Journal of Cellular Physiology最新文献

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.

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.

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.

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.

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.