Journal of Cellular Physiology最新文献

By delivering the environmental inputs to transport nutrients and growth factors, Mechanistic Target of Rapamycin (mTOR) plays a significant role in the growth and metabolism of eukaryotic cells through the regulation of numerous elementary cellular processes such as autophagy, protein synthesis, via translation of mitochondrial protein transcription factor A mitochondrial, mitochondrial ribosomal proteins, and mitochondrial respiratory complexes I &V that are encoded in the nucleus with the help of translation initiation factor 4E-BP. These mitochondrial proteins are involved in cell signaling to regulate proper cell growth, proliferation, and death which are essential for tumor growth and proliferation. This suggests that tumor cells are dependent on mTORC1 for various metabolic pathways. However, this crucial regulator is activated and regulated by calcium homeostasis. Mounting evidence suggests the role of calcium ions in regulating mitochondrial enzymes and proteins. Hence, disrupting calcium homeostasis leads to calcium-dependent cell death called "Oxytosis" through hampering the expression of various mitochondrial proteins. "Oxytosis" is a novel non-apoptotic cell death characterized by glutamate cytotoxicity and ferritin degradation. The present review focuses on the crosstalk between mTORC1 and mitochondrial proteins in the cancer pathophysiology and the impact of calcium ions on disrupting mTORC1 leading to the induction of "Oxytosis."

Bone marrow-derived mesenchymal stem cells (BMSC) are promising cellular reservoirs for treating degenerative diseases, tissue injuries, and immune system disorders. However, the stemness of BMSCs tends to decrease during in vitro cultivation, thereby restricting their efficacy in clinical applications. Consequently, investigating strategies that bolster the preservation of BMSC stemness and maximize therapeutic potential is necessary. Transcriptomic and single-cell sequencing methodologies were used to perform a comprehensive examination of BMSCs with the objective of substantiating the pivotal involvement of fibroblast growth factor 2 (FGF2) and integrin alpha 2 (ITGA2) in stemness regulation. To investigate the impact of these genes on the BMSC stemness in vitro, experimental approaches involving loss and gain of function were implemented. These approaches encompassed the modulation of FGF2 and ITGA2 expression levels via small interfering RNA and overexpression plasmids. Furthermore, we examined their influence on the proliferation and differentiation capacities of BMSCs, along with the expression of stemness markers, including octamer-binding transcription factor 4, Nanog homeobox, and sex determining region Y-box 2. Transcriptomic analyzes successfully identified FGF2 and ITGA2 as pivotal genes responsible for regulating the stemness of BMSCs. Subsequent single-cell sequencing revealed that elevated FGF2 and ITGA2 expression levels within specific stem cell subpopulations are closely associated with stemness maintenance. Moreover, additional in vitro experiments have convincingly demonstrated that FGF2 effectively enhances the BMSC stemness by upregulating ITGA2 expression, a process mediated by the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. This conclusion was supported by the observed upregulation of stemness markers following the induction of FGF2 and ITGA2. Moreover, administration of the BEZ235 pathway inhibitor resulted in the repression of stemness transcription factors, suggesting the substantial involvement of the PI3K/AKT pathway in stemness preservation facilitated by FGF2 and ITGA2. This study elucidates the involvement of FGF2 in augmenting BMSC stemness by modulating ITGA2 and activating the PI3K/AKT pathway. These findings offer valuable contributions to stem cell biology and emphasize the potential of manipulating FGF2 and ITGA2 to optimize BMSCs for therapeutic purposes.

Retraction: L. Wang, D. Liu, X. Wu, Y. Zeng, L. Li, Y. Hou, W. Li, Z. Liu, "Long non-coding RNA (LncRNA) RMST in triple-negative breast cancer (TNBC): Expression analysis and biological roles research," Journal of Cellular Physiology 233, no. 10 (2018): 6603-6612), https://doi.org/10.1002/jcp.26311. The above article, published online on 7 December 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal's Editor in Chief, Alexander Hutchison; and Wiley Periodicals LLC. The retraction has been agreed due to concerns related to the data presented in the article. Several flaws and inconsistencies between results presented and experimental methods described were found. Furthermore, duplications affecting Figure 3b and Figure 5a have been detected. Accordingly, the conclusions of this article are considered invalid by the editors.

Although the novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily manifests as severe respiratory distress, its impact on the cardiovascular system is also notable. Studies reveal that COVID-19 patients often suffer from certain vascular diseases, partly attributed to increased proliferation or altered phenotype of vascular smooth muscle cells (VSMCs). Although the association between COVID-19 and VSMCs is recognized, the precise mechanism underlying SARS-CoV-2's influence on VSMC phenotype remains largely under-reviewed. In this context, while there is a consistent body of literature dissecting the effect of COVID-19 on the cardiovascular system, few reports delve into the potential role of VSMC switching in the pathophysiology associated with COVID-19 and the molecular mechanisms involved therein. This review dissects and critiques the link between COVID-19 and VSMCs, with particular attention to pathways involving cholesterol, calcium, and phosphate. These pathways underpin the interaction between the virus and VSMCs. Such interaction promotes VSMC proliferation, and eventually potentiates vascular calcification as well as worsens prognosis in patients with COVID-19.

Simultaneous inhibition of transforming growth factor-β (TGF-β) type I receptors Acvr1b and Tgfbr1 signalling has been associated with excessive skeletal muscle hypertrophy in vivo. However, it remains unclear whether the increased muscle mass in vivo is a direct result of inhibition of intracellular TGF-β signalling or whether this is an indirect effect of an altered extracellular anabolic environment. Here, we tested whether individual or simultaneous knockdown of TGF-β type I receptors in C2C12 myotubes was sufficient to induce muscle hypertrophy. The expression levels of TGF-β type I receptors Acvr1b and Tgfbr1 in myotubes were knocked down individually or in combination in the absence or presence of TGF-β1 and myostatin. Knocking down either Acvr1b or Tgfbr1 did not significantly change cell phenotype. Unexpectedly, simultaneous knockdown of both receptors reduced C2C12 myotube diameter, mRNA expression levels of Hgf, Ccn2 and Mymx with or without TGF-β1 and myostatin administration. In spite of decreased phosphorylation of Smad2/3, phosphorylation of P70S6K was reduced. In addition, the gene expression level of β1-syntrophin (Sntb1), which encodes a protein associated with the dystrophin-glycoprotein complex, was increased. Parallel experiments where Sntb1 gene expression was reduced showed an increase in myotube diameter and fusion of C2C12 myoblasts. Together, these results indicate that the knockdown of both TGF-β type I receptors reduced myotube diameter. This atrophic effect was attributed to reduced protein synthesis signalling and an increased expression of β1-syntrophin. These results have implications for our fundamental understanding of how TGF-β signalling regulates skeletal muscle size.

Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

NORSF is a nuclear long noncoding RNA (lncRNA) that contributes to the follicular atresia and restrains 17β-estradiol (E₂) release by granulosa cells (GCs). Importantly, it is also a potential candidate gene in the quantitative trait locus (QTLs) for sow fertility traits. We identified NORSF as a candidate (causal) gene affecting sow fertility traits. A novel G-A variant was discovered at -478 nt of the NORSF promoter and termed as g.-478G>A. Association analysis revealed that this variant was associated with sow fertility traits (e.g., the total number of piglets born, the total number of piglets born alive, and the number of healthy piglets). Mechanistically, the g.-478G>A variant reduced the binding activity of the NORSF promoter to its transcription activator regulatory factor X7 (RFX7), leading to decreased NORSF promoter activity and transcription levels in sow GCs (sGCs), and weakened inhibitory effects on the transcription of CYP19A1, which encodes a rate-limiting enzyme for E₂ synthesis and E₂ release by sGCs. In addition, RFX7 is transcriptionally activated by P53, which restrains E₂ release from sGCs via the RFX7/NORSF/CYP19A1 pathway. These findings indicate that the lncRNA NORSF is a causal gene in QTLs for sow fertility traits and define the P53/NORSF/CYP19A1 pathway as a new signaling pathway affecting sow reproduction, which provides a new target for improving female fertility.

The protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is recognized as a tumor suppressor involved in diverse cellular processes and essential for maintaining cell viability in vivo. However, endogenous inhibitors of PP2A such as cancerous inhibitor of PP2A (CIP2A) and endogenous nuclear protein inhibitor 2 of PP2A (SET) counteract the anticancer function of PP2A, promoting tumorigenesis, development, and drug resistance in tumors. Surprisingly though, contrary to conventional understanding, inhibition of the tumor suppressor gene PP2A with exogenous small molecule compounds can enhance the efficacy of cancer treatment and achieve superior tumor inhibition. Moreover, exogenous PP2A inhibitors resensitize cancers to treatment and provide novel therapeutic strategies for drug-resistant tumors, which warrant further investigation.

Nuclear protein-1 (NUPR1) (also known as p8) is one of the genes associated with transcription factors that participate in various aspects of cancer initiation and development. However, the molecular mechanisms of NUPR1 in bladder cancer (BLCA) remain unclear. We conducted an analysis of the correlation between NUPR1 expression and related genes using the Gene Expression Omnibus (GEO) online database. We employed lentivirus-mediated small interfering RNA (siRNA) to knockdown the expression of NUPR1 in two human BLCA cell lines. In vitro experiments were conducted to validate the impact of NUPR1 interference on BLCA and the influence of NUPR1 on the transcription of chemokine receptor-2 (CCR2). Furthermore, transcription factors for CCR2 were predicted using the PROMO database. Co-immunoprecipitation (Co-IP) and immunofluorescence double staining were used to detect the binding between NUPR1 and CCAAT/enhancer binding protein γ (CEBPG). In vivo and in vitro experiments were conducted to validate that NUPR1 regulates CCR2 transcription through CEBPG. In vitro experiments indicate that the suppression of NUPR1 inhibited BLCA growth. Analysis of the GEO database revealed a positive correlation between the expression of NUPR1 and CCR2. Luciferase experiments confirmed that NUPR1 influences the transcription of CCR2. Online data indicates that CEBPG is a transcription factor for CCR2. Co-IP and immunofluorescence double staining confirmed binding between NUPR1 and CEBPG. Luciferase assays and chromatin immunoprecipitation (ChIP) demonstrate that CEBPG regulates the transcription of CCR2. Additionally, rescue experiments at the cellular level and animal experiments validated the aforementioned mechanism. NUPR1 promotes a promotional role in BLCA, and interference with NUPR1 can inhibit the proliferation and invasive abilities of BLCA. There was a correlation between the expressions of NUPR1 and CCR2, and NUPR1 binds with CEBPG in the cell nucleus. Transcriptional regulation of CCR2 by NUPR1 may be achieved through the involvement of CEBPG.

Front Cover Caption: The cover image is based on the article Ablation of Sam50 is associated with fragmentation and alterations in metabolism in murine and human myotubes by Bryanna Shao et al., https://doi.org/10.1002/jcp.31293.