Cell Cycle最新文献

Allergic rhinitis (AR) is very common in adolescents, and current treatment options are complex and unsatisfactory. The objective of this study was to analyze the association of lysyl oxidase (LOX) gene G473A polymorphism with susceptibility to AR in children. In addition, we analyzed the therapeutic effect of montelukast sodium on AR. Forty-five children with AR (research group, 8.16±2.88 years old) and 51 healthy children (control group, 8.22±3.87 years old) during the same period were selected. The LOX gene G473A polymorphism was detected with polymerase chain reaction (PCR)-restriction fragment length polymorphism method. The effect of G473A polymorphism in the occurrence of AR was assessed by logistic regression analysis. In addition, the levels of C-reactive protein (CRP), Interleukin (IL-6), and IL-8 were measured to observe the relationship between G473A polymorphism and inflammatory factors. Finally, montelukast sodium was given to children with AR to investigate the effect of G473A polymorphism on clinical outcomes. The number of G473A polymorphisms in the research group was not significantly different from the control group for GA-type (P = 0.521). However, the number of GG-type polymorphisms was less while the number of type AA was more than the control group (P = 0.044 and 0.046). Children carrying the AA gene had an approximately 4-fold increased risk of AR, while those carrying the GG gene had a decreased risk (P < 0.001). Moreover, children carrying the GG gene had lower levels of CRP, IL-6, and IL-8 and better clinical outcomes, while those carrying the AA gene had higher levels of inflammatory factors and worse outcomes (P<0.05). LOX gene G473A polymorphism is closely associated with AR pathogenesis and may have an important research value in antagonizing the therapeutic effect of montelukast sodium.

The mucosal renewal, which depends on the intestinal stem cell (ISC) activity, is the foundation of mucosal repairment. Importantly, activation of reserve ISCs (rISCs) plays a vital role in initiating mucosal repair after injury. However, the underlying regulatory mechanism of rISCs activation in chickens remains unclear. In this study, immediately after lipopolysaccharide (LPS) challenge, mitochondrial morphological destruction and dysfunction appeared in the crypt, accompanied by decreased epithelial secretion (decreased Muc2 mRNA abundance and LYSOZYME protein level). However, immediately after mucosal injury, the mucosal renewal accelerated, as indicated by the increased BrdU positive rate, proliferating cell nuclear antigen (PCNA) protein level and mRNA abundance of cell cycle markers (Ccnd1, Cdk2). Concerning the ISCs activity, during the early period of injury, there appeared a reduction of active ISCs (aISCs) marker Lgr5 mRNA and protein, and an increasing of rISCs marker Hopx mRNA and protein. Strikingly, upon LPS challenge, increased mRNA transcriptional level of Krüppel-like factor 5 (Klf5) was detected in the crypt. Moreover, under LPS treatment in organoids, the KLF5 inhibitor (ML264) would decrease the mRNA and protein levels of Stat5a and Hopx, the STAT5A inhibitor (AC-4-130) would suppress the Lgr5 mRNA and protein levels. Furthermore, the Dual-Luciferase Reporter assay confirmed that, KLF5 would bind to Hopx promoter and activate the rISCs, STAT5A would trigger Lgr5 promoter and activate the aISCs. Collectively, KLF5 was upregulated during the early period of injury, further activate the rISCs directly and activate aISCs via STAT5A indirectly, thus initiate mucosal repair after injury.

Spermatozoa released from the testis cannot fertilize an egg before becoming mature and motile in the epididymis. Based on three bulk and one single-cell RNA-seq (scRNA-seq) data series, we compared mRNA or miRNA expression between epididymal segment-specific samples and the other samples. Hereby, we identified 570 differentially expressed mRNAs (DE-mRNAs) and 23 differentially expressed miRNAs (DE-miRNAs) in the caput, 175 DE-mRNAs and 15 DE-miRNAs in the corpus, 946 DE-mRNAs and 12 DE-miRNAs in the cauda. In accordance with respective DE-miRNAs, we predicted upstream transcription factors (TFs) and downstream target genes. Subsequently, we intersected target genes of respective DE-miRNAs with corresponding DE-mRNAs, thereby obtaining 127 upregulated genes in the caput and 92 upregulated genes in cauda. Enriched upregulated pathways included cell motility-related pathways for the caput, smooth muscle-related pathways for the corpus, and immune-associated pathways for the cauda. Protein-protein interaction (PPI) network was constructed to extract key module for the caput and cauda, followed by identifying hub genes through cytohubba. Epididymis tissues from six mice were applied to validate hub genes expression using qRT-PCR, and 7 of the 10 genes displayed identical expression trends in mice caput/cauda. These hub genes were found to be predominantly distributed in spermatozoa using scRNA-seq data. In addition, target genes of DE-miRNAs were intersected with genes in the PPI network for each segment. Subsequently, the miRNA and mRNA regulatory networks for the caput and cauda were constructed. Conclusively, we uncover segment-specific miRNA-mRNA regulatory network, upstream TFs, and downstream pathways of the human epididymis, warranting further investigation into epididymal segment-specific functions.

Herein, we reported a rare case of bilateral intrapulmonary metastases spread through air spaces (STAS) and silicosis to advance understanding and knowledge of this disease. A middle-aged man was diagnosed with a left upper lung nodule with bilateral silicosis by preoperative imaging. Local pleural indentation and extensive metastases spread in the visceral pleura were observed during the operation. Pathological examination showed multiple metastases of lung adenocarcinoma, and STAS positive. Genetic testing indicated EGFR mutation, and ektinib was administered. STAS can promote lung cancer, leading to multiple pulmonary metastases, and silicosis can contribute to the carcinogenesis of lung cancer. This case provided valuable clinical lessons. More studies are warranted to elucidate the role and underlying mechanism of silicosis and STAS in the development of lung cancer. More accurate imaging methods and radiographic criteria should be formulated for different diffuse nodules and STAS grades, and the exploration of optimal therapeutic regimens to treat these concomitant patients is urgently needed to improve diagnostic rates and formulate more optimal therapies.

Ferroptosis is a new non-apoptotic cell death caused by the accumulation of dysregulated metabolism of ferric iron, amino acids or lipid peroxidation. Increasing studies suggest that ferroptosis is involved in the acute lung injury (ALI). This article aims to review the role of ferroptosis in ALI. ALI is a common respiratory disease and presents a high mortality rate. Inhibiting cell ferroptosis of lung improves the ALI. In addition, several signaling pathways are related to ferroptosis in ALI, involving in iron homeostasis, lipid peroxidation, and amino acid metabolism. Moreover, there are various key factors to regulate the occurrence of ferroptosis in ALI, such as ACSL4, NRF2, and P53. The ACSL4 promotes the ferroptosis, while the NRF2 alleviates the ferroptosis in ALI. The main effect of P53 is to promote ferroptosis. Accordingly, ferroptosis is involved in ALI and may be an important therapeutic target for ALI.

A growing number of studies have shown the prognostic importance of Cell division cycle protein 45 (CDC45) in hepatocellular carcinoma (HCC). This study aims to investigate the biological function and mechanism of CDC45 in HCC. The differential expression and prognostic significance of CDC45 in HCC and normal tissues were analyzed by bioinformatics. CDC45 was knocked down and the biological effects of CDC45 in HCC in vitro and in vivo were measured. Subsequently, using RNA m6A colorimetry and Methylated RNA Immunoprecipitation (MeRIP), the levels of m6A modification of total RNA and CDC45 were evaluated in cells. RIP was applied to establish that CDC45 and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) interact. A test using actinomycin D was performed to gauge the stability of the CDC45 mRNA. Furthermore, the regulatory role of IGF2BP2 on CDC45 expression in HCC progression was explored by overexpressing IGF2BP2. High expression of CDC45 was correlated with poor prognosis in HCC patients. Knocking down CDC45 inhibited HCC cell proliferation, migration, invasion, EMT, stemness, and glycolysis, and promoted apoptosis, which was verified through in vitro experiments. Additionally, IGF2BP2 was highly expressed in HCC cells, and it was found to interact with CDC45. Knocking down IGF2BP2 resulted in reduced stability of CDC45 mRNA. Moreover, overexpression of IGF2BP2 promoted HCC cell proliferation, migration, invasion, EMT, stemness, and glycolysis, while inhibiting apoptosis, which was reversed by knocking down CDC45. In general, IGF2BP2 promoted HCC glycolysis and stemness by stabilizing CDC45 mRNA via m6A modification. [Figure: see text].

Gallbladder cancer (GBC) is a major malignant carcinoma of the biliary tract with extremely poor prognosis. Currently, there is no useful therapy strategies for GBC treatment, indicating the unmet mechanism researches for GBC. In this study, our data showed that SNHG15 expression significantly up-regulated and its high expression associated with poor overall survival of patients suffer from GBC. Functional experiments showed that SNHG15 depletion delayed the proliferation and enhanced the apoptosis of GBC tumor cells under the nutrition stress condition, which further confirmed in the subcutaneous xenograft model and liver metastasis model. Mechanistically, SNHG15 could interact with AMPK and facilitate the phosphorylation of AMPK to Tuberous sclerosis complex TSC2, resulting in mTOR suppression and autophagy enhancement, and finally, conferring the GBC cell sustain proliferation under nutrition stress. Taken together, our findings revealed that SNHG15 promotes GBC tumor progression by enhancing the autophagy under poor nutrition tumor microenvironment, which could be a promising targets for GBC.

Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that stimulate the ERK pathway. Aberrantly high ERK activation triggers oncogene-induced senescence, which halts tumor progression. Here we report that low-grade pancreatic intraepithelial neoplasia displays very high levels of phospho-ERK consistent with a senescence response. However, advanced lesions that have circumvented the senescence barrier exhibit lower phospho-ERK levels. Restoring ERK hyperactivation in PDAC using activated RAF leads to ERK-dependent growth arrest with senescence biomarkers. ERK-dependent senescence in PDAC was characterized by a nucleolar stress response including a selective depletion of nucleolar phosphoproteins and intranucleolar foci containing RNA polymerase I designated as senescence-associated nucleolar foci (SANF). Accordingly, combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response in PDAC cells. Notably, comparable mechanisms were observed upon treatment with the platinum-based chemotherapy regimen FOLFIRINOX, currently a first-line treatment option for PDAC. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.

Mounting evidence indicates the potential involvement of ATP-citrate lyase (ACLY) in the modulation of various cancer types. Nevertheless, the precise biological significance of ACLY in gastric cancer (GC) remains elusive. This study sought to elucidate the biological function of ACLY and uncover its influence on peritoneal metastasis in GC. The expression of ACLY was assessed using both real-time quantitative PCR and western blot techniques. To investigate the impact of ACLY on the proliferation of gastric cancer (GC) cells, colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assays were performed. The migratory and invasive abilities of GC were evaluated using wound healing and transwell assays. Additionally, a bioinformatics analysis was employed to predict the correlation between ACLY and HIF-1A. This interaction was subsequently confirmed through a chromatin immunoprecipitation (ChIP) assay. ACLY exhibited upregulation in gastric cancer (GC) as well as in peritoneal metastasis. Its overexpression was found to facilitate the proliferation and metastasis of GC cells in both in vitro and in vivo experiments. Moreover, ACLY was observed to play a role in promoting angiogenesis and epithelial-mesenchymal transition (EMT). Notably, under hypoxic conditions, HIF-1A levels were elevated, thereby acting as a transcription factor to upregulate ACLY expression. Under the regulatory influence of HIF-1A, ACLY exerts a significant impact on the progression of gastric cancer, thereby facilitating peritoneal metastasis.

A normal somatic cell undergoes cycles of finite cellular divisions. The presence of surveillance checkpoints arrests cell division in response to stress inducers: oxidative stress from excess free radicals, oncogene-induced abnormalities, genotoxic stress, and telomere attrition. When facing such stress when undergoing these damages, there is a brief pause in the cell cycle to enable repair mechanisms. Also, the nature of stress determines whether the cell goes for repair or permanent arrest. As the cells experience transient or permanent stress, they subsequently choose the quiescence or senescence stage, respectively. Quiescence is an essential stage that allows the arrested/damaged cells to go through appropriate repair mechanisms and then revert to the mainstream cell cycle. However, senescent cells are irreversible and accumulate with age, resulting in inflammation and various age-related disorders. In this review, we focus on senescence-associated pathways and therapeutics understanding cellular senescence as a cascade that leads to aging, while discussing the recent details on the molecular pathways involved in regulating senescence and the benefits of therapeutic strategies against accumulated senescent cells and their secretions.