Showing papers in "Journal of immunology research in 2022"
TL;DR: This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification and the findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients.
Abstract: Lactic acid is a “metabolic waste” product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells' effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.
19 citations
TL;DR: The physiological origin of 4-HNE is described, its toxicity in aging-related diseases is elucidated, and the detoxifying effect of aldehyde dehydrogenase and glutathione in 4- HNE-driven aging- related diseases are discussed.
Abstract: Oxidative stress plays an important role in the development of aging-related diseases by accelerating the lipid peroxidation of polyunsaturated fatty acids in the cell membrane, resulting in the production of aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE) and other toxic substances. The compound 4-HNE forms adducts with DNA or proteins, disrupting many cell signaling pathways including the regulation of apoptosis signal transduction pathways. The binding of proteins to 4-HNE (4-HNE-protein) acts as an important marker of lipid peroxidation, and its increasing concentration in brain tissues and fluids because of aging, ultimately gives rise to some hallmark disorders, such as neurodegenerative diseases (Alzheimer's and Parkinson's diseases), ophthalmic diseases (dry eye, macular degeneration), hearing loss, and cancer. This review aims to describe the physiological origin of 4-HNE, elucidate its toxicity in aging-related diseases, and discuss the detoxifying effect of aldehyde dehydrogenase and glutathione in 4-HNE-driven aging-related diseases.
19 citations
TL;DR: This PROPAM study demonstrated that probiotic strains Ligilactobacillus salivarius LS01 and Bifidobacterium breve B632 (DSM 24706) were safe and significantly reduced by more than a third the frequency of asthma exacerbations.
Abstract: Background Type-2 inflammation commonly marks asthma in childhood. Also, gut and lung dysbiosis is detectable in patients with asthma. Strain-related probiotic supplementation may restore a physiological immune response, dampen airway inflammation, and repair dysbiosis. Therefore, the probiotics in pediatric asthma management (PROPAM) study is aimed at demonstrating that Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706) mixture could reduce asthma exacerbations in children, followed in a primary care setting. Methods The study was randomized, placebo-controlled, and double-blind. It involved 11 Italian primary care pediatricians. The probiotic mixture (containing Ligilactobacillus salivarius LS01 1 × 109 live cells and Bifidobacterium breve B632 1 × 109 live cells) or placebo was taken twice daily (1 sachet in the morning and 1 in the evening) for eight weeks and subsequently once daily for a further eight weeks. Outcomes included number, severity, and duration of asthma exacerbations, intensity of maintenance and as need treatments, and safety. Results The per-protocol population included 422 children (mean age seven years, 240 males and 182 females). The probiotic mixture significantly reduced the number of asthmatic exacerbations (OR = 3.17). In addition, the number of children with two exacerbations was less than a third in the active group (OR = 3.65). Conclusions This PROPAM study demonstrated that probiotic strains Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706) were safe and significantly reduced by more than a third the frequency of asthma exacerbations. At present, the first-line treatment of asthma is still drug-based, but specific strains of probiotics may be auxiliary remedies.
17 citations
TL;DR: Elevated expression of genes associated with interleukins, G protein-coupled receptors (GPCRs), heat shock proteins (HSPs), Toll-like receptors (TLRs), and metabolic-related pathways play major roles in disease progression of both monkeypox-infected monkey MK2 and human HeLa cell lines are discovered.
Abstract: Monkeypox virus (MPV) is a smallpox-like virus belonging to the genus Orthopoxvirus of the family Poxviridae. Unlike smallpox with no animal reservoir identified and patients suffering from milder symptoms with less mortality, several animals were confirmed to serve as natural hosts of MPV. The reemergence of a recently reported monkeypox epidemic outbreak in nonendemic countries has raised concerns about a global outburst. Since the underlying mechanism of animal-to-human transmission remains largely unknown, comprehensive analyses to discover principal differences in gene signatures during disease progression have become ever more critical. In this study, two MPV-infected in vitro models, including human immortal epithelial cancer (HeLa) cells and rhesus monkey (Macaca mulatta) kidney epithelial (MK2) cells, were chosen as the two subjects to identify alterations in gene expression profiles, together with co-regulated genes and pathways that are affected during monkeypox disease progression. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and MetaCore analyses, we discovered that elevated expression of genes associated with interleukins (ILs), G protein-coupled receptors (GPCRs), heat shock proteins (HSPs), Toll-like receptors (TLRs), and metabolic-related pathways play major roles in disease progression of both monkeypox-infected monkey MK2 and human HeLa cell lines. Interestingly, our analytical results also revealed that a cluster of differentiation 40 (CD40), plasmin, and histamine served as major regulators in the monkeypox-infected monkey MK2 cell line model, while interferons (IFNs), macrophages, and neutrophil-related signaling pathways dominated the monkeypox-infected human HeLa cell line model. Among immune pathways of interest, apart from traditional monkeypox-regulated signaling pathways such as nuclear factor- (NF-κB), mitogen-activated protein kinases (MAPKs), and tumor necrosis factors (TNFs), we also identified highly significantly expressed genes in both monkey and human models that played pivotal roles during the progression of monkeypox infection, including CXCL1, TNFAIP3, BIRC3, IL6, CCL2, ZC3H12A, IL11, CSF2, LIF, PTX3, IER3, EGR1, ADORA2A, and DUOX1, together with several epigenetic regulators, such as histone cluster family gene members, HIST1H3D, HIST1H2BJ, etc. These findings might contribute to specific underlying mechanisms related to the pathophysiology and provide suggestions regarding modes of transmission, post-infectious sequelae, and vaccine development for monkeypox in the future.
16 citations
TL;DR:
Abstract: MicroRNAs (miRNAs) are a class of small, mature, noncoding RNA that lead to posttranscriptional gene silencing to regulate gene expression. miRNAs are instrumental in biological processes such as cell development, cell differentiation, cell proliferation, and cell apoptosis. The miRNA-mediated gene silencing is an important part of the regulation of gene expression in many kinds of diseases. miR-155, one of the best-characterized miRNAs, has been found to be closely related to physiological and pathological processes. What is more, miR-155 can be used as a potential therapeutic target for inflammatory diseases. We analyze the articles about miR-155 for nearly five years, review the advanced study on the function of miR-155 in different inflammatory cells like T cells, B cells, DCs, and macrophages, and then summarize the biological functions of miR-155 in different inflammatory cells. The widespread involvement of miR-155 in human diseases has led to a novel therapeutic approach between Chinese and Western medicine.
15 citations
TL;DR: The present review aims at concisely summarizing the current knowledge available on the occurrence, properties, role, and biological consequences of SNPs within the IL-1 family members.
Abstract: Interleukins (ILs)—which are important members of cytokines—consist of a vast group of molecules, including a wide range of immune mediators that contribute to the immunological responses of many cells and tissues. ILs are immune-glycoproteins, which directly contribute to the growth, activation, adhesion, differentiation, migration, proliferation, and maturation of immune cells; and subsequently, they are involved in the pro and anti-inflammatory responses of the body, by their interaction with a wide range of receptors. Due to the importance of immune system in different organisms, the genes belonging to immune elements, such as ILs, have been studied vigorously. The results of recent investigations showed that the genes pertaining to the immune system undergo progressive evolution with a constant rate. The occurrence of any mutation or polymorphism in IL genes may result in substantial changes in their biology and function and may be associated with a wide range of diseases and disorders. Among these abnormalities, single nucleotide polymorphisms (SNPs) can represent as important disruptive factors. The present review aims at concisely summarizing the current knowledge available on the occurrence, properties, role, and biological consequences of SNPs within the IL-1 family members.
15 citations
TL;DR: KLRB1 may be a prognostic and immunological biomarker across tumors and reflect the sensitivity of cancer patients to chemotherapy drugs, and may become a new target for immunotherapy.
Abstract: Introduction KLRB1 is a gene encoding CD161 expressed in NK cells and some T cell subsets. At present, KLRB1 is believed to affect tumorigenesis and development by regulating the cytotoxicity of NK cells in several cancers. However, there is a lack of systematic reviews of KLRB1 in a variety of malignancies. Objectives Hence, our research is aimed at providing a relatively comprehensive understanding of the role of KLRB1 in different types of cancer, paving the way for further research on the molecular mechanism and immunotherapy potential of KLRB1. Methods In this study, we used relevant public databases, including TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus), CCLE (Cancer Cell Line Encyclopedia), GTEx (Genotype Tissue-Expression), and HPA (Human Protein Atlas), to perform a pan-cancer analysis of KLRB1 across 33 types of cancer. We explored the potential molecular mechanism of KLRB1 in clinical prognosis and tumor immunity from the aspects of gene expression, survival status, clinical phenotype, immune infiltration, immunotherapy response, and chemotherapeutic drug sensitivity. Results KLRB1 was downregulated in 13 cancers while upregulated in kidney cancer. Patients with high expression of KLRB1 have a better prognosis in most types of cancer. Moreover, the KLRB1 expression level is related to TMB and MSI and related to various immune signatures of tumor. The expression of KLRB1 can affect tumor immune cell infiltration. KLRB1 expression level can also affect the sensitivity of chemotherapy drugs. Conclusions KLRB1 may be a prognostic and immunological biomarker across tumors. At the same time, KLRB1 expression can reflect the sensitivity of cancer patients to chemotherapy drugs. KLRB1 may become a new target for immunotherapy.
15 citations
TL;DR: The theoretical background, as well as the opportunities and challenges of cancer immunotherapy are discussed, which center on recent progress made within the last 5 years.
Abstract: With the huge therapeutic potential, cancer immunotherapy is expected to become the mainstream of cancer treatment. In the current field of cancer immunotherapy, there are mainly five types. Immune checkpoint blockade therapy is one of the most promising directions. Adoptive cell therapy is an important component of cancer immunotherapy. The therapy with the cancer vaccine is promising cancer immunotherapy capable of cancer prevention. Cytokine therapy is one of the pillars of cancer immunotherapy. Oncolytic immunotherapy is a promising novel component of cancer immunotherapy, which with significantly lower incidence of serious adverse reactions. The recent positive results of many clinical trials with cancer immunotherapy may herald good clinical prospects. But there are still many challenges in the broad implementation of immunotherapy. Such as the immunotherapy cannot act on all tumors, and it has serious adverse effects including but not limited to nonspecific and autoimmunity inflammation. Here, we center on recent progress made within the last 5 years in cancer immunotherapy. And we discuss the theoretical background, as well as the opportunities and challenges of cancer immunotherapy.
14 citations
TL;DR: In this paper , a multicenter hospital-based descriptive cross-sectional study was implemented to study the knowledge, perception, and acceptability of healthcare staff towards COVID-19 vaccination.
Abstract: Elderly and patients with comorbid conditions have higher risk of infection and complications. Vaccination hesitancy is defined as the refusal of vaccine or the delay in accepting it despite the availability of vaccines and vaccination services. This study was aimed at assessing knowledge, perception, and acceptability of healthcare staff towards different types of COVID-19 vaccination. A multicenter hospital-based descriptive cross-sectional study was implemented to study the knowledge, perception, and acceptability of healthcare staff towards COVID-19 vaccination. Multistage sampling technique was applied. Data were collected through a self-administered questionnaire filled by the participants. 400 participants were studied. 61% of the participants were females, and the most frequent age reported was between 18 and 35 years (67%). A statistically significant association (p = 0.048) was found between knowledge about vaccination and professions. The most common vaccine type known and accepted was AstraZeneca vaccine. On assessing acceptability of COVID-19 vaccination, acceptance rate was high (63.8%) and 22.7% of the participants had already got vaccinated. The rejection rate among our staff was 27.4%. This study was conducted in April, 2021. Majority of our healthcare staff believed that vaccination is the key to combat the pandemic. One of the issues and concerns about vaccination was the safety and the risk of developing acute adverse events (p = 0.001). Encouraging factor for vaccination was the fear of getting infection themselves and their families. The present study revealed the presence of good knowledge and acceptability among medical staff towards COVID-19 vaccinations in Sudan.
13 citations
TL;DR: TUG1 increases the Siglec-15 level in HCC cells as a sponge to hsa-miR-582-5p, resulting in enhanced immunosuppression, and siRNA knockdown of TUG1 effectively led to tumor progression inhibition and immune response improvement in H CC cells both in vitro and in vivo.
Abstract: Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, and its biology remains poorly understood, especially in regards to the immunosuppression induced by immune checkpoints, such as Siglec-15. Most cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs display a better therapeutic effect in the clinic, including tumor progression inhibition and immunosuppression breaks. However, two or more drugs will result in a greater possibility of adverse effects. Thus, a double-function target is necessary for developing antitumor drugs, such as RNAi therapy. Methods The expression of TUG1, Siglec-15, and miRNAs was evaluated by qPCR, and protein expression was analyzed by western blotting. The immune responses were evaluated by a Jurkat-reporter gene assay, a T cell-induced cytotoxicity assay, and IFN-γ/IL-2 release. The interactions among TUG1, Siglec-15, and miRNAs were verified by dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. CCK-8 and Transwell assays were used to determine tumor cell proliferation, migration, and invasion. Results In HCC patients and cells, increased TUG1 levels were observed, positively regulating Siglec-15 expression. TUG1-induced Siglec-15 upregulation resulted in the suppression of the immune response of HCC cells. hsa-miR-582-5p directly targeted TUG1 and Siglec-15 mRNA, and ihsa-miR-582-5p knockout prevented the regulation of Siglec-15 induced by THU1. Changes in hsa-miR-582-5p expression negatively regulated Siglec-15 levels and immunosuppression but had no influence on TUG1 levels. siRNA knockdown of TUG1 effectively led to tumor progression inhibition and immune response improvement in HCC cells both in vitro and in vivo. Conclusion TUG1 increases the Siglec-15 level in HCC cells as a sponge to hsa-miR-582-5p, resulting in enhanced immunosuppression. TUG1 knockdown induced by siRNA not only reduces immunosuppression but also suppresses tumor progression both in vitro and in vivo. These novel findings may provide a potential and appropriate target for RNAi therapy to develop drugs with dual antitumor activity.
12 citations
TL;DR: The important role of ferroptosis-related lncRNAs in the tumor microenvironment and immune cell infiltration is revealed and may help determine personalized prognoses and treatment for patients with colon cancer.
Abstract: Ferroptosis is a newly defined mode of programmed oxidative cell death. Knowledge of ferroptosis-related long noncoding (lnc) RNA in the tumor immune microenvironment of colon cancer is lacking. We systematically analyzed the correlations between ferroptosis-related lncRNAs and the tumor microenvironment, immune cell infiltration, and patient prognosis for 379 colon cancer samples in the Cancer Genome Atlas (TCGA). Using consensus clustering, we divided the 379 colon cancer patients into two subgroups (clusters 1 and 2) based on the differentially expressed ferroptosis-related lncRNAs. Cluster 1 was preferentially associated with longer overall survival, upregulated immune checkpoint inhibitor expressions, higher immunoscores, higher stromal scores, higher estimated scores, and distinct immune cell infiltration. Cancer- and metabolism-related pathways were enriched by gene set enrichment analyses. We constructed a prognostic signature of 15 ferroptosis-related lncRNAs (ZEB1-AS1, LINC01011, AC005261.3, LINC01063, LINC02381, ELFN1-AS1, AC009283.1, LINC02361, AC105219.1, AC002310.1, AL590483.1, MIR4435-2HG, NKILA, AC021054.1, and AL450326.1) and divided the patients into the high- and low-risk-score groups. The signature was validated using TCGA training and testing cohorts. The risk signature was an independent prognostic factor for predicting survival and excellently predicted the prognoses of patients with colon cancer. Moreover, the risk signature was related to immune characteristics. Chemosensitivity analyses showed that low-risk-score patients were more sensitive to sorafenib. In summary, our work revealed the important role of ferroptosis-related lncRNAs in the tumor microenvironment and immune cell infiltration and may help determine personalized prognoses and treatment for patients with colon cancer.
TL;DR: The findings shed new light on the functions of upregulated m6A-RMRs in 41 diseases and cancers, nine cellular and molecular mechanisms, novel therapeutic targets for inflammatory disorders, metabolic cardiovascular diseases, autoimmune diseases, organ failures, and cancers.
Abstract: We performed a database mining on 102 transcriptomic datasets for the expressions of 29 m6A-RNA methylation (epitranscriptomic) regulators (m6A-RMRs) in 41 diseases and cancers and made significant findings: (1) a few m6A-RMRs were upregulated; and most m6A-RMRs were downregulated in sepsis, acute respiratory distress syndrome, shock, and trauma; (2) half of 29 m6A-RMRs were downregulated in atherosclerosis; (3) inflammatory bowel disease and rheumatoid arthritis modulated m6A-RMRs more than lupus and psoriasis; (4) some organ failures shared eight upregulated m6A-RMRs; end-stage renal failure (ESRF) downregulated 85% of m6A-RMRs; (5) Middle-East respiratory syndrome coronavirus infections modulated m6A-RMRs the most among viral infections; (6) proinflammatory oxPAPC modulated m6A-RMRs more than DAMP stimulation including LPS and oxLDL; (7) upregulated m6A-RMRs were more than downregulated m6A-RMRs in cancer types; five types of cancers upregulated ≥10 m6A-RMRs; (8) proinflammatory M1 macrophages upregulated seven m6A-RMRs; (9) 86% of m6A-RMRs were differentially expressed in the six clusters of CD4+Foxp3+ immunosuppressive Treg, and 8 out of 12 Treg signatures regulated m6A-RMRs; (10) immune checkpoint receptors TIM3, TIGIT, PD-L2, and CTLA4 modulated m6A-RMRs, and inhibition of CD40 upregulated m6A-RMRs; (11) cytokines and interferons modulated m6A-RMRs; (12) NF-κB and JAK/STAT pathways upregulated more than downregulated m6A-RMRs whereas TP53, PTEN, and APC did the opposite; (13) methionine-homocysteine-methyl cycle enzyme Mthfd1 downregulated more than upregulated m6A-RMRs; (14) m6A writer RBM15 and one m6A eraser FTO, H3K4 methyltransferase MLL1, and DNA methyltransferase, DNMT1, regulated m6A-RMRs; and (15) 40 out of 165 ROS regulators were modulated by m6A eraser FTO and two m6A writers METTL3 and WTAP. Our findings shed new light on the functions of upregulated m6A-RMRs in 41 diseases and cancers, nine cellular and molecular mechanisms, novel therapeutic targets for inflammatory disorders, metabolic cardiovascular diseases, autoimmune diseases, organ failures, and cancers.
TL;DR: Circular RNA RHOT1 enhances the CCND1 expression by sponging miR-142-5p to inhibit chondrocyte autophagy and promote chondROcyte proliferation in osteoarthritis and provided a promising therapeutic target for OA.
Abstract: Background Osteoarthritis (OA) serves as one of the most prevalent types of joint disorders and is a leading cause of symptoms of stiffness, swelling, and arthralgia. Circular RNAs (circRNAs) have been reported to participate in various cellular processes by competing with microRNAs. Meanwhile, cyclinD1 (CCND1) is a key cell cycle regulatory protein and plays a crucial role in OA progression. Nevertheless, the function of circRHOT1 in the modulation of OA progression is still obscure. Here, we explored the effect of circRHOT1 on autophagy and extracellular matrix (ECM) in OA. Methods The expression of circRHOT1 and autophagy markers was detected in OA samples. The effect of circRHOT1 on OA was analyzed in the OA rat model. The function of circRHOT1 in the regulation of OA was assessed by CCK-8, colony formation, flow cytometry analysis, quantitative real-time PCR, Western blot analysis, and luciferase reporter gene assay in chondrocytes. Results We observed that autophagy markers, including LC3 and beclin1, were repressed in clinical OA samples. The expression of circRHOT1 and CCND1 was induced but the miR-142-5p expression was reduced in clinical OA samples. The miR-142-5p expression was negatively correlated with circRHOT1 and CCND1, and the circRHOT1 expression was positively associated with CCND1 in clinical OA samples. Meanwhile, the apoptosis was induced in OA rats but the depletion of circRHOT1 could block the phenotype in the rats. The articular cartilage degeneration was promoted in OA rats, while the knockdown of circRHOT1 repressed the degeneration. The serum levels of CTX-II and COMP were increased in OA rats, and the silencing of circRHOT1 downregulated levels of these proteins. In addition, the expression of collagen II and aggrecan was promoted by the depletion of circRHOT1 in the OA rats. Significantly, the expression of LC3 and beclin1 was suppressed in OA rats, in which the knockdown of circRHOT1 could reverse the effect. Moreover, the depletion of circRHOT1 repressed the cell viability and proliferation but induced apoptosis of chondrocytes. The expression levels of LC3, beclin1, collagen II, and aggrecan were induced by circRHOT1 knockdown. Mechanically, circRHOT1 was able to enhance the CCND1 expression by sponging miR-142-5p in chondrocytes. The overexpression of CCND1 or the inhibition of miR-142-5p reversed circRHOT1 depletion-mediated chondrocyte phenotypes. Conclusions Circular RNA RHOT1 enhances the CCND1 expression by sponging miR-142-5p to inhibit chondrocyte autophagy and promote chondrocyte proliferation in osteoarthritis. Our findings provided a promising therapeutic target for OA.
TL;DR: The clinical significance of urinary exosomal lncRNA telomerase RNA component (TERC) levels to provide an urgently needed diagnostic and prognostic biomarker for BLCA is explored.
Abstract: Purpose Bladder cancer is one of the most common urological malignancies worldwide, and approximately 90% of bladder cancer cases are histologically typed as bladder urothelial carcinoma (BLCA). Exosomes are 30 to 200 nm extracellular vesicles that transport microRNAs, long noncoding RNAs (lncRNAs), mRNAs, circular RNAs, and proteins across tissues and through circulation. Urinary exosomes may contain genetic information from tumor cells. Herein, we explored the clinical significance of urinary exosomal lncRNA telomerase RNA component (TERC) levels to provide an urgently needed diagnostic and prognostic biomarker for BLCA. Materials and Methods In this study, we used RNA-sequencing of samples from four BLCA patients and three healthy controls to identify that TERC was differentially expressed in urinary exosomes. We then used quantitative PCR in different types of clinical samples to validate the biomarker and analyzed results using receiver operating characteristic curves. Results We found that TERC was significantly upregulated in urinary exosomes from BLCA patients compared with those from healthy controls (P < 0.0001). Urinary exosomal TERC showed higher sensitivity (78.65%) and accuracy (77.78%) than existing indicators including nuclear matrix protein-22 and urine cytometry. Using the cut-off value 4.302, the area under the curve for urinary exosomal TERC was 0.836 (95% confidence interval: 0.768–0.891, P < 0.0001). Furthermore, this noninvasive assay could distinguish low-grade and high-grade tumors (P = 0.0153). Conclusions TERC is enriched in urinary exosomes from BLCA patients. Urinary exosomal TERC could become a diagnostic and prognostic biomarker for BLCA that allows clinicians to realize noninvasive detection of BLCA.
TL;DR: The regulatory role of micronutrients in H. pylori-induced host immune response and their potential capacity, as intrinsic antioxidants, for reducing oxidative stress and inflammation are highlighted.
Abstract: Helicobacter pylori as a class I carcinogen is correlated with a variety of severe gastroduodenal diseases; therefore, H. pylori eradication has become a priority to prevent gastric carcinogenesis. However, due to the emergence and spread of multidrug and single drug resistance mechanisms in H. pylori, as well as serious side effects of currently used antibiotic interventions, achieving successful H. pylori eradication has become exceedingly difficult. Recent studies expressed the intention of seeking novel strategies to improve H. pylori management and reduce the risk of H. pylori-associated intestinal and extragastrointestinal disorders. For which, vitamin supplementation has been demonstrated in many studies to have a tight interaction with H. pylori infection, either directly through the regulation of the host inflammatory pathways or indirectly by promoting the host immune response. On the other hand, H. pylori infection is reported to result in micronutrient malabsorption or deficiency. Furthermore, serum levels of particular micronutrients, especially vitamin D, are inversely correlated to the risk of H. pylori infection and eradication failure. Accordingly, vitamin supplementation might increase the efficiency of H. pylori eradication and reduce the risk of drug-related adverse effects. Therefore, this review aims at highlighting the regulatory role of micronutrients in H. pylori-induced host immune response and their potential capacity, as intrinsic antioxidants, for reducing oxidative stress and inflammation. We also discuss the uncovered mechanisms underlying the molecular and serological interactions between micronutrients and H. pylori infection to present a perspective for innovative in vitro investigations, as well as novel clinical implications.
TL;DR: Wang et al. as mentioned in this paper found that hypoxia-inducible factor (HIF)-1α could positively regulate increased expression of WTAP under hypoxias, and further results revealed that WTAP expression was closely associated with the clinicopathological features of ovarian cancer, and high expression was predicted low survival rate in patients with OC.
Abstract: N6-methyladenosine (m6A) RNA methylation has been determined to execute crucial functions in tumorigenesis and cancer development. WT1-associated protein (WTAP) has an important "writer" role in m6A modification, and it is also a nuclear protein that colocalizes with splicing factors and plays a critical role in cell function and cancer progression. However, little is known about the role of WTAP in ovarian cancer (OC) and its mechanisms. In this study, we found for the first time that hypoxia-inducible factor (HIF)-1α could positively regulate increased expression of WTAP under hypoxia. And further results revealed that WTAP expression was closely associated with the clinicopathological features of OC, and high expression of WTAP predicted low survival rate in patients with OC. In addition, cell proliferation and invasive capacity were significantly reduced after knockdown of WTAP expression in OC cells. However, cell proliferation and invasive ability were significantly enhanced after overexpression of WTAP. Additionally, we find that WTAP interacts with DGCR8 (a crucial chip protein) to regulate the expression of microRNA-200 (miR-200) in an m6A-dependent way. Further experiments showed that the key glycolysis enzyme HK2 could be positively regulated by miR-200, which significantly affected the intracellular Warburg effect. In conclusion, this is considered uncovered that upregulation of WTAP expression by HIF-1α intercedes with miRNA processing, accelerates the Warburg impact, and advances the event and advancement of tumor, thus giving a novel viewpoint on m6A adjustment in OC movement.
TL;DR: ADSC-Exos therapy positively affected the promotion of hair regrowth by regulating miR-22, the Wnt/β-catenin signaling pathway, and the TNF-α signaling pathway; implying that ADSC- exos could be a promising cell-free therapeutic strategy for immune-mediated alopecia.
Abstract: Background Alopecia has become an exceedingly prevalent dermatological disorder. Etiologically, infection (bacterial and fungal infection), inflammation, and immune dysregulation are the main causes of immune-mediated hair loss. Treating hair loss has remained challenging as the available therapies are limited. Exosomes from adipose-derived stem cells (ADSC-Exos) have been used for treating neurodegenerative diseases and autoimmune diseases and in wound-healing treatments. However, the function and mechanism of ADSC-Exos in alopecia treatment remain unclear. This study is aimed at investigating the effects of ADSC-Exos on hair growth in vitro and in vivo for potentially treating immune-mediated alopecia and further exploring the underlying mechanism. Methods Cell proliferation, migration, and apoptosis of dermal papilla cells (DPCs) that were treated with ADSC-Exos were detected using the cell counting kit-8 (CCK-8) assay, scratch wound-healing assay, and flow cytometry assay, respectively. A C57BL/6 hair-depilated mouse model was established in vivo; then, ADSC-Exos were subcutaneously injected alone or in combined with minoxidil. The effects of ADSC-Exos on hair growth, pathological changes, and the related mechanism were investigated by HE staining, quantitative real‐time PCR (qRT-PCR), western blotting, and RNA sequencing (RNA-seq). Results ADSC-Exos significantly promoted DPC proliferation and migration while also reducing apoptosis. In addition, compared with the control group, ADSC-Exos-treated mice had better hair growth, more hair follicles (HFs) and thicker dermis. RNA-seq revealed that the miR-22 and TNF-α signaling pathways were markedly downregulated in DPCs after ADSC-Exos treatment. In addition, according to qRT-PCR and western blotting results, the Wnt/β-catenin signaling pathway was activated in the skin of ADSC-Exos-treated mice. Conclusion ADSC-Exos therapy positively affected the promotion of hair regrowth by regulating miR-22, the Wnt/β-catenin signaling pathway, and the TNF-α signaling pathway, implying that ADSC-Exos could be a promising cell-free therapeutic strategy for immune-mediated alopecia.
TL;DR: Evaluation of the impact of HLA variants on the outcome of bacterial and viral infections would improve the understanding of pathogenesis and identify those at risk from infectious diseases in distinct populations and may improve the individual treatment.
Abstract: The human leukocyte antigen (HLA) system is one of the most crucial host factors influencing disease progression in bacterial and viral infections. This review provides the basic concepts of the structure and function of HLA molecules in humans. Here, we highlight the main findings on the associations between HLA class I and class II alleles and susceptibility to important infectious diseases such as tuberculosis, leprosy, melioidosis, Staphylococcus aureus infection, human immunodeficiency virus infection, coronavirus disease 2019, hepatitis B, and hepatitis C in populations worldwide. Finally, we discuss challenges in HLA typing to predict disease outcomes in clinical implementation. Evaluation of the impact of HLA variants on the outcome of bacterial and viral infections would improve the understanding of pathogenesis and identify those at risk from infectious diseases in distinct populations and may improve the individual treatment.
TL;DR: Exosomal miR-452-5p secreted from HCC cells could induce polarization of M2 macrophage and therefore stimulating HCC progression by targeting TIMP3, and might be a potential biomarker for HCC prognosis.
Abstract: Background Hepatocellular carcinoma (HCC) cell-derived exosomes have shown effects on inducing M2 macrophage polarization and promoting HCC progression. MiR-452-5p was reported by recent studies to promote malignancy progression as an exosomal microRNA that secreted by HCC cells, of which the underlying mechanism remains unclear. Here, we further explored how miR-452-5p functions in HCC. Methods MiR-452-5p expressions in HCC cells was examined by in situ hybridization. Next, HCC cell lines were transfected with the mimics or the inhibitor of miR-452-5p. Transfected cells' biological behavior were analyzed by CCK-8, flow cytometry, and Transwell assay. Then, exosomes were purified from miR-452-5p inhibited or overexpressed HCC cells and cocultured with macrophages to examine the role of miR-452-5p in macrophage polarization. To examine the role of exosomal miR-452-5p on macrophage polarization and tumor growth. We also performed the dual-luciferase assay to explore the targeting relationship between miR-452-5p and TIMP3. Results The upregulation of miR-452-5p was identified in HCC. The effects of HCC cell-derived exosomes on accelerating HCC migration and invasion and inducing M2 macrophage polarization were confirmed, which were further enhanced after overexpressing miR-452-5p but neutralized after silencing miR-452-5p. In addition, in vivo experiments demonstrated the effect of miR-452-5p on accelerating HCC growth and metastasis. Also, we identified that TIMP3 overexpression inhibited the promoted cell invasion and migration by HCC cell-derived exosomes. Conclusion Exosomal miR-452-5p secreted from HCC cells could induce polarization of M2 macrophage and therefore stimulating HCC progression by targeting TIMP3. Thus, miR-452-5p might be a potential biomarker for HCC prognosis.
TL;DR: A prognostic signature consisting of 7 necroptosis-associated lncRNAs that can independently predict the clinical outcome of BRCA patients is established.
Abstract: Breast cancer (BRCA) is one of the leading causes of death among women worldwide, and drug resistance often leads to a poor prognosis. Necroptosis is a type of programmed cell death (PCD) and exhibits regulatory effects on tumor progression, but few studies have focused on the relationships between necroptosis-associated lncRNAs and BRCA. In this study, we established a signature basis of 7 necroptosis-related lncRNAs associated with prognosis and divided BRCA patients into high- and low-risk groups. Kaplan-Meier curves all showed an adverse prognosis for patients in the high-risk group. Cox assays confirmed that risk score was an independent prognostic factor for BRCA patients. The receiver operating characteristic (ROC) curve proved the predictive accuracy of the signature and the area under the curve (AUC) values of the risk score reached 0.722. The nomogram relatively accurately predicted the prognosis of the patients. GSEA analysis suggested that the related signaling pathways and biological processes enriched in the high- and low-risk groups may influence the tumor microenvironment (TME) of BRCA. ssGSEA showed the difference in immune cell infiltration, immune pathway activation, and immune checkpoint expression between the two risk groups, with the low-risk group more suitable for immunotherapy. According to the significant difference in IC50 between risk groups, patients can be guided for an individualized treatment plan. Overall, the authors established a prognostic signature consisting of 7 necroptosis-associated lncRNAs that can independently predict the clinical outcome of BRCA patients. The difference in the tumor immune microenvironment between the low- and high-risk populations may be the reason for the resistance to immunotherapy in some patients.
TL;DR: The role of exosomes in the pathogenesis of different chronic liver diseases and the latest research progresses of MSC-ex as the clinical therapeutic targets are summarized.
Abstract: Extracellular vesicles (EVs) are vesicular bodies (40-1000 nm) with double-layer membrane structures released by different cell types into extracellular environments, including apoptosis bodies, microvesicles, and exosomes. Exosomes (30-100 nm) are vesicles enclosed by extracellular membrane and contain effective molecules of secretory cells. They are derived from intracellular multivesicular bodies (MVBs) that fuse with the plasma membrane and release their intracellular vesicles by exocytosis. Research has shown that almost all human cells could secrete exosomes, which have a certain relationship with corresponding diseases. In chronic liver diseases, exosomes release a variety of bioactive components into extracellular spaces, mediating intercellular signal transduction and materials transport. Moreover, exosomes play a role in the diagnosis, treatment, and prognosis of various chronic liver diseases as potential biomarkers and therapeutic targets. Previous studies have found that mesenchymal stem cell-derived exosomes (MSC-ex) could alleviate acute and chronic liver injury and have the advantages of high biocompatibility and low immunogenicity. In this paper, we briefly summarize the role of exosomes in the pathogenesis of different chronic liver diseases and the latest research progresses of MSC-ex as the clinical therapeutic targets.
TL;DR: An overview of both the protective and harmful roles of commensal and pathogenic bacteria-derived EVs in host-bacterial and interbacterial interactions is presented.
Abstract: Extracellular vesicles (EVs) cause effective changes in various domains of life. These bioactive structures are essential to the bidirectional organ communication. Recently, increasing research attention has been paid to EVs derived from commensal and pathogenic bacteria in their potential role to affect human disease risk for cancers and a variety of metabolic, gastrointestinal, psychiatric, and mental disorders. The present review presents an overview of both the protective and harmful roles of commensal and pathogenic bacteria-derived EVs in host-bacterial and interbacterial interactions. Bacterial EVs could impact upon human health by regulating microbiota–host crosstalk intestinal homeostasis, even in distal organs. The importance of vesicles derived from bacteria has been also evaluated regarding epigenetic modifications and applications. Generally, the evaluation of bacterial EVs is important towards finding efficient strategies for the prevention and treatment of various human diseases and maintaining metabolic homeostasis.
TL;DR: It is reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one, regulated via PI3K/AKT, mTOR, and MAPK signaling pathways.
Abstract: Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of cancer patients. Artemisinin (ART), the most effective antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for cancer treatment. Although ART is reported to reduce MDSC levels in 4T1 breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in melanoma or liver tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce tumor growth in various mouse models. More importantly, the ART therapy remarkably enhanced the efficacy of anti-PD-L1 immunotherapy in tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy.
TL;DR: Repeated vaccination increases antibody avidity against the spike protein of the Omicron variant, suggesting that antibodies with high avidity and high neutralizing potential increase cross-protection against variants that carry several mutations on the RBD.
Abstract: Background The recently emerged SARS-CoV-2 Omicron variant exhibits several mutations on the spike protein, enabling it to escape the immunity elicited by natural infection or vaccines. Avidity is the strength of binding between an antibody and its specific epitope. The SARS-CoV-2 spike protein binds to its cellular receptor with high affinity and is the primary target of neutralizing antibodies. Therefore, protective antibodies should show high avidity. This study aimed at investigating the avidity of receptor-binding domain (RBD) binding antibodies and their neutralizing activity against the Omicron variant in SARS-CoV-2 infected patients and vaccinees. Methods Samples were collected from 42 SARS-CoV-2 infected patients during the first pandemic wave, 50 subjects who received 2 doses of mRNA vaccine before the Omicron wave, 44 subjects who received 3 doses of mRNA vaccine, and 35 subjects who received heterologous vaccination (2 doses of adenovirus-based vaccine plus mRNA vaccine) during the Omicron wave. Samples were tested for the avidity of RBD-binding IgG and neutralizing antibodies against the wild-type SARS-CoV-2 virus and the Omicron variant. Results In patients, RBD-binding IgG titers against the wild-type virus increased with time, but remained low. High neutralizing titers against the wild-type virus were not matched by high avidity or neutralizing activity against the Omicron variant. Vaccinees showed higher avidity than patients. Two vaccine doses elicited the production of neutralizing antibodies, but low avidity for the wild-type virus; antibody levels against the Omicron variant were even lower. Conversely, 3 doses of vaccine elicited high avidity and high neutralizing antibodies against both the wild-type virus and the Omicron variant. Conclusions Repeated vaccination increases antibody avidity against the spike protein of the Omicron variant, suggesting that antibodies with high avidity and high neutralizing potential increase cross-protection against variants that carry several mutations on the RBD.
TL;DR: Overall, this study showed that M2-MDEs promoted meningioma development and invasion by activating the TGF-β signaling pathway.
Abstract: Tumor-associated macrophages (TAMs) have been shown to be an essential component of the tumor microenvironment and facilitate the proliferation and invasion of a variety of malignancies. However, the contribution of TAMs to meningioma progression has not been characterized in detail. In this study, we aimed to discover a novel regulatory pathway by which exosome-mediated M2-polarized macrophages participate in meningioma tumorigenesis and progression. Methods. First, the distribution and functional phenotype of macrophages in meningioma tissues were assessed by immunohistochemistry. Macrophage-derived exosomes (MDEs) were characterized, and further cell coculture experiments were performed to explore the effects of M2-MDEs on the proliferation, migration, and invasion of meningioma cells. RNA sequencing was used to analyze the transcriptomic signatures in meningioma cells treated with M2-MDEs. Three-dimensional tumorspheres and xenograft tumor models were used to evaluate the effects of M2-MDEs on meningioma tumorigenesis and development. Results. We found that M2 macrophages were enriched in meningioma tissue. Coculture with meningioma cells induced the M2 polarization of macrophages. We also found that M2-MDEs were able to significantly promote cell proliferation, cell migration, cell invasion, and tumorigenesis in meningiomas. Bioinformatic analysis suggested that the TGF-β pathway was activated in meningioma cells treated with M2-MDEs. Functional experiments demonstrated that blocking the TGF-β signaling pathway could effectively reverse the tumor-promotive effects mediated by M2-MDEs. Conclusions. Overall, our study showed that M2-MDEs promoted meningioma development and invasion by activating the TGF-β signaling pathway. Targeting exosome-mediated intercellular communication in the tumor microenvironment may be a novel therapeutic strategy for meningioma patients.
TL;DR: The researchers observed that the expression of ISG20 and SERPINA3 was distinctly increased in renal fibrosis samples compared with normal samples, suggesting that ISg20 may be a novel therapeutic target of kidney fibrosis.
Abstract: Chronic kidney disease is characterized by the development of renal fibrosis. The basic mechanisms of renal fibrosis have not yet been fully investigated despite significant progress in understanding the etiology of the disease. In this work, the researchers sought to identify potential diagnostic indicators for renal fibrosis. From the GEO database, we were able to acquire two gene expression profiles with publically available data (GSE22459 and GSE76882, respectively) from human renal fibrosis and control samples. 215 renal fibrosis specimens and 124 normal specimens were examined for differentially expressed genes (DEGs). The SVM-RFE and LASSO regression models were used to discover potential markers. CIBERSORT was applied to estimate the combined cohorts' immune cell fraction compositional trends in renal fibrosis. RT-PCR was used to examine the expression of ISG20 in renal fibrosis and healthy samples. In vitro experiments were applied to examine the function of ISG20 knockdown on the progression of renal fibrosis. In this study, we identified 24 DEGs. The result of LASSO and SVM-RFE identified nine critical genes. ROC assays confirmed the diagnostic value of the above nine genes for renal fibrosis. Immune cell infiltration analysis revealed that ISG20 and SERPINA3 were both found to be correlated with T cell follicular helper, neutrophils, T cell CD4 memory activated, eosinophils, T cell CD8, dendritic cell activated, B cell memory, monocytes, macrophage M2, plasma cells, T cell CD4 naïve, mast cell resting, B cell naïve, T cell regulatory, and NK cell activated. Finally, we observed that the expression of ISG20 and SERPINA3 was distinctly increased in renal fibrosis samples compared with normal samples. ISG20 siRNA significantly suppressed the progression of renal fibrosis in vitro. Overall, this study identified nine diagnostic biomarkers for renal fibrosis. ISG20 may be a novel therapeutic target of renal fibrosis.
TL;DR: The formation of vascular tumor thrombi in breast cancer tissue and left breast cancer are risk factors for axillary lymph node metastasis in invasive breast cancer and might be helpful for preoperative detailed assessment of the patient's condition.
Abstract: Objective To investigate the risk factors of axillary lymph node metastasis in patients with invasive breast cancer. Methods This study retrospectively included 122 cases of invasive breast cancer patients admitted to the First Medical Center of PLA General Hospital from January 2019 to September 2020. According to postoperative pathological results, axillary lymph node metastasis was divided into axillary lymph node metastasis (ALNM) group (n =40) and non-axillary lymph node metastasis (NALNM) group (n =82). General demographic information was collected and compared between the two groups. Collected pathological results included lymphovascular invasion (LVI) and the expression of estrogen receptor (ER), progestogen receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 detected by immunohistochemistry. Imaging parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) including apparent diffusion coefficient (ADC), early enhanced rate, and time-intensity curve (TIC) were also included into univariate analysis. The variables with differences between the two groups were compared by univariate analysis, and the related factors of axillary lymph node metastasis were analyzed by logistic regression model. Results There was no significant difference in general demographic information between the two groups. No significant differences were found in the positive rates of HER-2, ER, PR, Ki-67, pathological types, and clavicular lymph node metastasis and skin chest wall invasion between the two groups (P > 0.05). The proportion of LVI in ALNM group was significantly higher than that in NALNM group (37.50% vs. 6.10%, P < 0.001). The proportion of breast cancer on the left side in the ALNM group was higher than that in the NALNM group, and the difference was statistically significant (70.00% vs. 47.56%, P = 0.019). There were no significant differences in the imaging parameters obtained by DCE-MRI between the two groups. Binary logistics regression analysis showed that LVI (OR =12.258, 95% CI =3.681-40.812, P < 0.001) and left breast cancer (OR =3.598, 95% CI =1.404-9.219, P = 0.008) were risk factors for axillary lymph node metastasis in patients with invasive breast cancer. Conclusion The formation of vascular tumor thrombi in breast cancer tissue and left breast cancer are risk factors for axillary lymph node metastasis in invasive breast cancer and might be helpful for preoperative detailed assessment of the patient's condition.
TL;DR: Targeting Tregs has become a novel direction for NSCLC patients, such as disrupting their immune-suppressive functions, blocking their trafficking into tumors, and inhibiting their development and/or activation.
Abstract: Non-small-cell lung cancer (NSCLC) is one of the most threatening malignant tumors to human health, with the overall 5-year survival rate being less than 30%. Regulatory T cells (Tregs), a functional subset of T cells, maintain immunologic immunological self-tolerance and homeostasis. Accumulating evidence has uncovered their implicated roles in various cancers in recent years. In NSCLC, they are associated with staging, therapeutic efficacy, and prognosis by infiltrating in tissues and thereby attenuating immunologic anticancer effects in patients. Tumor-associated Tregs display distinct immune signatures in NSCLC compared to thymus-derived Tregs, playing an important role in remodeling the tumor microenvironment (TME). Targeting Tregs has become a novel direction for NSCLC patients, such as disrupting their immune-suppressive functions, blocking their trafficking into tumors, and inhibiting their development and/or activation. This review is aimed at elucidating the molecular mechanisms of tumor-associated Tregs in NSCLC and providing therapeutic targets relevant to Tregs.
TL;DR: The results reveal that the combined use of inhibitors directed against the IL6R/STAT-3 axis and TIGIT enhances the functional activity of NK cells against castration-resistant prostate cancer cells.
Abstract: Methods We analyzed the secretion of cytokines, chemokines, and growth factors in 22Rv1, LNCaP, and DU145 cells. In these cells, we also evaluated the expression of NK ligands, IL6R, STAT-3, and phosporylated STAT-3. In NK-92 cells, we evaluated the effects of Stattic (Stt) and tocilizumab (Tcz) on NK receptors. In addition, we assessed if the disruption of the IL6R/STAT-3 pathway and blockade of TIGIT potentiated the cytotoxicity of NK-92 cells versus DU145 cells. Results DU145 abundantly secretes M-CSF, VEGF, IL-6, CXCL8, and TGF-β. Furthermore, the expression of CD155 was found to increase in accordance with aggressiveness and metastatic status in the prostate cancer cells. Stt and Tcz induce a decrease in STAT-3 phosphorylation in the DU145 cells and, in turn, induce an increase of NKp46 and a decrease of TIGIT expression in NK-92 cells. Finally, the disruption of the IL6R/STAT-3 axis in prostate cancer cells and the blocking of TIGIT on NK-92 were observed to increase the cytotoxicity of NK-92 cells against DU145 cells through an increase in sFasL, granzyme A, granzyme B, and granulysin. Conclusions Our results reveal that the combined use of inhibitors directed against the IL6R/STAT-3 axis and TIGIT enhances the functional activity of NK cells against castration-resistant prostate cancer cells.
TL;DR: It is revealed that TMAO exerts oncogenic effects by promoting cell proliferation and angiogenesis in colorectal cancer.
Abstract: Background. Of all intestinal microbiome-derived metabolites, trimethylamine N-oxide (TMAO) has received increasing attention because of its potent role in colorectal cancer development. Accumulating evidence suggests that TMAO generated by the gut microbiota is a new and important player in the etiological process of colorectal cancer. Nevertheless, the carcinogenic mechanism of TMAO in colorectal cancer remains unclear. In this study, TMAO induced colorectal cancer cell proliferation and produced higher vascular endothelial growth factor A (VEGFA) levels in vitro. In vivo, after long-term choline feeding in tumor-bearing mice, circulating TMAO levels, tumor volume, new blood vessel formation, and VEGFA and CD31 amounts were increased significantly. This study revealed that TMAO exerts oncogenic effects by promoting cell proliferation and angiogenesis in colorectal cancer.