The causal association between artificial sweeteners and the risk of cancer: a Mendelian randomization study.

Artificial sweeteners (ASs) have been widely added to food and beverages because of their properties of low calories and sweet taste. However, whether the consumption of ASs is causally associated with cancer risk is not clear. Here, we utilized the two-sample Mendelian randomization (MR) method to study the potential causal association. Genetic variants like single-nucleotide polymorphisms (SNPs) associated with exposure (AS consumption) were extracted from a genome-wide association study (GWAS) database including 64 949 Europeans and the influence of confounding was removed. The outcome was from 98 GWAS data and included several types of cancers like lung cancer, colorectal cancer, stomach cancer, breast cancer, and so on. The exposure-outcome SNPs were harmonized and then MR analysis was performed. The inverse-variance weighted (IVW) with random effects was used as the main analytical method accompanied by four complementary methods: MR Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses consisted of heterogeneity, pleiotropy, and leave-one-out analysis. Our results demonstrated that ASs added to coffee had a positive association with high-grade and low-grade serous ovarian cancer; ASs added to tea had a positive association with oral cavity and pharyngeal cancers, but a negative association with malignant neoplasm of the bronchus and lungs. No other cancers had a genetic causal association with AS consumption. Our MR study revealed that AS consumption had no genetic causal association with major cancers. Larger MR studies or RCTs are needed to investigate small effects and support this conclusion.

miRNA-449c-5p regulates the JAK-STAT pathway in inhibiting cell proliferation and invasion in human breast cancer cells by targeting ERBB2.

BACKGROUND: Breast cancer is a highly prevalent disease worldwide, and early diagnosis and treatment could reduce the mortality rate of breast cancer patients. microRNAs (miRNA) have been shown to regulate the occurrences and progression of many types of cancers. Thus, it is crucial to find novel biomarkers in breast cancer. miR-449c-5p acted as a biomarker in non-small cell lung cancer, gastric carcinoma, and so forth. ERBB2 is an ideal target for breast cancer therapy. However, the molecular mechanisms between miR-449c-5p and ERBB2 in breast cancer remain poorly understood. Our study focused on the regulatory role of miR-449c-5p in breast cancer and its targeting relationship with ERBB2. METHODS: The miR-449c-5p expression in breast cancer tissue and normal tissue was searched from the online database (Starbase). The clinical prognosis of miR-449c-5p and ERBB2 was predicted by using the Kaplan-Meier analysis method. The expression of miR-449c-5p mimics and inhibitors was measured by qRT-PCR. T47D cells were transfected with miR-449c-5p mimics and miR-449c-5p inhibitors. After that, CCK-8, colony formation assays and Transwell assays were used to evaluate the cell proliferation ability, migration and invasion. Whether ERBB2 was the target gene of the miR-449c-5p was predicted by Starbase and verified by dual-luciferase activity assay. In addition, protein levels and the relationship between signalling pathways were measured and validated using western blotting analysis. RESULTS: We confirmed that miR-449c-5p was highly expressed in breast cancer tissue, and its downregulation was linked with poor prognosis. Overexpression of miR-449c-5p inhibited the proliferation, migration and invasion of breast cancer cells. ERBB2 was a target of miR-449c-5p. The invasion, migration, and proliferation of breast cancer cells were inhibited by miR-449c-5p/ERBB2 through JAK-STAT. CONCLUSION: This study demonstrated that miR-449c-5p inhibits breast cancer cell proliferation, migration and invasion by targeting ERBB2 via JAK/STAT, which means miR-449c-5p, is a potential biomarker for breast cancer and provides a novel insight for diagnosis.

Identification and verification of PTPN3 as a novel biomarker in predicting cancer prognosis, immunity, and immunotherapeutic efficacy.

BACKGROUND: The importance of protein tyrosine phosphatase non-receptor type 3 (PTPN3) in controlling multifaceted tumor cell behaviors throughout cancer development has received widespread attention. Nevertheless, little is known about the biological roles of PTPN3 in drug sensitivity, immunotherapeutic effectiveness, tumor immune microenvironment, and cancer prognosis. METHODS: The Cancer Genome Atlas (TCGA) database's RNAseq data were used to examine the expression of PTPN3 in 33 different cancer types. In addition, immunohistochemistry (IHC) was performed to validate the expression of PTPN3 across various cancer types within our clinical cohorts. The features of PTPN3 alterations were demonstrated throughout the cBioPortal database. This study focused on examining the prognostic and clinicopathological importance of PTPN3 through the acquisition of clinical data from the TCGA database. The investigation of PTPN3's probable role in the tumor immune microenvironment was demonstrated by the application of CIBERSORT, ESTIMATE algorithms, and the TISIDB database. Using Spearman's rank correlation coefficient, the relationships between PTPN3 expression and tumor mutation burden (TMB) and microsatellite instability (MSI) were evaluated. To further investigate the putative biological activities and downstream pathways of PTPN3 in various cancers in humans, Gene Set Enrichment Analysis (GSEA) was carried out. In addition, an examination was conducted to explore the associations between PTPN3 and the effectiveness of PD-1/PD-L1 inhibitors, utilizing data extracted from the GEO database. RESULTS: PTPN3 was abnormally expressed in multiple cancer types and was also strictly associated with the prognosis of cancer patients. IHC was used to investigate and confirm the various expression levels of PTPN3 in various malignancies, including breast cancer, lung cancer, sarcoma, and kidney renal clear cell carcinoma in our clinical cohorts. There is a high correlation between the levels of PTPN3 expression in different cancers and infiltrating immune cells, including mast cells, B cells, regulatory T cells, CD8 + T cells, macrophages, and dendritic cells. Infiltrating immune cells, such as regulatory T cells, CD8 + T cells, macrophages, B cells, dendritic cells, and mast cells, are strongly correlated with PTPN3 expression levels in various tumors. The expression of PTPN3 exhibited a substantial correlation with many immune-related biomolecules and the expression of TMB and MSI in multiple types of cancer. In addition, PTPN3 has demonstrated promise in predicting the therapeutic benefits of PD-1/PD-L1 inhibitors and the susceptibility to anti-cancer medications in the treatment of clinical cancer. CONCLUSIONS: Our findings highlight the importance of PTPN3 as a prognostic biomarker and predictor of immunotherapy success in various forms of cancer. Furthermore, PTPN3 appears to have an important role in modifying the tumor immune microenvironment, highlighting its potential as a promising biomarker for prognosis prediction, immunotherapeutic efficacy evaluation, and identification of immune-related characteristics in diverse cancer types.

Ferroptosis-related gene HIC1 in the prediction of the prognosis and immunotherapeutic efficacy with immunological activity.

Background: Hypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence has supported the critical roles of HIC1 in cancer initiation and development, its roles in tumor immune microenvironment and immunotherapy are still unclear, and no comprehensive pan-cancer analysis of HIC1 has been conducted. Methods: HIC1 expression in pan-cancer, and differential HIC1 expression between tumor and normal samples were investigated. Immunohistochemistry (IHC) was employed to validate HIC1 expression in different cancers by our clinical cohorts, including lung cancer, sarcoma (SARC), breast cancer, and kidney renal clear cell carcinoma (KIRC). The prognostic value of HIC1 was illustrated by Kaplan-Meier curves and univariate Cox analysis, followed by the genetic alteration analysis of HIC1 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was conducted to illustrate the signaling pathways and biological functions of HIC1. The correlations between HIC1 and tumor mutation burden (TMB), microsatellite instability (MSI), and the immunotherapy efficacy of PD-1/PD-L1 inhibitors were analyzed by Spearman correlation analysis. Drug sensitivity analysis of HIC1 was performed by extracting data from the CellMiner™ database. Results: HIC1 expression was abnormally expressed in most cancers, and remarkable associations between HIC1 expression and prognostic outcomes of patients in pan-cancer were detected. HIC1 was significantly correlated with T cells, macrophages, and mast cell infiltration in different cancers. Moreover, GSEA revealed that HIC1 was significantly involved in immune-related biological functions and signaling pathways. There was a close relationship of HIC1 with TMB and MSI in different cancers. Furthermore, the most exciting finding was that HIC1 expression was significantly correlated with the response to PD-1/PD-L1 inhibitors in cancer treatment. We also found that HIC1 was significantly correlated with the sensitivity of several anti-cancer drugs, such as axitinib, batracylin, and nelarabine. Finally, our clinical cohorts further validated the expression pattern of HIC1 in cancers. Conclusions: Our investigation provided an integrative understanding of the clinicopathological significance and functional roles of HIC1 in pan-cancer. Our findings suggested that HIC1 can function as a potential biomarker for predicting the prognosis, immunotherapy efficacy, and drug sensitivity with immunological activity in cancers.

To Investigate the Potential Mechanism of Huanglian Jiangtang Formula Lowering Blood Sugar in View of Network Pharmacology and Molecular Docking Technology.

Objective: In view of network pharmacology and molecular docking technology, to explore the targets as well as effect mechanism of the Huanglian Jiangtang formula (including Coptis chinensis, Anemarrhena asphodeloides, rhubarb wine, Cortex Moutan, Rehmannia glutinosa, and dried ginger) in the type II diabetes therapy. Methods: TCMSP and Batman database (DB) were used to retrieve the chemical components and action targets of drugs; GeneCards, OMIM, TTD, DrugBank, and other databases were applied to screen the disease targets. We used the UniProt DB to annotate the targets before building the drug-compound-target network with Cytoscape 3.9.1. We also exploited the String DB to construct the protein-protein interaction (PPI) network. In addition, the targets for the treatment of type II diabetes were searched in the DrugBank, OMIM, GeneCards, and TTD database; then, we utilized Venn to intersect the key targets for the therapy of type II diabetes and active ingredient targets to obtain common targets. Furthermore, we exploited the common targets using GO and KEGG enrichment analysis method. The common targets and core components were analyzed by molecular docking using the AutoDock software. Results: A total of 61 effective components of this compound were screened out; drugs and type II diabetes have 278 common targets; the PPI network screened core target proteins such as CDKN1A, CDK2, and E2F1 with the help of molecular docking technology; the three main compounds including quercetin, kaempferol, and gamma-aminobutyric acid were obtained. Besides, the key target proteins had excellent binding properties with the main components. The signal pathways of six compound interventions in type II diabetes were mostly related to cancer, cocaine addiction, aminoacyl-tRNA biosynthesis, glycine, serine, threonine metabolism, platinum drug resistance, and other pathways, according to the KEGG enrichment analysis method. Conclusion: In the treatment of diabetes, the Huanglian Jiangtang formula has sorts of properties especially in the aspects of composition, target, and pathway. Its molecular target and mechanism of action may be related to pathways in cancer, cocaine addiction, aminoacyl-tRNA biosynthesis, glycine, serine, threonine metabolism, platinum drug resistance, and other pathways. This conclusion can provide theoretical support and science for further research.

Recent advances in gout drugs.

Gout is an autoinflammatory disease caused by the deposition of urate crystals. As the most common inflammatory arthritis, gout has a high incidence and can induce various severe complications. At present, there is no effective cure method in the world. With the deepening of medical research, gout treatment drugs continue to progress. In this review, we provide a landscape view of the current state of the research on gout treatment drugs, including the research progress of anti-inflammatory and analgesic drugs, drugs that promote uric acid excretion, and drugs that inhibit uric acid production. We mainly emphasize the understanding of gout as an auto-inflammatory disease and the discovery strategy of related gout drugs to provide a systematic and theoretical basis for the new exploration of gout drug discovery.

RNA adenosine modifications related to prognosis and immune infiltration in osteosarcoma.

BACKGROUND: RNA adenosine modifications, which are primarily mediated by "writer" enzymes (RMWs), play a key role in epigenetic regulation in various biological processes, including tumorigenesis. However, the expression and prognostic role of these genes in osteosarcoma (OS) remain unclear. METHODS: Univariate and multivariate Cox analyses were used to construct the RMW signature for OS using Target datasets. RMW expression in OS tissue was detected by qPCR analysis. Xcell and GSVA were used to determine the relationship between RMWs and immune infiltration. The DGIdb and CMap databases were used for drug prediction. In vivo and in vitro experiments showed that strophanthidin elicited antitumor activity against OS. RESULTS: A 3-RMW (CSTF2, ADAR and WTAP) prognostic signature in OS was constructed using the Target dataset and verified using GEO datasets and 63 independent OS tissues via qPCR analysis. High-risk OS patients had poor overall survival, and the prognostic signature was an independent prognostic factor for OS. Functional studies showed that tumour-, metabolism-, cell cycle- and immune-related pathways were related to high risk. Next, we found that RMW-derived high-risk patients exhibited increased infiltration of M2 macrophages and cDCs. Furthermore, we predicted the potential drugs for OS using the DGIdb and CMap databases. In vivo and in vitro experiments showed that strophanthidin elicited antitumor activity against OS by repressing cell growth and inducing cell cycle arrest at the G1 phase. CONCLUSION: The 3-RWM-based prognostic signature established in this study is a novel gene signature associated with immune infiltration, and strophanthidin was identified as a candidate therapy for OS by repressing OS cell growth and the cell cycle.

Plasma Leukocyte Cell-Derived Chemotaxin 2 (LECT2) as a Risk Factor of Coronary Artery Disease: A Cross-Sectional Study.

Many studies have shown that leukocyte cell-derived chemotaxin 2 (LECT2) is associated with metabolic disorders, which is a risk factor of arteriosclerosis. We assessed the level of LECT-2 in patients with coronary artery disease (CAD) and its severity and prognosis. We selected 666 participants who underwent coronary angiography in our hospital and included patients with non-CAD, patients with stable angina pectoris (SAP), patients with unstable angina (UA), patients with non-ST-segment elevation myocardial infarction (NSTEMI) and patients with ST-segment elevation myocardial infarction (STEMI). The serum level of LECT-2 was higher in patients with CAD than in patients with non-CAD and was an independent predictor for CAD. Subgroup analysis showed that compared with the SAP group, the UA, NSTEMI, and STEMI groups had higher serum levels of LECT-2. In addition, the level of LECT-2 was related to the SYNTAX score and SYNTAX II score. Finally, patients with acute myocardial infarction (AMI) with elevated levels of LECT-2 had a higher risk of major adverse cardiovascular events (MACEs) within 12 months than those with lower levels of LECT-2. Plasma LECT-2 levels may be useful for the diagnosis of CAD and as predictors of MACE in patients with AMI.

Inhibition of Mitochondrial Oxidative Damage Improves Reendothelialization Capacity of Endothelial Progenitor Cells via SIRT3 (Sirtuin 3)-Enhanced SOD2 (Superoxide Dismutase 2) Deacetylation in Hypertension.

OBJECTIVE: Dysfunction of endothelial progenitor cells (EPCs) leads to impaired endothelial repair capacity in patients with hypertension, but the mechanisms remain incompletely understood. Mitochondrial oxidative stress is involved in endothelial injury in hypertension. In this study, we aim to investigate the role of mitochondrial oxidative stress in the deficient endothelial reparative capacity of EPCs and identify enhanced SIRT3 (sirtuin 3)-mediated SOD2 (superoxide dismutase 2) deacetylation as a novel endothelial protective mechanism in hypertension. Approach and Results: Hypertension-EPCs displayed increased mitochondrial reactive oxygen species and mitochondrial damage, including loss of mitochondrial membrane potential, abnormal mitochondrial ultrastructure, and mtDNA oxidative injury, which was coincided with impaired in vitro function and in vivo reendothelialization capacity. The harmful effects of hypertension on mitochondrial function of EPCs were in vitro mimicked by angiotensin II coincubation. Scavenging of mitochondrial reactive oxygen species with mitoTEMPO attenuated mitochondrial oxidative damage and rescued reendothelialization capacity. Enzymatic activity and deacetylation level of SOD2 were significantly reduced in hypertension-EPCs, which was accompanied with decreased SIRT3 expression. Knockdown of SIRT3 in EPCs resulted in mitochondrial oxidative damage, hyperacetylation of SOD2, and suppression of reendothelialization capacity. SIRT3 physically interacted with SOD2 and eliminated excess mitochondrial reactive oxygen species, restored mitochondrial function through enhancing SOD2 activity by deacetylation of K68. Upregulation of SIRT3/SOD2 signaling improved reendothelialization capability of EPCs. CONCLUSIONS: The present study demonstrated for the first time that mitochondrial oxidative damage because of deficient SIRT3/SOD2 signaling contributes to the decline in reendothelialization capacity of EPCs in hypertension. Maintenance of mitochondrial redox homeostasis in EPCs may be a novel therapeutic target for endothelial injury.

Chronic remote ischemic preconditioning-induced increase of circulating hSDF-1α level and its relation with reduction of blood pressure and protection endothelial function in hypertension.

Although previous data showed that remote ischemic preconditioning (RIPC) has beneficial effect on blood pressure (BP) reduction, the efficacy of RIPC-induced decline in BP and the favorable humoral factors in hypertension is elusive. This present study is performed to evaluate whether RIPC reduces BP, improves microvascular endothelial function and increases circulating hSDF-1α generation in hypertension. Fifteen hypertensive patients received 3 periods of 5-min inflation/deflation of the forearm with a cuff on the upper arm daily for 30 days. Clinic and 24-h ambulatory blood pressure monitoring (ABPM) were examined before and after the end of this procedure. Microvascular endothelial function was measured by finger reactive hyperemia index (RHI) using the Endo-PAT 2000 device. The circulating hSDF-1α level was tested by ELISA. RIPC significantly decreased systolic BP (139.13 ± 6.68 versus 131.45 ± 7.45 mmHg) and diastolic BP (89.67 ± 4.98 versus 83.83 ± 6.65 mmHg), meanwhile 24-h ambulatory systolic and diastolic BP dropped from 136.33 ± 9.10 mmHg to 131.33 ± 7.12 mmHg and 87.60 ± 6.22 mmHg to 82.47 ± 4.47 mmHg respectively. RHI was improved (1.95 ± 0.34 versus 2.47 ± 0.44). Plasma hSDF-1α level was markedly increased after RIPC (1585.86 ± 167.17 versus 1719.54 ± 211.17 pg/ml). The increase in hSDF-1α level was associated with the fall in clinic and 24-h ABPM and rise in RHI. The present data suggests that RIPC may be a novel alternative or complementary intervention means to treat hypertension and protect endothelial function.