Journal of Biomedical Research最新文献

Glioblastoma multiforme (GBM) is a highly aggressive and lethal brain tumor with limited treatment options. To improve therapeutic efficacy, we developed a novel multifunctional nanoplatform, GM@P(T/S), comprised of polymeric nanoparticles coated with GBM cell membranes as well as co-loaded with temozolomide (TMZ) and superparamagnetic iron oxide (SPIO) nanoparticles. The successful preparation was confirmed in terms of particle size, morphology, stability, the in vitro drug release, and cellular uptake assays. We demonstrated that GM@P(T/S) exhibited the enhanced homotypic targeting, the prolonged blood circulation, and efficient blood-brain barrier penetration in both in vitro and in vivo studies. The combination of TMZ and SPIO nanoparticles within GM@P(T/S) synergistically improved chemo-radiation therapy, leading to a reduced tumor growth, an increased survival, and minimal systemic toxicity in the orthotopic GBM mouse models. Our findings suggest that GM@P(T/S) holds a great promise as a targeted and efficient therapeutic strategy for GBM.

Given the extremely high inter-patient heterogeneity of acute myeloid leukemia (AML), the identification of biomarkers for prognostic assessment and therapeutic guidance is critical. Cell surface markers (CSMs) have been shown to play an important role in AML leukemogenesis and progression. In the current study, we evaluated the prognostic potential of all human CSMs in 130 AML patients from The Cancer Genome Atlas (TCGA) based on differential gene expression analysis and univariable Cox proportional hazards regression analysis. By using multi-model analysis, including Adaptive LASSO regression, LASSO regression, and Elastic Net, we constructed a 9-CSMs prognostic model for risk stratification of the AML patients. The predictive value of the 9-CSMs risk score was further validated at the transcriptome and proteome levels. Multivariable Cox regression analysis showed that the risk score was an independent prognostic factor for the AML patients. The AML patients with high 9-CSMs risk scores had a shorter overall and event-free survival time than those with low scores. Notably, single-cell RNA-sequencing analysis indicated that patients with high 9-CSMs risk scores exhibited chemotherapy resistance. Furthermore, PI3K inhibitors were identified as potential treatments for these high-risk patients. In conclusion, we constructed a 9-CSMs prognostic model that served as an independent prognostic factor for the survival of AML patients and held the potential for guiding drug therapy.

Premature ovarian insufficiency (POI) caused by chemotherapy is a common complication in female cancer survivors of childbearing age. Traditional methods, including mesenchymal stem cell (MSC) transplant and hormone replacement therapy, have limited clinical application because of their drawbacks, and more methods need to be developed. In the current study, the potential effects and underlying mechanisms of human umbilical cord MSC-derived extracellular vesicles (hUCMSC-EVs) were investigated in a cisplatin (CDDP)-induced POI mouse model and a human granulosa cell (GC) line. The results showed that hUCMSC-EVs significantly attenuated body weight loss, ovarian weight loss, ovary atrophy, and follicle loss in moderate-dose (1.5 mg/kg) CDDP-induced POI mice, similar to the effects observed with hUCMSCs. We further found that the hUCMSC-EVs inhibited CDDP-induced ovarian GC apoptosis by upregulating anti-apoptotic miRNA levels in GCs, thereby downregulating the mRNA levels of multiple pro-apoptotic genes. In general, our findings indicate that the moderate-dose chemotherapy may be a better choice for clinical oncotherapy, considering effective rescue of the oncotherapy-induced ovarian damage with hUCMSC-EVs. Additionally, multiple miRNAs in hUCMSC-EVs may potentially be used to inhibit the chemotherapy-induced ovarian GC apoptosis, thereby restoring ovarian function and improving the life quality of female cancer patients.

The KCNQ family of genes ( KCNQ1- KCNQ5), encoding voltage-gated K ⁺ (Kv) channels, have been demonstrated to play potential pathophysiological roles in cancers. However, the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear. In this study, a large-scale cohort comprising 1135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival (OS). Based on the survival evaluation of all five KCNQ family genes, KCNQ1 was selected for subsequent genetic analysis. In both Cox regression model and stepwise Cox regression model used to evaluate survival-related genetic variants, we found that KCNQ1 rs10832417G>T was associated with an increased OS in gastric cancer patients (adjusted hazards ratio [HR] = 0.84, 95% confidence interval [CI]: 0.72-0.98, P = 0.023). Subsequently, a nomogram was constructed to enhance the prognostic capacity and clinical translation of rs10832417 variants. The rs10832417 T allele was predicted to increase the minimum free energy of the secondary structure. Furthermore, we observed that gastric cancer patients with downregulated KCNQ1 expression had a poorer survival across multiple public datasets. The findings of the present study indicate that KCNQ1 rs10832417 may serve as an independent prognostic predictor of gastric cancer, providing novel insights into the progression and survival of the disease.

The abnormality of the p53 tumor suppressor is crucial in lung cancer development, because p53 regulates target gene promoters to combat cancer. Recent studies have shown extensive p53 binding to enhancer elements. However, whether p53 exerts a tumor suppressor role by shaping the enhancer landscape remains poorly understood. In the current study, we employed several functional genomics approaches to assess the enhancer activity at p53 binding sites throughout the genome based on our established TP53 knockout (KO) human bronchial epithelial cells (BEAS-2B). A total of 943 active regular enhancers and 370 super-enhancers (SEs) disappeared upon the deletion of p53, indicating that p53 modulates the activity of hundreds of enhancer elements. We found that one p53-dependent SE, located on chromosome 9 and designated as KLF4-SE, regulated the expression of the Krüppel-like factor 4 ( KLF4) gene. Furthermore, the deletion of p53 significantly decreased the KLF4-SE enhancer activity and the KLF4 expression, but increased colony formation ability in the nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced cell transformation model. Subsequently, in TP53 KO cells, the overexpression of KLF4 partially reversed the increased clonogenic capacity caused by p53 deficiency. Consistently, KLF4 expression also decreased in lung cancer tissues and cell lines. It appeared that overexpression of KLF4 significantly suppressed the proliferation and migration of lung cancer cells. Collectively, our results suggest that the regulation of enhancer formation and activity by p53 is an integral component of the p53 tumor suppressor function. Therefore, our findings offer some novel insights into the regulation mechanism of p53 in lung oncogenesis and introduce a new strategy for screening therapeutic targets.

The extensive spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout China in late 2022 has underscored the correlation between this virus and severe psychiatric disorders. However, there remains a lack of reported clinical and pathological features. Accordingly, we retrospectively reviewed the electronic medical records of psychiatric inpatients for seven days from early January 2023. Twenty-one inpatients who developed first-episode psychiatric disorders within two weeks after SARS-CoV-2 infection were recruited, while 24 uninfected first-episode psychiatric inpatients were selected as controls. Comparative analyses of clinical manifestations, routine laboratory tests, and imaging examinations were performed. Our investigation demonstrated a 330% increase in the incidence of first-episode psychiatric inpatients after SARS-CoV-2 infection in 2023, compared with the preceding year without SARS-CoV-2 infections. Most cases exhibited psychiatric symptoms within one week of SARS-CoV-2 infection, which resolved after approximately two weeks, with no residual symptoms after three months. One-way ANOVA demonstrated a significant difference in the highest fever temperature between inpatients with and without psychotic symptoms. Infected inpatients displayed elevated levels of interleukin-4, interleukin-8, and interferon-α, but decreased levels of eosinophils and basophils. These findings suggest that SARS-CoV-2 may contribute to the development of psychiatric disorders, likely mediated by the virus-induced inflammatory response and neuronal dysfunction in the context of psychological distress.

Liquid-liquid phase separation, a novel biochemical phenomenon, has been increasingly studied for its medical applications. It underlies the formation of membrane-less organelles and is involved in many cellular and biological processes. During transcriptional regulation, dynamic condensates are formed through interactions between transcriptional elements, such as transcription factors, coactivators, and mediators. Cancer is a disease characterized by uncontrolled cell proliferation, but the precise mechanisms underlying tumorigenesis often remain to be elucidated. Emerging evidence has linked abnormal transcriptional condensates to several diseases, especially cancer, implying that phase separation plays an important role in tumorigenesis. Condensates formed by phase separation may have an effect on gene transcription in tumors. In the present review, we focus on the correlation between phase separation and transcriptional regulation, as well as how this phenomenon contributes to cancer development.

Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) is known to play a critical role in the development of gastric cancer, but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk. By using the genome-wide association study data from the database of Genotype and Phenotype (dbGAP), we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583 G>C in C1GALT1 was associated with gastric cancer risk (odds ratio, 0.83; 95% confidence interval [CI], 0.75-0.92; P = 3.95 × 10 ^-4). C1GALT1 mRNA expression levels were significantly higher in gastric tumor tissues than in normal tissues, and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates (hazards ratio, 1.33; 95% CI, 1.05-1.68; P _log-rank = 1.90 × 10 ^-2). Furthermore, we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4 ⁺ T cells and macrophages. These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 into a promising predictor of gastric cancer susceptibility and immune status.

The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia. Therefore, macrophage-based therapeutic targets need to be explored for ischemic disease. In the current study, we found that the mRNA levels of scavenger receptor A1 ( Sr-a1) were elevated in patients with critical limb ischemia, based on an analysis of the Gene Expression Omnibus data. We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia (HLI) model. Compared with the Sr-a1 ^fl/fl mice, the Lyz ^Cre/+/ Sr-a1 ^flox/flox ( Sr-a1 ^ΔMΦ) mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI. Consistently, histological analysis revealed that the ischemic limb of the Sr-a1 ^ΔMΦ mice exhibited more severe and prolonged necrotic morphology, inflammation, fibrosis, decreased vessel density, and delayed regeneration than that of the control Sr-a1 ^fl/fl mice. Furthermore, restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI. Consistent with these in vivo findings, co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1 ^-/- bone marrow macrophages significantly inhibited myoblast differentiation in vitro. Mechanistically, SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation. These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.

Glioblastoma (GBM) is a highly vascularized malignant brain tumor with poor clinical outcomes. Vasculogenic mimicry (VM) formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to the failure of anti-angiogenic therapy. To date, there is still a lack of effective drugs that target VM formation in GBM. In the present study, we evaluated the effects of the plant cyclopeptide moroidin on VM formed by GBM cells and investigated its underlying molecular mechanisms. Moroidin significantly suppressed cell migration, tube formation, and the expression levels of α-smooth muscle actin and matrix metalloproteinase-9 in human GBM cell lines at sublethal concentrations. The RNA sequencing data suggested the involvement of the epithelial-mesenchymal transition (EMT) pathway in the mechanism of moroidin. Exposure to moroidin led to a concentration-dependent decrease in the expression levels of the EMT markers N-cadherin and vimentin in GBM cells. Moreover, moroidin significantly reduced the level of phosphorylated extracellular signal-regulated protein kinase (p-ERK) and inhibited the activation of β-catenin. Finally, we demonstrated that the plant cyclopeptide moroidin inhibited VM formation by GBM cells through inhibiting the ERK/β-catenin-mediated EMT. Therefore, our study indicates a potential application of moroidin as an anti-VM agent in the treatment of GBM.