17 July 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by the third party, which revealed multiple inconsistencies found in Figure 2(g) and Figure 4(a), and additional inconsistencies were found in Figure 1(d). The explanation and raw data provided by the authors could not sufficiently address these concerns. Overall, the editors have lost confidence in the integrity and reliability of the full body of data presented in the article and consider the conclusions of this manuscript substantially compromised. The authors disagree with the retraction.
Single-Cell Sequencing-Based Exploration of the Role of Tip Cells on Astrocytes and Macrophages After Spinal Cord Injury.
Zeng X, Long Y, Li G … +6 more , Zhang D, Deng Y, Zhi X, Wan Y, Wang L, Li X
J Cell Physiol · 2025 Sep · PMID 40891625 · Publisher ↗
Excessive inflammation is a capital cause of scar formation and inflammation microenvironment that result in challenge of axonal regeneration after spinal cord injury (SCI). Macrophages and astrocytes play important role...
Excessive inflammation is a capital cause of scar formation and inflammation microenvironment that result in challenge of axonal regeneration after spinal cord injury (SCI). Macrophages and astrocytes play important roles in the inflammatory response. Tip cells, a critical endothelial sub-population, play pivotal roles in post-injury vascular regeneration. Nevertheless, their characteristics in SCI remain poorly documented. This study based on single cell RNA sequencing (scRNA-seq) and in vitro experiment, investigates the effects of tip cells on astrocytes and macrophages. For astrocytes, tip cells can recruit astrocytes to migrant, contribute to the formation of fence-like structure of astrocytes, finally inhibit the diffusion of inflammation via the Angptl4-Sdc4 ligand-receptor pathway. For macrophages, similarly through the Angptl4-Sdc4 ligand-receptor pathway, tip cells can promote macrophages to polarize more toward the M2 phenotype and inhibit their polarization toward M1 phenotype, thus alleviate the inflammatory response. Tip cells after SCI exhibit conserved ribosomal protein expression, implicating ribosome-dependent signaling in their function. These finding highlight the critical role of tip cells in microenvironment after SCI, offering a potential treatment target for SCI.
Regulation of Ghrelin Production and Food Intake by Gastric Adenylyl Cyclase Type 8.
Wu S, Deng H, Yu R … +6 more , Yu Q, Li W, Zhao Y, Yang K, Gao L, Xu G
J Cell Physiol · 2025 Aug · PMID 40874807 · Publisher ↗
Ghrelin is a peptide hormone primarily produced by ghrelin cells in the stomach, playing a vital role in the regulation of eating behavior. Adenyl cyclase 8 (ADCY8), a key downstream signaling factor of G protein-coupled...
Ghrelin is a peptide hormone primarily produced by ghrelin cells in the stomach, playing a vital role in the regulation of eating behavior. Adenyl cyclase 8 (ADCY8), a key downstream signaling factor of G protein-coupled receptors, is essential for maintaining energy homeostasis by modulating levels of cyclic adenosine monophosphate (cAMP). Nevertheless, how ADCY8 modulates ghrelin levels and affects food intake is not well understood. Our findings demonstrated that Adcy8 mice exhibited elevated levels of ghrelin and increased food consumption under both normal and high-fat diet conditions. These changes were associated with a reduction in the activity of the cAMP-PKA-mTOR signaling pathway within the gastric mucosa. The administration of the ghrelin receptor antagonist d-Lys-3-GH-releasing peptide-6 significantly decreased calorie intake in both wild-type and Adcy8 mice. Furthermore, forskolin was shown to inhibit ghrelin and calorie intake in normal mice, an effect that was absent in Adcy8 mice. Treatment with forskolin or overexpression of Adcy8 in both primary ghrelin-producing cells and mHypoE-42 cells resulted in decreased ghrelin levels, accompanied by activation of the cAMP-PKA-mTOR signaling pathway. Conversely, the use of the inhibitor SQ22536 or knockdown of Adcy8 produced opposing effects. In conclusion, gastric ADCY8 regulates the expression and secretion of ghrelin via the cAMP-PKA-mTOR signaling pathway, thereby influencing food intake.
RETRACTION: Involvement of Notch-1 in Resistance to Regorafenib in Colon Cancer Cells.
J Cell Physiol · 2025 Aug · PMID 40842101 · Publisher ↗
G. Mirone, S. Perna, A. Shukla, G. Marfe, "Involvement of Notch-1 in Resistance to Regorafenib in Colon Cancer Cells," Journal of Cellular Physiology 231, no. 5 (2015): 1097-1105, https://doi.org/10.1002/jcp.25206. The a...
G. Mirone, S. Perna, A. Shukla, G. Marfe, "Involvement of Notch-1 in Resistance to Regorafenib in Colon Cancer Cells," Journal of Cellular Physiology 231, no. 5 (2015): 1097-1105, https://doi.org/10.1002/jcp.25206. The above article, published online on 30 September 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by the third party, which revealed inappropriate figure duplications in Figure 5B and Figure 7D, by different groups of authors in different articles. In addition, there are inconsistencies in Figure 2B. The corresponding author has responded in accordance with the concerns and provided the original western blots for Figure 5B and explanation for Figure 2B. However, data issues were found in the last authors' other articles and the Editor-in-Chief now has lost confidence in the integrity and reliability of the full body of data presented in the article and consider the conclusions of this manuscript substantially compromised. The authors were informed of the retraction.
Connexin 43 Role in Mitochondrial Transfer and Homeostasis in the Central Nervous System.
Gervasi A, D'Aprile S, Denaro S … +3 more , Amorini MA, Vicario N, Parenti R
J Cell Physiol · 2025 Aug · PMID 40838510 · Full text
Connexin 43 (Cx43) is a transmembrane protein involved in the assembly of gap junctions (GJs) and hemichannels (HCs), organized structures that allow the transferring of ions and small signaling molecules between cells a...
Connexin 43 (Cx43) is a transmembrane protein involved in the assembly of gap junctions (GJs) and hemichannels (HCs), organized structures that allow the transferring of ions and small signaling molecules between cells and/or extracellular environment, thereby contributing to tissue homeostasis intercellular communication. Cx43 has recently been identified within the mitochondria of cells, suggesting that it may have additional functions beyond its canonical role. Most studies of mitochondrial Cx43 (mt-Cx43) have been limited to cells of the cardiovascular system, where it appears to play a role in ATP production, calcium homeostasis, and the response to oxidative stress. However, its functions within the central nervous system (CNS) are not fully understood. Recently, it has been observed that Cx43-forming GJs is one of the key mechanisms that cells use for the transfer of organelles, including mitochondria. Cx43-mediated mitochondrial transfer is crucial in the CNS, supporting cellular homeostasis and neuroprotection under both physiological and pathological conditions. The dual roles of Cx43 in regulating mitochondrial function and in mediating mitochondrial transfer, raise important questions about how it coordinates these mechanisms. Herein, we reviewed recent findings on the importance of Cx43 and mt-Cx43 in the healthy and altered CNS environment, with the aim of shedding light on its potential role in CNS homeostasis and as a therapeutic target in neurological disorder in which Cx43 plays a predominant function.
View Micronuclei in the Extent of Evolution: New Insight Into an Old Issue.
Yang S, Yao H, Zhang Y … +7 more , Zhang W, Jin S, Huang K, Song J, Feng Y, Li X, Wang X
J Cell Physiol · 2025 Aug · PMID 40820677 · Publisher ↗
Micronuclei (MNs), once regarded as cellular debris or genotoxicity markers, can also be recognized as dynamic structures with potential evolutionary significance. In tumor models, MNs promote clonal diversification, mut...
Micronuclei (MNs), once regarded as cellular debris or genotoxicity markers, can also be recognized as dynamic structures with potential evolutionary significance. In tumor models, MNs promote clonal diversification, mutagenesis, and adaptation. MNs' interaction with the conserved cGAS-STING pathway reflects dual roles in immune defense for the individual and adaptive response for cell under stress. MNs may also contribute to aging-related evolution and be functional in embryonic development. MN's presence and function across species suggests the ability of MN to offer genomic diversity and selective advantage. Therefore, our understanding is that MN may contribute to evolution throughout life processes of organisms.
IPSC-Derived Conditioned Medium Reduces Oxidative Stress and Vascular Remodeling in Rat Models of Pulmonary Arterial Hypertension.
Cheng CC, Hsu LF, Chung HH … +7 more , Lee CW, Chiang CH, Yang HC, Chi MC, Lee MH, Huang WC, Chi PL
J Cell Physiol · 2025 Aug · PMID 40819237 · Publisher ↗
Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by elevated pulmonary vascular resistance, leading to right ventricular (RV) hypertrophy and eventual heart failure. Although current...
Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by elevated pulmonary vascular resistance, leading to right ventricular (RV) hypertrophy and eventual heart failure. Although current therapies provide symptomatic relief, they offer limited efficacy in reversing the underlying vascular remodeling. In this preclinical study, we investigated the therapeutic potential of induced pluripotent stem cell-derived conditioned medium (iPSC-CM) in a monocrotaline (MCT)-induced rat model of PAH, employing both prophylactic and therapeutic administration strategies. iPSC-CM treatment significantly reduced right ventricular systolic pressure (RVSP) and mitigated RV hypertrophy compared to MCT-only controls. Histological analyses revealed attenuated pulmonary arterial wall thickening and muscularization. At the molecular level, iPSC-CM downregulated the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and platelet-derived growth factor-BB (PDGF-BB) in lung tissues, and modulated oxidative stress by decreasing NADPH oxidase 1 (Nox1) and increasing superoxide dismutase 1 (SOD1) levels. In vitro, iPSC-CM suppressed the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) under hypoxic and PDGF-BB-stimulated conditions. These findings suggest that iPSC-CM targets key pathogenic pathways involved in vascular remodeling and redox imbalance in PAH. Together, these findings support iPSC-CM as a promising acellular approach for targeting vascular remodeling and oxidative stress in PAH, warranting further investigation toward clinical translation.
Growth Factor Receptor-Binding Protein 10 Promotes High Glucose-Induced H9c2 Cardiomyoblast Apoptosis via Inhibition of the ERK1/2 and JAK2/STAT3 Signaling Pathways.
Wang Y, Bu F, Zhang M … +3 more , Zhang Y, Hu Y, Liu L
J Cell Physiol · 2025 Aug · PMID 40819235 · Publisher ↗
Cardiomyocyte apoptosis is crucial in the occurrence of diabetic cardiomyopathy; thus, it is important to elucidate the underlying mechanisms involved in elevated glucose and cardiomyocyte apoptosis. Growth factor recept...
Cardiomyocyte apoptosis is crucial in the occurrence of diabetic cardiomyopathy; thus, it is important to elucidate the underlying mechanisms involved in elevated glucose and cardiomyocyte apoptosis. Growth factor receptor-binding protein 10 (Grb10) has been proved to participate in the regulation of cell proliferation, migration, and apoptosis. The purpose of this study was to explore the role of Grb10 in high glucose-induced H9c2 cardiomyoblast apoptosis and investigate the underlying molecular mechanisms. H9c2 cardiomyoblasts were cultured and exposed to an elevated glucose at a level of 33 mM. Grb10 expression was inhibited using small interfering RNA (siRNA), and the activities of ERK1/2 and STAT3 were stimulated by specific activators. Western blot analysis was used to detect the expression levels of Grb10, (phosphorylated) ERK1/2, (phosphorylated) JAK2/STAT3, Bax, Bcl2, and cleaved caspase-3, and the TdT-mediated UTP nick end labeling test was used to measure the apoptosis rate. High glucose treatment in H9c2 cardiomyoblasts led to increased Grb10 expression and cell apoptosis. Grb10-siRNA treatment attenuated high glucose-induced H9c2 cell apoptosis. Furthermore, the repressed activities of ERK1/2 and JAK2/STAT3 signaling pathways induced by high glucose were reversed by Grb10-siRNA treatment. Upregulated ERK1/2 or STAT3 activity partially reversed the apoptosis of H9c2 cardiomyoblast caused by high glucose treatment. Our findings show that Grb10 is involved in high glucose-induced H9c2 cardiomyoblast apoptosis and might exert its apoptosis-promoting role through inhibition of the ERK1/2 and JAK2/STAT3 signaling pathways.
Mitochondrial Pyruvate Carrier Differentially Controls the Self-Renewal and Differentiation of Human Pluripotent Stem Cells.
Jiang D, Wang Y, Chen Y … +6 more , Tian C, Li X, Li S, Gu X, Jiang C, Ding Q
J Cell Physiol · 2025 Aug · PMID 40802829 · Publisher ↗
Mitochondria are crucial for cell fate determination, yet their roles in human pluripotent stem cell (hPSC) fate changes have remained underexplored. Here, we designed a CRISPR library targeting 661 mitochondrial protein...
Mitochondria are crucial for cell fate determination, yet their roles in human pluripotent stem cell (hPSC) fate changes have remained underexplored. Here, we designed a CRISPR library targeting 661 mitochondrial proteins and identified the MPC (mitochondrial pyruvate carrier) as a critical regulator of hPSC self-renewal and pluripotency. Notably, MPC inhibition reduced hPSC self-renewal and endoderm differentiation while promoting mesoderm differentiation, with no effect on ectoderm differentiation, all mediated by influencing glycolytic acetyl-CoA production. Specifically, the decrease in acetyl-CoA following MPC inhibition affected histone acetylation in hPSCs, compromising self-renewal. In contrast, MPC inhibition did not impact histone acetylation in differentiated cells; instead, it reduced the acetylation of non-histone proteins-EP300 and SMAD2-thereby enhancing mesoderm differentiation and repressing endoderm differentiation, respectively. These findings suggest that distinct effector proteins respond to variations in acetyl-CoA levels at different developmental stages, leading to a context-dependent regulation of cell fate determination by glycolytic acetyl-CoA in hPSCs.
Fasting-Induced Hepatic Gluconeogenesis Is Compromised In Anxa6 Mice.
Alvarez-Guaita A, Bernaus-Esqué M, Blanco-Muñoz P … +9 more , Liu Y, Sebastian D, Meneses-Salas E, Nguyen MKL, Zorzano A, Tebar F, Enrich C, Grewal T, Rentero C
J Cell Physiol · 2025 Aug · PMID 40802799 · Full text
Maintaining constant blood glucose levels is essential for energizing glucose-dependent tissues. During the fed state, insulin lowers elevated blood glucose, while in the fasted state, glucagon maintains blood glucose le...
Maintaining constant blood glucose levels is essential for energizing glucose-dependent tissues. During the fed state, insulin lowers elevated blood glucose, while in the fasted state, glucagon maintains blood glucose levels through hepatic stimulation of fatty acid oxidation, glycogenolysis, and gluconeogenesis (GNG). The liver plays a crucial role in these metabolic adaptations. Deregulation of GNG is a hallmark of type 2 diabetes mellitus (T2DM), driven by hepatic insulin resistance, elevated glucagon levels, and excess circulating free fatty acids. The glucose metabolism of 8- to 12-week-old WT and Anxa6 knock-out (Anxa6) mice was analysed during regular feeding and fasting using indirect calorimetry, tolerance tests and biochemical analysis. Despite normal insulin-sensitive control of glucose levels and effective glycogen mobilization, Anxa6 mice display rapid hypoglycaemia during fasting. This metabolic disarrangement, in particular during the early stages of fasting is characterized by a low respiratory exchange ratio (RER) and increased lipid oxidation during the diurnal period, indicating a reliance on lipid oxidation due to hypoglycaemia. Elevated glucagon levels during fasting suggest deficiencies in GNG. Further analysis reveals that Anxa6 mice are unable to utilize alanine for hepatic GNG, highlighting a specific impairment in the glucose-alanine cycle in fasted Anxa6 mice, underscoring the critical role of ANXA6 in maintaining glucose homeostasis under metabolic stress. During fasting, slightly reduced expression levels of alanine aminotransferase 2 (Gpt2) and lactate dehydrogenase (Ldha2), enzymes converting alanine to pyruvate, and the hepatic alanine transporter SNAT4 might contribute to these observations in the Anxa6 mice. These findings identify that ANXA6 deficiency causes an inability to maintain glycolytic metabolism under fasting conditions due to impaired alanine-dependent GNG.
Correction to "The Role of TREM-1 in Septic Myocardial Pyroptosis and Septic Cardiomyopathy In Vitro and In Vivo".
J Cell Physiol · 2025 Aug · PMID 40765327 · Publisher ↗
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Interpreting the Origins and Functions of Noncoding RNAs From the Ribosomal Genes.
Moss T, Sibai DS, Lessard F
J Cell Physiol · 2025 Aug · PMID 40765316 · Full text
The Ribosomal DNA (rDNA) in mammals is organised into large clusters of tandem repeats each of which encodes a single 47S precursor for the 18S, 5.8S, and 28S ribosomal RNAs (rRNAs) that is flanked upstream and downstrea...
The Ribosomal DNA (rDNA) in mammals is organised into large clusters of tandem repeats each of which encodes a single 47S precursor for the 18S, 5.8S, and 28S ribosomal RNAs (rRNAs) that is flanked upstream and downstream by an Intergenic Spacer (IGS) originally referred to as the Non-Transcribed Spacer (NTS). However, in certain cells and under certain environmental conditions the IGS has been found to be transcribed at low level to generate a range of "Noncoding" RNAs (ncRNAs). These ncRNAs have been implicated in the regulation of rRNA synthesis, rDNA silencing and protein sequestration in response to environmental and oncogenic stresses and tumour suppression. Here we review data on the generation, regulation and potential functions of these ncRNAs. We suggest that the majority of the ncRNAs originate from a failure of RNA polymerase I transcription termination by the Reb1- and Myb-related transcriptional "road-block" factor TTF1 and link their expression with tumour suppression.
Targeting GPX4 to Overcome Sorafenib Resistance of Human Hepatocellular Carcinoma by Inducing Ferroptosis.
Tang HH, Hsu CP, Su PY … +8 more , Tsai SP, Doan LH, Chen CY, Chen HC, Wang PY, Cheng TS, Huang CF, Su CL
J Cell Physiol · 2025 Aug · PMID 40763203 · Publisher ↗
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death. Sorafenib, a multikinase inhibitor, has been approved as a first-line systemic therapeutic for HCC patients based on the results of two large c...
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death. Sorafenib, a multikinase inhibitor, has been approved as a first-line systemic therapeutic for HCC patients based on the results of two large clinical trials, in which sorafenib significantly increased life expectancy of patients with Child Pugh A advanced stage of liver cancer, no matter which races they were or whether being infected with hepatitis B or C virus; however, its efficacy is compromised by the resistance of the tumor cells. By using integrative bioinformatics analysis, we identified ferroptosis as a candidate to modulate sorafenib-resistant HCC. Ferroptosis is a novel, iron-dependent, non-apoptotic regulated cell death with characteristics of impaired lipid peroxide repair, redox active iron, and the oxidation of polyunsaturated fatty acids. Here, glutathione peroxidase 4 (GPX4) was further identified as a favorable prognostic factor in cancer survival by analyzing data repositories. Compared to the parental human HCC Huh7 cells, lower expression of GPX4, dysregulated iron homeostasis, and higher expression of acyl-CoA synthetase long-chain family member 4 were observed in sorafenib-resistant Huh7R cells, and the Huh7R cells exhibited higher sensitivity to ferroptosis induction exerted by RSL3, a GPX4 inhibitor. The RSL3-induced ferroptosis was attenuated by lysosomal blocker bafilomycin A1, indicating that lysosomal degradation of ferritin may confer sensitivity to GPX4-inactivation-induced ferroptosis by providing accessible iron. Taken together, our findings demonstrate that GPX4-inactivation-induced ferroptosis is a promising and effective treatment option capable of overcoming sorafenib resistance in liver cancer, and our novel gene expression-screening platform via integrated analysis of differentially expressed genes and pathways allows efficient identification of therapeutic strategies.
The Role of Cellular Stress, Antioxidant System Response, Mitochondrial Function, and Metabolic Alterations in the Pathophysiology of Propionic Acidemia: A Systematic Review.
Vardar Acar N, Özgül RK
J Cell Physiol · 2025 Aug · PMID 40763199 · Publisher ↗
Propionic acidemia (PA) is a rare, life-threatening inherited metabolic disorder. Despite early therapy and effective metabolic control with current treatments, patients with PA face recurrent severe metabolic decompensa...
Propionic acidemia (PA) is a rare, life-threatening inherited metabolic disorder. Despite early therapy and effective metabolic control with current treatments, patients with PA face recurrent severe metabolic decompensations and multisystemic complications. The exact pathophysiological mechanisms of these complications remain unclear. This systematic review aims to enhance understanding of molecular mechanisms underlying PA by simultaneously evaluating ROS-mediated cellular stress, antioxidant response, mitochondrial dysfunction, metabolic alterations, and mitohormesis. For this purpose, a literature search was conducted across PubMed, Scopus, ScienceDirect, Web of Science, Cochrane Library, and ClinicalTrials.gov databases. This review included 42 experimental studies, comprising 13 human studies, 27 animal studies, and 2 studies involving both animals (rat and mice/mouse) and humans. As a result: (i) both oxidative and reductive stress can occur in PA, with individual variability; (ii) ROS-mediated cellular damage generally accompanies PA; (iii) the antioxidant response can vary depending on the type, severity, and duration of cellular stress; (iv) secondary mitochondrial dysfunction accompanies PA; (v) ROS-mediated stress effects correlate with alterations in interconnected metabolic pathways in PA; and (vi) mitohormesis can play a role in PA. In conclusion, using antioxidants or preventive treatments for PA without assessing cellular stress during diagnosis and treatment may further disturb the delicate oxidant-antioxidant balance. Simultaneous evaluation of ROS-mediated cellular stress and associated pathways in PA has potential to both revise existing treatments and discover new therapies, thereby improving the quality of life and longevity of patients with PA, as well as elucidating the unclear pathophysiology of PA.
RETRACTION: Exosomes Derived From SDF1-Overexpressing Mesenchymal Stem Cells Inhibit Ischemic Myocardial Cell Apoptosis and Promote Cardiac Endothelial Microvascular Regeneration in Mice With Myocardial Infarction.
J Cell Physiol · 2025 Jul · PMID 40726436 · Publisher ↗
X.-H. Gong, H. Liu, S.-J. Wang, S.-W. Liang, and G.-G. Wang, "Exosomes Derived From SDF1-Overexpressing Mesenchymal Stem Cells Inhibit Ischemic Myocardial Cell Apoptosis and Promote Cardiac Endothelial Microvascular Rege...
X.-H. Gong, H. Liu, S.-J. Wang, S.-W. Liang, and G.-G. Wang, "Exosomes Derived From SDF1-Overexpressing Mesenchymal Stem Cells Inhibit Ischemic Myocardial Cell Apoptosis and Promote Cardiac Endothelial Microvascular Regeneration in Mice With Myocardial Infarction." Journal of Cellular Physiology 234, no. 8 (2019): 13878-13893. https://doi.org/10.1002/jcp.28070. The above article, published online on February 5, 2019, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Robert Heath, and Wiley Periodicals LLC. A third party shared a report from the National Natural Science Foundation of China, which indicated that data in this article had been purchased from an external company (National Natural Science Foundation of China 2015). An investigation by the publisher found that this fact is not reported in the article and also that the article is missing necessary information on the ethical approval for animal and human experiments performed as part of this study. The authors responded to an inquiry by the publisher requesting original data and evidence of approval for animal and human experiments. The authors stated that they conducted partial pre-experiments and then commissioned third-party companies to conduct the main experiments. The authors further stated that those companies could not provide raw data. The authors did not provide information regarding ethical approval for the animal and human experiments reported in the article. The authors requested the withdrawal of their article. The retraction has been agreed to because the data and ethical approval of experiments reported in this article cannot be validated.
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