Although various malignant tumors have been associated with the aberrant expression of Neural Epidermal Growth Factor-Like 2 (NELL2), its involvement in hepatocellular carcinoma (HCC) has not been previously documented. In this study, NELL2, recognized as a crucial tumor-suppressor gene, was found to be infrequently expressed in HCC. In vitro experiments demonstrated that the overexpression of NELL2 significantly inhibited the proliferation, migration, and invasion of liver cancer cells, whereas the suppression of NELL2 markedly enhanced these oncogenic properties. Further investigation revealed that NELL2 impedes epithelial-mesenchymal transition (EMT) via the Notch signaling pathway. Inhibition of the Notch pathway reversed the increased tumor proliferation, migration, and invasion observed following the downregulation of NELL2 expression. Notably, gene enrichment analysis and in vitro studies indicated that NELL2 effectively induced ferroptosis in HCC cells, as evidenced by increased levels of cellular malondialdehyde (MDA), iron, and Reactive Oxygen Species (ROS), alongside decreased glutathione (GSH) levels. The blockade of the Notch signaling pathway substantially diminished NELL2’s capacity to induce ferroptosis. In summary, our findings suggest that NELL2 modulates the Notch signaling pathway to inhibit EMT and promote ferroptosis. Consequently, NELL2 may serve as a novel therapeutic target, potentially functioning as a tumor suppressor gene in HCC.

Colon cancer is a common cancer with high mortality globally. The role of chondroitin polymerizing factor (CHPF) has been elucidated in various cancers. However, its role and mechanism remain unknown in colon cancer. CHPF expression was examined by GEPIA database, reverse transcription-quantitative polymerase chain reaction and western blot. The relationship between CHPF expression and the clinicopathologic characteristics as well as miR-214-3p level was determined in colon cancer patients. The role and mechanism of CHPF in the growth, ferroptosis, and glycolysis of colon cancer cells were evaluated by cell counting kit-8, biochemical detections, luciferase, and western blot experiments. Additionally, the role of CHPF was explored in xenografted mice. CHPF expression was increased and was related to advanced TNM stage, poor differentiation and shorter overall survival in patients with colon cancer. Knockdown of CHPF inhibited colon cancer cell growth, and downregulated the expression of proteins involving in ferroptosis and glycolysis both in vitro and in vivo. Besides, CHPF silencing increased the levels of ferrous iron and ROS, but decreased glucose uptake, lactate product, and ATP level in vitro. Mechanically, miR-214-3p directly targeted CHPF and negatively regulated its expression. Upregulation of miR-214-3p reduced cell viability, glucose uptake, lactate product, and ATP level, but increased the levels of ferrous iron and ROS, which were reversed by the overexpression of CHPF. Upregulation of CHPF predicted poor prognosis, and miR-214-3p/CHPF axis inhibited growth, downregulated the levels of glycolysis-related indexes, and promoted ferroptosis in colon cancer cells.

ObjectiveRecently, 10 plasmid-mediated mobile colistin resistance genes, mcr-1 to mcr-10, and their variants have been identified, posing a new threat to the treatment of clinical infections caused by Gram-negative bacteria. Our objective was to develop a rapid, sensitive, and accurate molecular assay for detecting mcr genes in clinical isolates.MethodsThe primers and corresponding TaqMan-MGB probes were designed based on the sequence characteristics of all reported MCR family genes, multiplex Taqman-MGB probe-based qPCR assays were developed and optimized, and the sensitivity, specificity and reproducibility of the method were evaluated. The assay contained 8 sets of primers and probes in 4 reaction tubes, each containing 2 sets of primers and probes.ResultsThe standard curves for both the single and multiplex systems showed good linearity (R2 > 0.99) between the starting template amount and the Ct value, with a lower limit of detection of 102 copies/μL. The specificity test showed positive amplification results only for strains containing the mcr genes, whereas the other strains were negative. The results of intra-and inter-group repeatability experiments demonstrated the stability and reliability of the newly developed method. It was used to detect mcr genes in 467 clinically-obtained Gram-negative isolates, which were multidrug-resistant. Twelve strains containing the mcr genes were detected (seven isolates carrying mcr-1, four isolates carrying mcr-10, and one isolate carrying mcr-9). The products amplified by the full-length PCR primer were identified by sequencing, and the results were consistent with those of the multiplex qPCR method.ConclusionThe assay developed in this study has the advantages of high specificity, sensitivity, and reproducibility. It can be used to specifically detect drug-resistant clinical isolates carrying the mcr genes (mcr-1 to mcr-10), thus providing a better basis for clinical drug treatment and drug resistance research.

Activating transcription factor 4 (ATF4) is an adaptive response regulator of metabolic and oxidative homeostasis. In response to cellular stress, ATF4 is activated and functions as a regulator to promote cell adaptation for survival. As a transcriptional regulator, ATF4 also widely participates in the regulation of amino acid metabolism, autophagy, redox homeostasis and endoplasmic reticulum stress. Moreover, ATF4 is associated with the initiation and progression of glioblastoma, hepatocellular carcinoma, colorectal cancer, gastric cancer, breast cancer, prostate cancer and lung cancer. This review primarily aims to elucidate the functions of ATF4 and its role in multiple cancer contexts. This review proposes potential therapeutic targets for clinical intervention.

Dysregulation of splicing factor expression plays a crucial role in the progression of hepatocellular carcinoma (HCC). Our research found that the expression level of splicing factor ZMAT2 was increased in HCC, promoting the proliferation of HCC cells. RNAseq data indicated that the absence of ZMAT2 induced skipping exon of mRNA, while RIPseq data further revealed the mRNA binding motifs of ZMAT2. A comprehensive analysis of RNAseq and RIPseq data indicateed that ZMAT2 played a crucial role in the maturation process of TRIM28 mRNA. Knocking down of ZMAT2 led to the deletion of 25 bases in exon 11 of TRIM28, ultimately resulting in nonsense-mediated decay (NMD). Our data revealed that ZMAT2 could regulate TRIM28 to reduce the accumulation of ROS in HCC cells, thereby promoting their proliferation. Our research also discovered that ZMAT2 was capable of undergoing phase separation, resulting in the formation of liquid droplet condensates within HCC cells. Additionally, it was found that ZMAT2 was able to form protein-nucleic acid condensates with TRIM28 mRNA. In summary, this study is the first to reveal that ZMAT2 and TRIM28 mRNA form protein-nucleic acid condensates, thereby regulating the splicing of TRIM28 mRNA. The increased expression of ZMAT2 in HCC leads to upregulated TRIM28 expression and reduced ROS accumulation, ultimately accelerating the proliferation of HCC cells.

Thyroid cancer, as one of the most common cancers in many countries, has attracted increasing attention, but its pathogenesis is still unclear. This research explored the effects of miR-144-3p and GABRB2 on thyroid cancer cells and the underlying mechanism. Gene expression data was obtained from the GEO database to analyze differential expression of mRNAs and miRNAs in patients with thyroid cancer. CCK-8, transwell, scratch, and flow cytometry assays were performed to detect cell proliferation, invasion, migration, and apoptosis, respectively. Dual-luciferase reporters were used to detect the binding of miR-144-3p to GABRB2. GABRB2 was highly expressed and miR-144-3p was underexpressed in thyroid cancer. In thyroid cancer cells, inhibiting GABRB2 or upregulating miR-144-3p reduced proliferation, invasion, and migration and increased apoptotic rates; GABRB2 overexpression or miR-144-3p inhibition brought about the opposite results. miR-144-3p targeted GABRB2 and negatively regulated its expression. PI3K/AKT activation was reduced in thyroid cancer cells overexpressing miR-144-3p. GABRB2 overexpression partially mitigated the tumor-suppressive effect of miR-144-3p overexpression. In conclusion, miR-144-3p targets GABRB2 to inhibit PI3K/AKT activation, thereby inhibiting the progression of thyroid cancer in vitro.

Abstract Background: During the early stages after diagnosis, the time impact of radiotherapy and chemotherapy on the occurrence of fatal cardiac disease in lung cancer patients has received limited research attention. Patients and methods: Lung cancer patient data was obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Propensity-score matching methods were employed to equalize baseline confounding. The training set was utilized to construct a time-dependent (time cut = 6 months) Cox regression model and a Random survival forest model, whereas the test set was employed for model validation. The discrimination and accuracy of the model were assessed using the Concordance Index and the Integrated Brier score. Results: A total of 49,294 patients diagnosed with lung cancer between 2018 and 2019 were included in the analysis. Propensity score-matched analyses, accounting for important confounding covariates, demonstrated that patients who received CT only, RT only, or CT plus RT had significantly improved CHH-specific survival compared to those who did not receive CT and RT (P <0.001). Cox regression analysis indicated that within the first 6 months, RT and CT (P <0.001) independently acted as protective factors against CHH-specific mortality, while RT plus CT (P <0.001) was identified as an independent risk factor. At 6 months or later, RT (P <0.05) emerged as an independent risk factor, while the impact of CT on CHH-specific mortality became statistically insignificant compared to the initial six months. The results of the Rsf analysis indicated that the variables in descending order of importance were CT, RT, and CT plus RT. Additionally, independent risk factors included the year of diagnosis, T4, Stage Group, and Msite brain (P <0.05). Conclusions: These findings establish a critical time frame to raise awareness regarding the risk of CHH-specific death in lung cancer during the early post-diagnostic period.

This study aimed to investigate the role of ERG in the HLX/STAT4/Perforin signaling axis, impacting natural killer (NK) cell cytotoxicity and myocardial infarction (MI) progression. NK cell cytotoxicity was assessed via co-culture and 51Cr release assays. Datasets GSE34198 and GSE97320 identified common differentially expressed genes in MI. NK cell gene expression was analyzed in MI patients and healthy individuals using qRT-PCR and Western blotting. ERG's regulation of HLX and STAT4's regulation of perforin were studied through computational tools (MEM) and ChIP experiments. HLX's influence on STAT4 was explored with the MG132 proteasome inhibitor. Findings were validated in a mouse MI model. ERG, a commonly upregulated gene, was identified in NK cells from MI patients and mice. ERG upregulated HLX, leading to STAT4 proteasomal degradation and reduced Perforin expression. Consequently, NK cell cytotoxicity decreased, promoting MI progression. ERG mediates the HLX/STAT4/Perforin axis to inhibit NK cell cytotoxicity, fostering MI progression. These results provide vital insights into MI's molecular mechanisms.

Epidemiological studies have reported that among participants with impaired cognitive, overweight and mild obesity are associated with substantially improved survival, this finding has been termed the “obesity paradox” and has led to uncertainty about secondary prevention. To explore whether the association of BMI with mortality differed in different MMSE score, and whether the obesity paradox in patient with cognitive impairment (CI) is real. The study used data from CLHLS, a representative prospective population-based cohort study in China, which included 8348 participants aged ≥ 60 years between 2011 and 2018. The independent association between BMI and mortality in differed MMSE score by calculating hazard ratios (HRs) in multivariate Cox regression analysis. During a median (IQR) follow-up of 41.18 months, a total of 4216 participants died. In the total population, underweight increased the risk of all-cause mortality (HRs, 1.33; 95

Objective Cognitive impairment (CI) has been demonstrated as a useful proxy measure of mortality in Western populations. However, the predictive value of CI in Chinese populations is unknown. We aimed to explore whether CI is independently associated with increased long-term all-cause and cardiovascular disease (CVD) mortality in Chinese older adults and the association of performance in specific MMSE sub-domains to subsequent mortality. Methods and results A total of 4,499 older adults [mean (SD) age, 70.3(6.7) years] who received a sample investigation from 2011 to 2014 were followed up till 2021 for mortality. The Mini-Mental State Examination was used to assess cognitive function, and Cox's proportional hazard models were used to evaluate the effects of cognitive function on the risk of all-cause and CVD mortality. Demographic characteristics, lifestyle, and health status were included as covariates. During a 10-year follow-up, a total of 667 (14.8%) died. In the fully adjusted model, compared with cognitively normal participants with CI had a 1.33-fold [HR, 1.33; (95% CI, 1.10–1.61)] greater risk of all-cause mortality and a 1.45-fold [HR, 1.45; (95% CIs, 1.11–1.92)] greater risk of CVD mortality. After a similar multivariable adjustment, a per-SD increase in MMSE scores was associated with a reduced risk of all-cause mortality [HR, 0.85; (95% CI, 0.78–0.93)] and CVD mortality [HR, 0.74; (95% CI, 0.65–0.84)]. In the unadjusted model, MMSE sub-domains (apart from immediate recall) were associated with mortality. But only orientation and calculation and attention were still independently associated with all-cause and CVD mortality in a multivariable model. Conclusion These findings confirmed that CI is a marker of all-cause and CVD mortality risk in Chinese older adults, independently of other commonly assessed risk factors, and some sub-domains of the MMSE may have stronger associations with mortality. Further research is needed to identify the mechanisms underlying the observed associations.

Background Diabetes mellitus (DM) or cognitive impairment (CI) is known to be strongly associated with mortality. DM commonly coexists with CI and proportionally increases with age. However, little is known about the combined effect of cognitive function and diabetes on mortality. This study aimed to evaluate the combined effects of DM and CI on all-cause and cause-specific mortality in Chinese older adults. Methods This prospective population-based cohort study was based on the Beijing Elderly Comprehensive Health Cohort Study. A total of 4,499 older adults were included. Cox’s proportional hazard models were utilized to calculate the effect of DM and CI on all-cause, cardiovascular disease (CVD) mortality and cancer mortality, and a multiplicative term was introduced to study a potential interaction between DM and CI on outcomes. Results During a median follow-up of 6.8 years (ranging from 6.6 to 11.7 years), 667 (14.8%) participants died from all causes, 292 from CVD, and 215 from cancer. In the fully adjusted model, participants with coexisting DM and CI had the highest risk of all-cause mortality [hazard ratios (HRs), 3.08; 95% confidence intervals (CIs), 2.30,4.11] and CVD mortality (HRs, 3.85; 95% CIs, 2.60,5.71) compared with individuals with normal cognition and non-DM. We also found a multiplicative interaction between DM and CI in respect to all-cause (HRs, 2.46; 95% CI, 1.87,3.22) and CVD mortality (HRs, 3.15 95% CI, 2.19,4.55). In the diabetic population, CI was associated with an increased risk of all-cause mortality (HRs, 2.09; 95% CIs, 1.51,2.89) and CVD mortality (HRs, 3.16; 95% CIs, 2.02,5.05) compared with the normal cognition group. Restricted cubic spline revealed a linear inverse association between Mini-Mental State Examination (MMSE) score and all-cause, CVD mortality in the total sample and participants without diabetes. However, a nearly reverse J association was observed between MMSE and mortality from all causes and CVD in the diabetes group. Conclusion The findings highlighted that cognitive impairment concomitant with diabetes further increases the risk of mortality. In addition to strengthening routine screening of cognitive functioning in older adults with early-stage diabetes, more extensive assessment of prognostic risks has high clinical value for developing comprehensive treatment plans.

Many studies have found that the dysregulation of long noncoding RNA (lncRNA) contributed to cancer initiation, progression, and recurrence via multiple signaling pathways. However, the underlying mechanisms of lncRNA in temozolomide (TMZ)-resistant gliomas were not well understood, hindering the improvement of TMZ-based therapies. The present study demonstrated that the lncRNA KCNQ1OT1 increased in TMZ-resistant glioma cells compared to the TMZ-sensitive cells. The introduction of KCNQ1OT1 promoted cell viability, clonogenicity, and rhodamine 123 efflux while hampering TMZ-induced apoptosis. Moreover, KCNQ1OT1 directly sponged miR-761, which decreased in TMZ-resistant sublines. The overexpression of miR-761 attenuated cell viability and clonogenicity, while triggering apoptosis and rhodamine 123 accumulation post-TMZ exposure, leading to a response to TMZ. The interaction between miR-761 and 3′-untranslated region of PIM1 attenuated PIM1-mediated signaling cascades. Furthermore, the knockdown of KCNQ1OT1 augmented the TMZ-induced tumor regression in TMZ-resistant U251 mouse models. Briefly, the present study evaluated that KCNQ1OT1 conferred TMZ resistance by releasing PIM1 expression from miR-761, resulting in the upregulation of PIM-mediated MDR1, c-Myc, and Survivin. The present findings demonstrated that the interplay of KCNQ1OT1: miR-761: PIM1 regulated chemoresistance in gliomas and provided a promising therapeutic target for TMZ-resistant glioma patients.

Glioblastomas (GBMs) are the most frequent primary malignancies in the central nervous system. Aberrant activation of WNT/β-catenin signaling pathways is critical for GBM malignancy. However, the regulation of WNT/β-catenin signaling cascades remains unclear. Presently, we observed the increased expression of ZEB2 and the decreased expression of miR-637 in GBM. The expression of miR-637 was negatively correlated with ZEB2 expression. miR-637 overexpression overcame the ZEB2-enhanced cell proliferation and G1/S phase transition. Besides, miR-637 suppressed the canonical WNT/β-catenin pathways by targeting WNT7A directly. Gain- and loss-of-function experiments with U251 mice demonstrated that miR-637 inhibited cell proliferation and arrested the G1/S phase transition, leading to tumor growth suppression. The collective findings suggest that ZEB2 and WNT/β-catenin cascades merge at miR-637, and the ectopic expression of miR-637 disturbs ZEB2/WNT/β-catenin-mediated GBM growth. The findings provide new clues for improving β-catenin-targeted therapy against GBM.

Nuclear receptor coactivator 4 mediated ferritinophagy is an autophagic phenomenon that specifically involves ferritin to release intracellular free iron. Ferritinophagy is implicated in maintaining efficient erythropoiesis. Notably, ferritinophagy also plays a central role in driving some pathological processes, including Parkinson’s disease (PD) and urinary tract infections. Some evidence has demonstrated that ferritinophagy is critical to induce ferroptosis. Ferroptosis is a newly nonapoptotic form of cell death, characterized by the accumulation of iron‐based lipid reactive oxygen species. Ferroptosis plays an important role in inhibiting some types of cancers, such as hepatocellular carcinoma, pancreatic carcinoma, prostate cancer, and breast cancer. Conversely, the activation of ferroptosis accelerates neurodegeneration diseases, including PD and Alzheimer’s disease. Therefore, in this review, we summarize the regulatory mechanisms related to ferritinophagy and ferroptosis. Moreover, the distinctive effects of ferritinophagy in human erythropoiesis and some pathologies, coupled with the promotive or inhibitory role of tumorous and neurodegenerative diseases mediated by ferroptosis, are elucidated. Obviously, activating or inhibiting ferroptosis could be exploited to achieve desirable therapeutic effects on diverse cancers and neurodegeneration diseases. Interrupting ferritinophagy to control iron level might provide a potentially therapeutic avenue to suppress urinary tract infections.