Cell Biology International最新文献

Acquired drug resistance is a major cause of poor prognosis in multiple myeloma (MM). Bortezomib (BTZ), a first-line therapeutic agent, is highly effective in MM; however, resistance remains a significant clinical challenge. Our previous work implicated Solute Carrier Family 19 Member 1 (SLC19A1) in hypoxia and immune modulation, suggesting its potential role in malignant progression. Here, we found that SLC19A1 expression was elevated in MM patients, particularly in those with acquired resistance. Overexpression of SLC19A1 enhanced the proliferation and invasiveness of human myeloma cell lines but did not confer primary BTZ resistance. Using a continuous-BTZ-exposure model, we demonstrated that SLC19A1 overexpression mediated acquired resistance via chronic activation of the stimulator of interferon genes (STING) pathway. This sustained activation triggered the unfolded protein response, dysregulated the endoplasmic reticulum–mitochondrial axis, and induced mitochondrial DNA (mtDNA) release. Treatment with the SLC19A1 inhibitor sulfasalazine or the STING inhibitor H-151 reduced mtDNA release and restored BTZ sensitivity. These findings highlight SLC19A1 and STING signaling as potential therapeutic targets for overcoming acquired drug resistance in MM.

Evasion of programmed cell death, including apoptosis and necroptosis, is a critical hallmark of cancer that contributes to tumorigenesis and chemoresistance. While microRNAs (miRNAs) are known to modulate cell death pathways, the role of specific miRNA families in coordinated death resistance remains incompletely understood. Through functional screening, we identified the miR-148/152 family as potent suppressors of tumor necrosis factor (TNF)-induced cell death, prompting an investigation into their regulatory mechanism in both apoptosis and necroptosis and their oncogenic role. Ectopic expression of miR-148a or miR-152 inhibits TNF-induced apoptosis and necroptosis in multiple human cancer cell lines, accompanied by reduced activation of caspase-8, caspase-3, RIPK1, and RIPK3. Mechanistically, the miR-148/152 family directly target the 3′UTR of RIPK1, which is a critical regulator in TNF-mediated cell death, thus downregulating its expression. Functionally, miR-152 enhances cancer cell proliferation and colony formation. Clinically, high expression of miR-152 correlates with poor prognosis in gastric cancer patients. Importantly, this miRNA confers resistance to cisplatin-induced, RIPK1-mediated cell death, promoting gastric cancer cell survival and proliferation. Our study defines the miR-148/152 family as critical oncogenic drivers that promote cancer cell survival and chemoresistance by directly suppressing RIPK1 expression. These findings highlight this miRNA family as a promising therapeutic target to overcome cell death evasion in cancer.

Myocardial ischemia–reperfusion injury (MIRI) is one of the leading causes of morbidity and mortality from cardiovascular diseases worldwide. Protein N-glycosylation plays an important role in MIRI. However, there is limited knowledge regarding N-glycoproteins in MIRI and their alterations during MIRI. This study aims to investigate the dynamic changes of N-glycosylation modification in MIRI and the regulatory mechanisms of key proteins in MIRI to provide new therapeutic targets for the clinical diagnosis and treatment of MIRI. This study systematically explored the dynamic changes of N-glycosylation modification in MIRI through an integrated glycoproteomic analysis, combining a clinical sample, animal models, and cell models. Differential glycoproteins were identified using quantitative N-glycoproteomic mass spectrometry. Key regulatory molecules were screened through GO functional annotation and KEGG pathway enrichment. The integrated analysis identified 698 N-glycosylated proteins. Pathway enrichment analysis showed that the differentially expressed proteins were mainly involved in the PI3K/AKT/mTOR signaling pathway. The study of differentially expressed N-glycoproteins revealed that CD44 was upregulated and could regulate AKT. One possible reason is that N-glycosylation of CD44 affects its stability.

Tetrachlorobisphenol A (TCBPA) is an organic compound extensively utilized in industrial production as an alternative to Tetrabromobisphenol A (TBBPA). Currently, TCBPA has been frequently detected in various environmental media. TCBPA residues have been detected in environmental samples, prompting concerns about its potential toxicological impact on human health. This study focuses on the potential impact of TCBPA on vascular health, particularly its effects on vascular endothelial cells. Through CCK8 and EdU assays, we observed that TCBPA treatment inhibited the proliferation of vascular endothelial cells. Further studies showed that TCBPA triggers an inflammatory response in vascular endothelial cells, including IL-6, IL-1β, and TNF-α. Additionally, TCBPA was found to trigger oxidative stress in vascular endothelial cells, as evidenced by increased levels of reactive oxygen species (ROS). Further studies demonstrated that TCBPA led to programmed necrosis and senescence in vascular endothelial cells. Mechanistically, we discovered that ROS-induced mitochondrial Z-DNA played a critical role in this process. Our findings suggest that TCBPA may inhibit vascular endothelial cell proliferation, posing a potential risk for vascular damage. This study highlights the importance of regulating TCBPA usage to minimize potential health risks.

The adult mammalian heart exhibits minimal regenerative capacity as cardiomyocytes are quiescent, whereas the adult zebrafish robustly regenerates injured myocardium. Understanding the mechanisms of this natural cardiac regeneration capacity may inform strategies to stimulate cardiomyocyte proliferation in adult mammals. The Golgi apparatus plays a critical role within the cardiovascular system. Here, we identified a Golgi-associated protein, Gopc, as a novel regulator of myocardial proliferation and regeneration in zebrafish. Sequence alignment and phylogenetic analysis showed high conservation of Gopc from zebrafish to humans. In zebrafish, its transcript is highly expressed in cardiomyocytes following cardiac injury. To elucidate the impact of Gopc on cardiac regeneration, we established a transgenic zebrafish model with gopc overexpression specifically in cardiomyocytes. Under uninjured conditions, this transgenic fish possesses increased cardiomyocyte proliferation compared to wild-type fish. At 7 days post-amputation (dpa), the cardiomyocyte proliferation at the injury site remains higher in transgenic fish than in wild-type fish. However, at 30 dpa, compared to the control fish, the myocardial regeneration in the transgenic fish is delayed, accompanied by substantial scar tissue at the amputation site. Coronary endothelial tube regeneration also exhibits a corresponding delay, which may contribute to the impaired cardiac regeneration observed. Taken together, our data identify Gopc as a critical modulator that uncouples cardiomyocyte proliferation from the later stages of regenerative resolution, expanding our understanding of cardiac regeneration mechanisms and highlighting the necessity of balanced regulation across distinct phases of the healing process.

Spermatogonial stem cells (SSCs) are essential for maintaining sperm production but are highly susceptible to damage from testicular ischemia-reperfusion (IR) injury, a common consequence of conditions like testicular torsion. This injury leads to oxidative stress, disruption of the blood-testis barrier (BTB), and germ cell death. While the transcription factor EGR1 is known to promote SSC survival in laboratory settings, its protective mechanisms within a living organism remained unclear. This study aimed to identify the downstream targets through which EGR1 confers protection against IR injury. Through bioinformatic analysis, a potential binding site for EGR1 was discovered in the promoter of the Nudt16L1 gene. A series of experiments, including chromatin immunoprecipitation and luciferase reporter assays, confirmed that EGR1 directly binds to this site and activates Nudt16L1 expression. In a mouse model of testicular IR injury, overexpression of EGR1 was found to alleviate tissue damage, improve sperm motility, and preserve the integrity of the BTB. Crucially, when Nudt16L1 was experimentally silenced, the protective benefits of EGR1 were lost. Conversely, overexpressing Nudt16L1 alone was sufficient to mimic EGR1's protective effects, reducing reactive oxygen species and preventing cell death in SSCs subjected to oxygen-glucose deprivation/reperfusion, an in vitro model of IR. In conclusion, this research identifies Nudt16L1 as a critical downstream effector of EGR1. The EGR1-Nudt16L1 signaling axis protects SSCs from IR injury by mitigating oxidative stress, maintaining BTB integrity, and inhibiting apoptosis. These findings highlight this pathway as a promising therapeutic target for preventing infertility resulting from testicular torsion and similar ischemic events.

γδ T cells, which express the T cell receptor γδ, contribute to both innate and adaptive immune responses, yet their role in dental pulp pathology remains poorly understood. This study investigated the impact of γδ T cells on the calcification of human dental pulp stem cells (HDPSCs) through interleukin-17A (IL-17A) signaling. Dental pulp tissues and peripheral blood mononuclear cells (PBMCs) were analyzed to detect the presence of γδ T cells using immunofluorescence and flow cytometry. γδ T cells were efficiently generated from PBMCs with IL-2 and zoledronate stimulation, producing IL-17A as confirmed by ELISA. In healthy pulp, γδ T cells constituted the predominant CD3-positive T cell population. Their presence increased significantly in inflamed pulp tissues, with IL-17A-expressing γδ T cells specifically localized to these areas. Functionally, recombinant IL-17A and conditioned media from γδ T cells enhanced alkaline phosphatase (ALP) activity and mineral deposition in HDPSCs, as shown by ALP and Alizarin Red staining. Additionally, qPCR revealed upregulation of dentinogenic markers, particularly ALP, following exposure to γδ T cell-derived factors. These effects were accompanied by increased mineral nodule formation, suggesting that IL-17A acts as a pro-calcific cytokine in the pulp microenvironment. Collectively, these findings indicate that γδ T cells infiltrate the dental pulp and actively contribute to tissue calcification by secreting IL-17A, suggesting a novel immunoregulatory role in dental pulp repair and regeneration. This insight may have clinical relevance in modulating inflammation-induced pulp healing and promoting dentin bridge formation in endodontic therapies.

Among solid tumors, colorectal cancer (CRC) ranks as one of the most frequently diagnosed. This study aimed to investigate the role and underlying mechanism of family with sequence similarity 117 member B (FAM117B) in CRC. Western blotting was applied to detect FAM117B levels in both human normal colorectal epithelial cells and CRC cells. The malignant capabilities of CRC cells were assessed using flow cytometry, colony formation assays, and Transwell assays. In vivo, subcutaneous tumorigenesis and splenic-to-liver metastasis models were established in nude mice by injecting CRC cells. The effects of FAM117B knockdown on CRC subcutaneous tumor growth and liver metastasis were evaluated. Co-immunoprecipitation (Co-IP) and immunoprecipitation (IP) were employed to examine the FAM117B-dual specificity tyrosine (Y)-Regulated Kinase 1 A (DYRK1A) interaction, as well as the effect of DYRK1A on Polo-like kinase 2 (PLK2) phosphorylation. Cellular experiments demonstrated elevated FAM117B expression in CRC. Knockdown of FAM117B attenuated CRC cell proliferation, migration, and invasion. In vivo, FAM117B knockdown diminished CRC tumor growth and liver metastasis. A specific interaction exists between FAM117B and DYRK1A, with FAM117B acting as an upstream regulator of DYRK1A. Furthermore, DYRK1A induced PLK2 phosphorylation in CRC cells, thereby upregulating PLK2 protein expression. DYRK1A overexpression reversed the inhibitory effects of FAM117B inhibition on CRC cell malignancy. Conversely, PLK2 knockdown counteracted the effects mediated by DYRK1A overexpression. In conclusion, FAM117B promoted the pathological progression of CRC through enhancing the DYRK1A/PLK2 signaling pathway. Our study provided insights for potential therapeutic strategies against CRC.