Cell Proliferation最新文献

Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we demonstrate that pioglitazone significantly mitigates mitochondrial reactive oxygen species (ROS) generation, lowers cyclooxygenase-2 (COX-2) mRNA levels, and rescues aberrant mitochondrial dynamics in vitro (increasing Opa-1 expression while decreasing Drp-1 expression). Furthermore, similar effects were observed with the selective Drp-1 inhibitor mdivi-1, suggesting that inhibiting mitochondrial fission mediates the therapeutic effects of pioglitazone. Pioglitazone administration activated AMPK phosphorylation, but these effects, along with pioglitazone's ability to reverse oxidative stress, inflammation, and mitochondrial fission, were abolished by the AMPK inhibitor compound C. In vivo, pioglitazone alleviated motor dysfunction, prolonged lifespan, and promoted weight gain in Ndufs4 KO mice. This was accompanied by enhanced mitochondrial fusion and increased levels of mitochondrial complex subunits. Consistently, pioglitazone attenuated neuroinflammation and oxidative stress in vivo. Collectively, our findings indicate that pioglitazone alleviates mitochondrial oxidative stress and inflammation through an AMPK-dependent inhibition of Drp-1-mediated mitochondrial fission. Therefore, suppression of mitochondrial fission may represent a novel therapeutic strategy for Leigh syndrome (LS).

S. Yu, Q. Tang, M. Xie, et al., “Circadian BMAL1 Regulates Mandibular Condyle Development by Hedgehog Pathway,” Cell Proliferation 53, no. 1 (2020): e12727, https://doi.org/10.1111/cpr.12727.

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The maternal gene products stored in oocytes control the initial development of multicellular animals. Alteration within the dual allelic variants of transcription factor TCF12 causes female infertility; however, its impact on female reproduction is still unknown. In this study, we provide evidence that TCF12 is abundantly expressed within the nucleus of oocytes during growth at the germinal vesicle (GV) stage, recognising and binding to the functional domain of target genes to moderate transcriptional activity. The absence of Tcf12 in oocytes during the primordial follicular phase causes female sterility. Tcf12 does not participate in meiotic maturation; however, unlike Tcf3, it is essential for fertilisation and preimplantation development. Tcf12 maintains fertilisation competence by controlling the proper expression and location of cortical granules and protease ovastacin (encoded by Astl). In contrast, zygotes without TCF12 have a prolonged mitotic cell cycle upon a decrease in protein phosphatase 2A (PP2A) activity inhibition, resulting in zygotic genome activation (ZGA) failure during the 2-cell stage. Maternal knockout embryos gradually lose their developmental potential in subsequent developmental processes. These observations indicate that the maternal effect induced by Tcf12 ensures preimplantation development.

Traumatic brain injury (TBI) represents a global health burden, often resulting in persistent neurological deficits due to impaired hippocampal neurogenesis. Nevertheless, the temporal progression of post-TBI neurogenesis and its molecular mechanisms remain elusive. To investigate the mechanism of impaired hippocampal neurogenesis and neurological deficits following TBI. Single-cell RNA sequencing (scRNA-seq) was employed to explore the mechanism of abnormal hippocampal neurogenesis after TBI in mice. Antagonists and conditional gene knockout (CKO) strategies were applied to dissect the molecular function of target genes. Here, we found that neural stem cells (NSCs) were hyperactivated as observed in Nestin-GFP reporter mice in hippocampus during the early phases of TBI, followed by progressive depletion of the NSC pool, impaired neurogenesis, and the onset of progressive cognitive dysfunction. ScRNA-seq transcriptomic analysis revealed sustained upregulation of Rho-associated coiled-coil protein kinase 1 (ROCK1) in hippocampal NSCs post-TBI. Pharmacological inhibition of ROCK1 or ROCK1 CKO rescued chronic neurogenic deficits and improved cognitive functions in TBI mice. Mechanistically, ROCK1 dysregulation impaired neurogenesis via aberrant AKT hyperphosphorylation, establishing a unidirectional ROCK1-AKT signalling axis in adult hippocampal neurogenesis. Our findings position ROCK1 as a pivotal regulator of the post-TBI NSC pool hyperactivation and aberrant neurogenesis and propose targeted kinase inhibition strategies as a potential therapy to mitigate abnormal neurogenesis in TBI patients.

Cuproptosis, a copper-dependent cell death mechanism driven by tricarboxylic acid (TCA) cycle collapse, shows limited efficacy in hypoxic or glycolytic renal cell carcinoma (RCC). Here, through systematic screening of 688 glycolysis inhibitors combined with elesclomol (ES), we identified PIK-III as a potent cuproptosis sensitiser. Multi-omics analysis revealed that PIK-III restores sensitivity by rewiring thiamine metabolism. Mechanistically, PIK-III induces macropinocytosis, enabling thiamine uptake to replenish thiamine pyrophosphate (TPP), which activates pyruvate dehydrogenase E1-alpha 1 (PDHA1) and redirects pyruvate into the TCA cycle. Concurrently, ES-induced DLAT oligomerisation disrupts TCA flux, creating a metabolic crisis. In vivo, PIK-III synergises with ES to suppress tumour growth in xenograft and patient-derived models without systemic toxicity. Our work uncovers a metabolic vulnerability in cuproptosis-resistant RCC and positions PIK-III as a therapeutic candidate to overcome resistance via dual targeting of thiamine transport and mitochondrial dysfunction.

Melanoma is the most serious type of skin cancer. About half of all melanomas have activating BRAF mutations. Targeted therapy for malignant melanoma with BRAF inhibitor (BRAFi) or its combination with MEK inhibitor (MEKi) improves the clinical outcomes of patients, but resistance develops invariably. The underlying mechanisms remain incompletely understood. Here, we show that caveolae number is increased in both BRAFi and BRAFi + MEKi-resistant melanoma cells, and the expression of the critical caveolae component PTRF is significantly upregulated in drug-resistant melanoma cell lines and tumour tissues. Knockdown of PTRF in drug-resistant cells reduces proliferation with increased apoptosis, whereas ectopic expression of PTRF confers resistance on parental cells to BRAFi or BRAFi + MEKi. On the contrary, the knockdown of PTRF in parental cells reduces their ability to acquire drug resistance induced by BRAFi treatment. Interestingly, we find that the expression of EGFR is increased along with PTRF and caveolin-1 in drug-resistant cells and in PTRF transduced parental cells, whereas knockdown of PTRF results in down-regulation of EGFR expression and attenuates drug resistance of parental cells induced by PTRF expression. Together, these results suggest that PTRF contributes to therapy resistance through upregulating EGFR in melanoma cells.

Keratinocyte differentiation factor 1 (Kdf1) reportedly plays a significant role in enamel formation. In terms of tooth morphogenesis, human KDF1 variants are associated with crown morphological abnormalities, suggesting that Kdf1 may also be essential for tooth morphogenesis. However, the involvement of Kdf1 in tooth morphogenesis and its underlying mechanisms remains unclear. In this study, we observed that mice lacking epithelial Kdf1 (K14-Cre;Kdf1^fl/fl) displayed rounded and blunt molar cusps, resembling the morphological anomalies observed in patients with Kdf1 variants. 5-Ethynyl-2'-deoxyuridine assays revealed increased proliferative activity of the inner enamel epithelial (IEE) cells in the cusp region of K14-Cre;Kdf1^fl/fl mice during the bell stage. RNA sequencing and western blot analysis confirmed the overactivation of PI3K/AKT/mTOR signalling in the molar IEE cells of K14-Cre;Kdf1^fl/fl mice. Furthermore, in utero microcapillary injection of the PI3K/AKT/mTOR pathway inhibitor LY294002 partially rescued the molar cusp defects in K14-Cre;Kdf1^fl/fl mice. Collectively, our findings provide in vivo evidence supporting the regulatory role of Kdf1 in molar cusp morphogenesis, highlighting its function in modulating dental epithelial cell proliferation via the PI3K/AKT/mTOR signalling pathway.

Transcriptomics studies have identified integrin receptor β2 subunit (ITGB2) as a core gene in osteoarthritis (OA), strongly linked to osteoclast function in the subchondral bone. However, the mechanism through which ITGB2 regulates osteoclast function in OA remains unclear. In this study, we found that ITGB2 was negatively correlated with ITGB1 in the human subchondral bone. Proteomic analysis indicated that integrin binding is crucial in OA subchondral bone, with ITGB2 identified as a significantly upregulated protein in OA. In vitro experiments using immunoprecipitation and bimolecular fluorescence complementation revealed that ITGB2, but not ITGB1, directly interacts with Rac1 during osteoclast differentiation. Activated Rac1 promotes osteoclast differentiation and bone resorption through several mechanisms. ITGB2 knockdown reduced Rac1-GTP levels and increased ITGB1 expression. ITGB2 inhibition reduced actin ring formation and microtubule migration to the cell edge during osteoclast differentiation. Additionally, overexpression of ITGB1 in ITGB2-knockdown cells not only further suppressed ITGB2 expression but also exacerbated the inhibition of osteoclast differentiation. In a DMM mouse model, ITGB2 was associated with osteoclast activity in the subchondral bone. ITGB2 knockdown significantly reduced bone resorption and slowed OA progression by inhibiting osteoclastogenesis. In conclusion, our study identified a novel mechanism for the reciprocal regulation of integrin subunits. Moreover, inhibition of the ITGB2 signalling pathway slows subchondral bone remodelling in osteoarthritis by inhibiting osteoclast differentiation, offering a potential strategy for targeted therapeutic interventions.

Differences in gene expression, which arise from divergence in cis-regulatory elements or alterations in transcription factors (TFs) binding specificity, are one of the most important causes of phenotypic diversity during evolution. On one hand, changes in the cis-elements located in the vicinity of target genes affect TF binding and/or local chromatin environment, thereby modulating gene expression in cis. On the other hand, alterations in trans-factors influence the expression of their target genes in a more pleiotropic fashion. Although the evolution of amino acid sequences is much slower than that of non-coding regulatory elements, particularly for the TF DNA binding domains (DBDs), it is still possible that changes in TF-DBD might have the potential to drive large phenotypic changes if the resulting effects have a net positive effect on the organism's fitness. If so, species-specific changes in TF-DBD might be positively selected. So far, however, this possibility has been largely unexplored. By protein sequence analysis, we observed high sequence conservation in the DBD of the TF caudal-type homeobox 2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells to study the cis effects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent. There were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Moreover, Cdx2 binding is largely divergent between mouse and rat; the transcriptional effect induced by Cdx2 is conserved to a much larger extent.

MFG-E8 promotes oxidative stress by upregulating NOX4 and activating the MAPK pathway, which increases ROS production and affects vascular smooth muscle cell (VSMC) apoptosis, thereby driving the progression of abdominal aortic aneurysm (AAA). Resveratrol can inhibit the expression and function of MFG-E8, reduce ROS generation, and lower the incidence and severity of AAA, making it a potential therapeutic agent for AAA.