Human Cell最新文献

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke, and the neuroprotective effects of nimodipine following SAH have been well-documented. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, plays a significant role in mitigating oxidative stress in various neurodegenerative conditions. However, the role of SIRT3 in the neuroprotective mechanisms of nimodipine after SAH remains unclear. In this study, the in vitro cytotoxicity of neurons exposed to 2% ethanol (to stimulate oxidative stress) was assessed. An in vivo experimental SAH model was established in adult mice through internal carotid perforation. A series of in vitro and in vivo experiments were conducted to investigate the function of SIRT3 and its potential mechanisms in nimodipine-treated SAH. Nimodipine, at a concentration of 10 μM within 48 h of incubation, exerted significant neuroprotective effects, enhancing SIRT3 protein expression under oxidative stress. Functional in vitro studies revealed that elevated SIRT3 expression improved mitochondrial function and promoted neuronal autophagy. Additional studies unveiled that SIRT3 knockdown or inhibition of autophagosome formation using inhibitor 3-methyladenine suppressed nimodipine-induced autophagy. The absence of autophagy increased neuronal cytotoxicity and mitochondrial dysfunction, decreased the release of anti-inflammatory cytokines, and increased the release of proinflammatory cytokines. Furthermore, blocking autophagy exacerbated neuronal apoptosis worsened neurological outcomes, and nullified the neuroprotective effects of nimodipine in the SAH mouse model. These findings highlight a mechanism where SIRT3 mediates nimodipine's neuroprotective effects by regulating mitochondrial function and autophagy. This suggests that SIRT3 serves as a promising therapeutic target for SAH.

Cancer, a complicated disease characterized by aberrant cellular metabolism, has emerged as a formidable global health challenge. Since the discovery of abnormal aldolase A (ALDOA) expression in liver cancer for the first time, its overexpression has been identified in numerous cancers, including colorectal cancer (CRC), breast cancer (BC), cervical adenocarcinoma (CAC), non-small cell lung cancer (NSCLC), gastric cancer (GC), hepatocellular carcinoma (HCC), pancreatic cancer adenocarcinoma (PDAC), and clear cell renal cell carcinoma (ccRCC). Moreover, ALDOA overexpression promotes cancer cell proliferation, invasion, migration, and drug resistance, and is closely related to poor prognosis of patients with cancer. Although originally discovered to promote cancer initiation and progression by accelerating glycolysis, recent studies have revealed its atypical roles in cancer, e.g., adjusting cytoskeleton, regulating mRNA translation, cell signaling pathways, and DNA repair. These aforementioned findings challenge our traditional understanding of ALDOA function and prompt deep exploration of its novel roles in tumor biology. The present review summarizes the latest insights into ALDOA as a potential cancer biomarker and therapeutic target.

We previously examined the antitumor effects of short interfering RNA nanoparticles targeting mammalian target of rapamycin (mTOR) in an orthotopic pancreatic cancer mouse model. We herein report the inhibitory effects of the mTOR inhibitor rapamycin on tumor growth in a novel established mouse model of pancreatic cancer using human pancreatic cancer cell line-derived organoids. Gemcitabine, 5-fluorouracil, and gemcitabine plus nab-paclitaxel are clinically used to treat advanced pancreatic cancer. In vitro assays showed that rapamycin strongly inhibited cell invasion, while gemcitabine, 5-fluorouracil, and gemcitabine plus paclitaxel primarily inhibited cell proliferation with minimal effects on invasion. In vivo mouse experiments demonstrated that rapamycin exhibited superior antitumor activity to S-1 (a metabolically activated prodrug of 5-fluorouracil) and another mTOR inhibitor, everolimus, while its efficacy was similar to that of gemcitabine plus paclitaxel (which was used instead of nab-paclitaxel due to concerns about allergic reactions in mice to human albumin) in a mouse model of pancreatic cancer using human pancreatic cancer cell line-derived organoids. Furthermore, the combination of rapamycin with gemcitabine plus paclitaxel exerted synergistic inhibitory effects on the growth of pancreatic cancer tumors. Although the inhibition of tumor growth was significantly stronger in everolimus-treated mice than in control mice, there were no additive anti-growth effects when combined with gemcitabine plus paclitaxel. The present results suggest that the combination of rapamycin with gemcitabine plus paclitaxel achieved the greatest reduction in tumor volumes in the mouse xenograft model and, thus, has significant clinical promise.

Autophagy, a cellular degradation process involving the formation and clearance of autophagosomes, is mediated by autophagic proteins, such as microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (p62), and modulated by 3-methyladenine (3-MA) as well as chloroquine (CQ). Senescence, characterised by permanent cell cycle arrest, is marked by proteins such as cyclin-dependent kinase inhibitor 1 (p21) and tumour protein 53 (p53). This study aims to investigate the relationship between cell senescence and renal function in diabetic kidney disease (DKD) and the effect of autophagy on high-glucose-induced cell senescence. We categorised 46 patients with DKD diagnosed by renal biopsy into classes I, IIa, IIb, III and IV and used four normal kidney specimens from patients with renal trauma as controls. We evaluated pathological changes, LC3 and p21. We used streptozotocin-induced DKD models in rats and 35 mM glucose-cultured human proximal tubular epithelial cells (HK-2) with or without 3-MA and CQ. We assessed p53, p21, LC3 and p62. We observed autophagosomes and detected senescence-associated galactosidase (SA-β-gal) activity. In patients with DKD, p21 and LC3 expression levels increased over time and correlated positively with blood creatinine and proteinuria. In DKD rats and HK-2 cells, p21, p53, LC3 and p62 expression levels were higher than in the controls, as were SA-β-gal-positive cells, renal tubular autophagosomes and co-expression of p21 and LC3. The 3-MA reduced p16, p21 and p53 expression compared with the high glucose group, whereas CQ had the opposite effect. These results suggest that renal tubular cell senescence is associated with the progression of DKD. Additionally, autophagic flux may play a role in mediating high-glucose-induced senescence in renal tubular cells.

The study explores the development and characterization of lymph node stromal cell cultures (LNSCs) from patients with oral squamous cell carcinoma (OSCC), highlighting the importance of understanding tumor-node cross-talk for effective prognostic and therapeutic interventions. Herein, we describe the development and characterization of primary lymph node stromal cells (LNSCs, N = 14) from nodes of metastatic and non-metastatic OSCC patients. Primary cultures were established by the explant method from positive (N + ; N = 2), and negative nodes (N0_m; N = 4) of the metastatic patients (N = 3) as well as negative (N0_nm; N = 8) nodes from non-metastatic (N = 4) patients. STR profiling confirmed the purity and novelty, while characterization by immunocytochemistry/flow cytometry revealed heterogeneous cell populations consisting of fibroblastic reticular cells (CD31-Gp38 +) and double negative cells (CD31-Gp38-). Transcriptomic profiling indicated molecular alterations in the cells based on the non-metastatic, the pre-metastatic or metastatic status of the nodes, pro-inflammatory, matrix remodeling, and immune evasion being the primary pathways. Assessment of the protein levels for five selected markers (MX1, ISG15, CPM, ITGB4 and FOS) in the cell lines revealed that CPM levels were significantly reduced in the N + and N0_m nodes whereas ISG15 levels reduced in N0_m. Significantly, the profiling also provided insights into possible glycosylation of CPM (N0_nm) and ISGylation of ISG15 (N0_m). Cytokine profiling indicated release of chemokines/anti-proliferative cytokines from the negative nodes, while angiogenic/pro-metastatic cytokines were released from the nodes of metastatic patients. The lymph node stromal cell models established in the study with distinctive transcriptomic/cytokine characteristics will be invaluable in delineating the processes underlying nodal metastasis.

This research delves into Primary Hyperoxaluria Type 2 (PH2), an autosomal recessive disorder precipitated by a unique case of compound heterozygous deleterious mutations in the GRHPR gene, specifically the intron2/3 c.214-2 T > G and the exon8 c.864-865delTG, leading to a premature stop codon at p.Val289fsTer22. The intron 2/3 variant (c.214-2 T > G) is a novel finding and is reported for the first time. These mutations are associated with profound alterations in protein structure and function. Employing patient-derived induced pluripotent stem cells (iPSCs), we have successfully generated a patient-specific model that exhibits the hallmarks of pluripotency, including typical stem cell morphology, expression of pluripotency markers, and a normal karyotype. The iPSCs are capable of differentiating into all three germ layers, underscoring their potential for regenerative medicine. The established iPSC line offers a promising platform for drug screening and regenerative medicine approaches for PH2.

The escalating diabetes prevalence has heightened interest in innovative therapeutic strategies for this disease and its complications. Human amniotic epithelial stem cells (HAESCs), originate from the innermost layer of the placenta closest to the fetus and express stem cell markers in the amniotic membrane's umbilical cord attachment area, which have garnered significant attention. This article critically examines emerging research advancements and potential application values of hAESCs in treating diabetes and its complications. Initially, we will discuss the characteristics, origin, and advantages of hAESCs in differentiating into insulin-secreting cells. Subsequently, we will focus on the potential applications of hAESCs in treating diabetes complications such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy, etc. We will scrutinize the progress of relevant clinical studies and trials involving hAESC therapy. In conclusion, as an emerging diabetes treatment method, hAESCs exhibit immense potential and application value. Despite numerous challenges in practical application, we are confident that with scientific advancement and technological progress, hAESCs will play a pivotal role in treating diabetes and its related complications.

Hepatocellular carcinoma (HCC) is a primary malignant neoplasm exhibiting a high mortality rate. Taxifolin is a naturally occurring flavonoid compound that exhibits a range of pharmacological properties. The effects of taxifolin on HCC remain largely unexplored. Therefore, the aim of this study was to examine the potential roles of taxifolin in the development and progression of HCC. In this study, CCK-8 assay was utilized to examine the impact of taxifolin on the cell viability. The copper ions level and the activity of mitochondrial respiratory chain were determined by the correspondent kits. The biological properties of HCC cells were evaluated using colony formation, transwell, flow cytometry, and TUNEL assays, respectively. Transcriptome sequencing was carried out either with or without taxifolin treatment. The expression of cuproptosis-related proteins was determined by Western blot. We observed significant decrease of cell viability, Glutathione (GSH), and mitochondrial respiratory chain under the treatment of taxifolin, while an increase of copper ions level. Taxifolin was observed to suppress HCC progression both in vitro and in vivo. The intersection analysis was performed between upregulated genes and cuproptosis-related genes to obtain one intersection gene-SLC31A1. The knockdown of SLC31A1 reversed the tumor-suppressive effects induced by taxifolin. Taxifolin inhibited HCC progression through inducing cuproptosis in an SLC31A1-mediated manner.

Imatinib resistance is a major obstacle to the successful treatment of gastrointestinal stromal tumors (GIST). Long non-coding RNAs (LncRNAs) have been identified as important regulatory factors in chemotherapy resistance. This study aimed to identify key lncRNAs involved in imatinib resistance of GISTs. First, MSC-AS1 was found to be upregulated in imatinib-resistant GIST tissues and imatinib-resistant GIST cells. Cellular experiments demonstrated that MSC-AS1 overexpression decreased imatinib sensitivity of GIST cells, evidenced by increased cell survival, colony formation, migration, and invasion. Moreover, suppression of MSC-AS1 improved the imatinib resistance of imatinib-resistant GIST cells. Furthermore, MSC-AS1 upregulated the expression of FNDC1 and Anillin via sponging miR-200b-3p, activated the phosphatidylinositol-3-kinase-AKT signaling pathway, and thereby driving imatinib resistance in vitro and in vivo. Overall, this study elucidates the crucial role and mechanism of MSC-AS1 in the imatinib resistance of GIST, providing the potential therapeutic strategy for overcoming the imatinib resistance of GIST.