Tumor‐associated macrophages (TAMs) are vital constituents in mediating cell‐to‐cell communication within the tumor microenvironment. However, the molecular mechanisms underlying the interplay ...between TAMs and tumor cells that guide cell fate are largely undetermined. Extracellular vesicles, also known as exosomes, which are derived from TAMs, are the components exerting regulatory effects. Thus, understanding the underlying mechanism of “onco‐vesicles” is of crucial importance for prostate cancer (PCa) therapy. In this study, we analyzed micro RNA sequences in exosomes released by THP‐1 and M2 macrophages and found a significant increase in miR‐95 levels in TAM‐derived exosomes, demonstrating the direct uptake of miR‐95 by recipient PCa cells. In vitro and in vivo loss‐of‐function assays suggested that miR‐95 could function as a tumor promoter by directly binding to its downstream target gene, JunB, to promote PCa cell proliferation, invasion, and epithelial–mesenchymal transition. The clinical data analyses further revealed that higher miR‐95 expression results in worse clinicopathological features. Collectively, our results demonstrated that TAM‐mediated PCa progression is partially attributed to the aberrant expression of miR‐95 in TAM‐derived exosomes, and the miR‐95/JunB axis provides the groundwork for research on TAMs to further develop more‐personalized therapeutic approaches for patients with PCa.
Our results demonstrated that TAM‐mediated prostate cancer (PCa) progression is partially attributed to the aberrant expression of miR‐95 in TAM‐derived exosomes, and the miR‐95/JunB axis provides the groundwork for research on tumor‐associated macrophages (TAMs) to further develop more‐personalized therapeutic approaches for patients with PCa.
Patients with type 2 diabetes (T2D) have decreased butyrate-producing bacteria. We hypothesized that supplementation with butyrate-producing bacteria may exert beneficial effects on T2D. The current ...study investigated the effects of well-characterized butyrate-producing bacteria Clostridium butyricum CGMCC0313.1 (CB0313.1) on hyperglycemia and associated metabolic dysfunction in two diabetic mouse models. CB0313.1 was administered daily by oral gavage to leptin
mice for 5 weeks starting from 3 weeks of age, and to HF diabetic mice induced by high fat diet (HFD) plus streptozotocin (STZ) in C57BL/6J mice for 13 weeks starting from 4 weeks of age. CB0313.1 improved diabetic markers (fasting glucose, glucose tolerance, insulin tolerance, GLP-1 and insulin secretion), and decreased blood lipids and inflammatory tone. Furthermore, CB0313.1 reversed hypohepatias and reduced glucose output. We also found that CB0313.1 modulated gut microbiota composition, characterized by a decreased ratio of Firmicutes to Bacteroidetes, reduced Allobaculum bacteria that were abundant in HF diabetic mice and increased butyrate-producing bacteria. Changes in gut microbiota following CB0313.1 treatment were associated with enhanced peroxisome proliferator-activated receptor-γ (PPARγ), insulin signaling molecules and mitochondrial function markers. Together, our study suggests that CB0313.1 may act as a beneficial probiotic for the prevention and treatment of hyperglycemia and associated metabolic dysfunction.
Ferredoxin 1 (FDX1) functions by transferring electrons from NADPH to mitochondrial cytochrome P450 via the ferredoxin reductase and is the key regulator in copper-dependent cell death. Although ...mounting evidence supports a vital role for FDX1 in tumorigenesis of some cancers, no pan-cancer analysis of FDX1 has been reported. Therefore, we aimed to explore the prognostic value of FDX1 in pan-cancer and investigate its potential immune function. Based on data from The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, Human Protein Atlas, and Gene Set Cancer Analysis, we used a range of bioinformatics approaches to explore the potential carcinogenic role of FDX1, including analyzing the relationship between FDX1 expression and prognosis, DNA methylation, RNA methylation-related genes, mismatch repair (MMR) gene, microsatellite instability (MSI), tumor mutation burden (TMB), tumor microenvironment (TME), immune-related genes, and drug sensitivity in different tumors. The results show that FDX1 was lowly expressed in most cancers but higher in glioblastoma multiforme, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Moreover, FDX1 expression was positively or negatively associated with prognosis in different cancers. FDX1 expression was significantly associated with DNA methylation in 6 cancers, while there was a correlation between FDX1 expression and RNA methylation-related genes and MMR gene in most cancers. Furthermore, FDX1 expression was significantly associated with MSI in 8 cancers and TMB in 10 cancers. In addition, FDX1 expression was also significantly correlated with immune cell infiltration, immune-related genes, TME, and drug resistance in various cancers. An experiment
in vitro
showed FDX1 is downregulated by elesclomol, resulting in inhibiting cell viability of bladder cancer, clear cell renal cell carcinoma, and prostate cancer cells. Our study reveals that FDX1 can serve as a potential therapeutic target and prognostic marker for various malignancies due to its vital role in tumorigenesis and tumor immunity.
Cuproptosis-related genes (CRGs) are important for tumor development. However, the functions of CRGs across cancers remain obscure. We performed a pan-cancer investigation to reveal the roles of CRGs ...across cancers. In an analysis of 26 cancers, 12 CRGs were differentially expressed, and those CRGs were found to have prognostic value across different cancer types. The expression of CRGs exhibited varied among tumors of 6 immune subtypes and were significantly correlated with the 16 sensitivities of drugs. The expression of CRGs were highly correlated with immunological subtype and tumor microenvironment (TME) of prostate cancer. We also established CRGs-related prognostic signatures that closely correlated with prognosis and drug sensitivity of prostate cancer patients. Single-cell RNA-seq revealed that several CRGs were enriched in the cancer cells. Finally, an in vitro experiment showed that elesclomol, a cuproptosis inducer, targets ferredoxin 1 and suppress cell viability in prostate cancer cells. In conclusion, we carried out a comprehensive investigation for determining CRGs in differential expression, prognosis, immunological subtype, TME, and cancer treatment sensitivity across 26 malignancies; and validated the results in prostate cancer. Our research improves pan-cancer knowledge of CRGs and identifies more effective immunotherapy strategies.
This work prepared and investigated the impact of carboxymethyl chitosan nanoparticles (MC-NPs) on the proliferative capability of keloid fibroblasts (KFBs) while analyzing the mechanistic roles of ...miR-214 and adenosine A2A receptor (A2AR) in fibroblasts within hypertrophic scars. MC-NPs were synthesized through ion cross-linking, were characterized using transmission electron microscopy (TEM) and laser particle size scattering. The influence of MC-NPs on the proliferation capacity of KFBs was assessed using the MTT method. Changes in the expression levels of miR-214 and A2AR in KFBs, normal skin fibroblasts (NFBs), hypertrophic scar tissue, and normal skin tissue were analyzed. KFBs were categorized into anti-miR-214, anti-miR-NC, miR-214 mimics, miR-NC, si-A2AR, si-con, anti-miR-214+ si-con, and anti-miR-214+ si-A2AR groups. Bioinformatics target prediction was conducted to explore the interaction between miR-214 and A2AR. Real-time quantitative PCR and immunoblotting (WB) were employed to detect the expression levels of miR-214, A2AR, apoptotic protein Bax, and TGF-β in different cells. Cell counting kit-8 (CCK8) and flow cytometry were employed to assess cell proliferation activity and apoptosis. The results indicated that MC-NPs exhibited spherical particles with an average diameter of 236.47 ± 4.98 nm. The cell OD value in the MC-NPs group was lower than that in KFBs (P < 0.05). The mRNA levels of miR-214 in KFBs and hypertrophic scar tissue were lower than those in NFBs and normal tissue (P < 0.001), while the mRNA and protein levels of A2AR were significantly elevated (P < 0.05). Compared to the control group and anti-miR-NC, the anti-miR-214 group showed significantly increased cell OD values and Bcl-2 protein expression (P < 0.001), decreased levels of apoptotic gene Bax protein, TGF-β gene mRNA, and protein expression (P < 0.001). Continuous complementary binding sites were identified between miR-214 and A2AR. Compared to the control group, the si-A2AR group exhibited a significant decrease in A2AR gene mRNA and protein expression levels (P < 0.001), reduced cell viability (P < 0.001), increased apoptosis rate (P < 0.001), and a significant elevation in TGF-β protein expression (P < 0.001). miR-214 targetedly regulated the expression of A2AR, inducing changes in TGF-β content, promoting the proliferation of keloid fibroblasts, and inhibiting cell apoptosis.
Gut metabolites are products of the crosstalk between microbes and their host and play an important role in the occurrence, development, diagnosis, and treatment of autoimmune diseases. This work ...profiled the fecal metabolome of patients with systemic lupus erythematosus (SLE) using gas chromatography-mass spectrometry (GC-MS) and analyzed the potential roles of metabolites in the diagnosis and development of SLE. Fecal sample from 29 SLE patients without any other diseases and 30 healthy controls (HCs) were analyzed by metabolomics profiling. All participants took no antibiotics in the month before sampling and clinical data collecting. The metabolome profiles of patients with SLE and HCs were significantly different. Thirty fecal metabolites, such as deoxycholic acid, erucamide, L-tryptophan and putrescine, were significantly enriched, while nine metabolites, such as glyceric acid, γ-tocopherol, (Z)-13-octadecenoic acid and 2,4-di-tert-butylphenol, were depleted in SLE patients vs. HCs. The areas under the curve (AUCs) of L-valine, pyrimidine, erucamide, and L-leucine during ROC analysis were 0.886, 0.833, 0.829, and 0.803, indicating their good diagnostic potential. Moreover, the combination of L-valine, erucamide and 2,4-di-tert-butylphenol gave an AUC of 0.959. SLE-altered metabolites were significantly located in 28 pathways, such as ABC transporters (
= 3.40E-13) and aminoacyl-tRNA biosynthesis (
= 2.11E-12). Furthermore, SLE-altered fecal metabolites were closely correlated with SLE indicators, e.g., L-tryptophan was positively correlated with the SLEDAI-2K (
= 0.007). Our results suggest that the SLE fecal metabolome is closely associated with the occurrence and development of SLE and is of great diagnostic value.
An expanding body of research indicates a correlation between the gut microbiota and various diseases. Metabolites produced by the gut microbiota act as mediators between the gut microbiota and the ...host, interacting with multiple systems in the human body to regulate physiological or pathological functions. However, further investigation is still required to elucidate the underlying mechanisms. One such metabolite involved in choline metabolism by gut microbes is trimethylamine (TMA), which can traverse the intestinal epithelial barrier and enter the bloodstream, ultimately reaching the liver where it undergoes oxidation catalyzed by flavin-containing monooxygenase 3 (FMO3) to form trimethylamine N-oxide (TMAO). While some TMAO is eliminated through renal excretion, remaining amounts circulate in the bloodstream, leading to systemic inflammation, endoplasmic reticulum (ER) stress, mitochondrial stress, and disruption of normal physiological functions in humans. As a representative microbial metabolite originating from the gut, TMAO has significant potential both as a biomarker for monitoring disease occurrence and progression and for tailoring personalized treatment strategies for patients. This review provides an extensive overview of TMAO sources and its metabolism in human blood, as well as its impact on several major human diseases. Additionally, we explore the latest research areas related to TMAO along with future directions.
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•Review of the known pathways of TMAO production and the catalytic enzymes involved.•Summary of recent advances in the role of TMAO in cancer and other diseases.•TMAO can enhance the response to anti-PD-1 immunotherapy in tumors.•TMAO plays a crucial role in the pathogenesis of various diseases.•Discussion of future prospects and directions for TMAO research.
Disk-like domain receptor 1 (DDR1) is a crucial regulator of pro-inflammatory mediators and matrix-degrading enzymes. Although mounting evidence supports a vital role for DDR1 in the tumorigenesis of ...some cancers, no pan-cancer analysis of DDR1 has been reported. Therefore, we aimed to explore the prognostic value of DDR1 in 33 cancer types and investigate its potential immune function. We used a range of bioinformatics approaches to explore the potential carcinogenic role of DDR1 in multiple cancers. We found that DDR1 was expressed at high levels in most cancers. DDR1 expression was positively or negatively associated with prognosis in different cancers. DDR1 expression was significantly associated with DNA methylation in 8 cancers, while there was a correlation between DDR1 expression and RNA methylation-related genes and mismatch repair gene in most cancers. Furthermore, DDR1 expression was significantly associated with microsatellite instability in 6 cancers and tumor mutation burden in 11 cancers. In addition, DDR1 expression was also significantly correlated with immune cell infiltration, tumor microenvironment, immune-related genes, and drug resistance in various cancers. In conclusion, DDR1 can serve as a potential therapeutic target and prognostic marker for various malignancies due to its vital role in tumorigenesis and tumor immunity.
The excessive accumulation of saturated fatty acids and cholesterol have been linked to prostate cancer (Pca). Here, we found that lipoproteins, apolipoproteins, triglycerides and free fatty acids ...are significantly higher in the peripheral blood of prostate cancer patients than in non-cancer patients. Furthermore, the expression of ACC1, FASN and HMGCR is significantly higher in prostate cancer tissues than that in non-cancer tissues, and positively correlated with the gleason score. Using genetically engineered mouse models, we found that in a mouse model of high grade prostatic intraneoplasia (HGPIN), a combination of fatty acid synthase (FASN) overexpression and cholesterol efflux pump (Abca1) knockout resulted in the progression of prostatic intraneoplasia (PIN) to invasive PCa with 100% penetrance, as well as an increase in prostate cancer stem cell (PCSC)population, accompanied by activation of PGE2 and TGF-β signaling pathway. Our study suggests that the steady rise in prostate cancer incidence and mortality among Chinese population during the last several decades may be attribute to a combinational effect of fatty acid and cholesterol, and reduction in dietary fat and cholesterol intake could slow down the progression from occult lesions to prostate cancer.
Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, ...collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2–induced lymphangiogenesis. Intriguingly, the VEGFR-3–mediated signaling was required for the lymphatic tip cell formation in both FGF-2– and VEGF-C–induced lymphangiogenesis. Consequently, a VEGFR-3–specific neutralizing antibody markedly inhibited FGF-2–induced lymphangiogenesis. Thus, the VEGFR-3–induced lymphatic endothelial cell tip cell formation is a prerequisite for FGF-2–stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting of the FGF-2– and VEGF-C–induced angiogenic and lymphangiogenic synergism could be potentially important approaches for cancer therapy and prevention of metastasis.
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