EGFR upregulates miRNA subset to inhibit CYBRD1 and cause DDP resistance in gastric cancer.

Chemoresistance is a considerable challenge for gastric cancer (GC), and the combination of cisplatin (DDP) and anti-EGFR therapy failed to show remarkable benefit. So other targets in EGFR-overexpressed and DDP-resistant GC need to be explored. Both cytological experiments and database bioinformatics analysis were applied in this study. It was confirmed that the prognosis of GC patients with EGFR oe was poor. EGFR regulated intracellular redox metabolism, enhanced GSH content and led to DDP resistance. A subset of miRNAs including miR-135b, miR-106a, miR-29a, miR-23a and miR-15a was upregulated in EGFR-overexpressed and DDP-resistant GC cells. Furthermore, EGFR inhibited CYBRD1 via enhancing the miRNA subset and scavenged the redundant ROS to cause DDP resistance. Therefore, to inhibit the miRNA subset at the same time of anti-EGFR therapy might reverse DDP resistance, serving as a potential novel drug for the future treatment of EGFR-overexpressed and DDP-resistant GC.

Association Between Serum 25-Hydroxyvitamin D and Trichomonas vaginalis Infection Among American Adults: NHANES 2013-2016.

BACKGROUND: Previous studies have suggested that vitamin D may possess anti-infection properties, but the relationship between vitamin D and Trichomonas vaginalis infection remains unexplored. METHODS: Using data from the National Health and Nutrition Examination Survey between 2013 and 2016, we conducted multivariate regression analyses and subgroup analyses to investigate the association between 25-hydroxyvitamin D (25[OH]D) levels and T. vaginalis infection, ensuring the robustness of our results. RESULTS: The final sample included data from 4318 individuals aged 20 to 59 years, among which 92 were diagnosed with T. vaginalis infection. For every 10 nmol/L increase in serum 25(OH)D level, there was a 22% reduction in the likelihood of T. vaginalis infection incidence (adjusted odds ratio [aOR], 0.78; 95% confidence interval [CI], 0.69-0.90). Similarly, higher concentration tertiles demonstrated relatively lower infection ratios compared with the tertile with the lowest 25(OH)D concentration (aOR, 0.54 [95% CI, 0.30-0.95; P = 0.030] for T2; aOR, 0.23 [95% CI, 0.09-0.61; P < 0.001] for T3). CONCLUSIONS: Our cross-sectional study indicates a negative association between 25(OH)D levels and the prevalence of T. vaginalis infection. However, further high-quality evidence is needed to establish a causal relationship between 25(OH)D levels and T. vaginalis infection, as well as to evaluate the potential role of vitamin D supplementation in preventing T. vaginalis infection.

Association between sugar-free beverage intake and childhood obesity among Chinese children and adolescents.

BACKGROUND: The relationship between sugar-free beverage (SFB) intake and childhood obesity among Chinese children is unknown. OBJECTIVES: To describe the status of SFB consumption among children and adolescents in China and assess the association between SFB intake and different types of obesity. METHODS: The study was based on the baseline data of an ongoing cohort project named Evaluation and Monitoring on School-based Nutrition and Growth in Shenzhen (EMSNGS). Food frequency questionnaires were used to collect information on SFB consumption in 3227 students aged 9-17. Physical and clinical examinations were conducted by trained investigators and clinicians. Multivariable binary logistic regression models were performed to assess the association between SFB intake and general obesity, overweight/obesity, abdominal obesity, metabolically unhealthy overweight (MUOW)/metabolically unhealthy obesity (MUO). RESULTS: The median age of the participants was 13.28 years. Among the participants, 55.2% were boys, and 66.1% were adolescents. The median SFB consumption was 16.67 mL/d. After adjusting for potential confounding factors, each 100 mL increase in daily SFB intake was associated with an increased risk of overweight/obesity (OR = 1.14; 95%CI: 1.06-1.23), abdominal obesity (OR = 1.12; 95%CI: 1.03-1.23), and MUOW/MUO (OR = 1.12; 95%CI: 1.02-1.21), respectively. Stratified analyses showed that family income may have an impact on the association between SFB intake and overweight/obesity (P for interaction = 0.021) and abdominal obesity (P for interaction = 0.031). CONCLUSION: SFB intake was positively associated with childhood obesity in Chinese children, particularly among individuals with high-income families.

Non-metabolic enzyme function of PKM2 in hepatocellular carcinoma: A review.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors with the highest incidence and mortality in the world, causing a serious burden on society. Pyruvate kinase M2 (PKM2) is one of the principal metabolic enzymes involved in glycolysis. Studies have shown that PKM2 is highly expressed in HCC and can be translocated to the nucleus, where it interacts with various transcription factors and proteins such as hypoxia-inducible factor-1α, sterol regulatory element-binding protein 1a, signal transducer and activator of transcription 3, nuclear factor erythroid 2-like 2 and histone H3, exerting non-metabolic enzyme functions to regulate the cell cycle, proliferation, apoptosis, immune escape, migration, and invasion, as well as HCC angiogenesis and tumor microenvironment. This review is focused on the recent progress of PKM2 interacting with various transcription factors and proteins affecting the onset and development of HCC, as well as natural drugs and noncoding RNA impacting diverse biological functions of liver cancer cells by regulating PKM2 non-metabolic enzyme functions, thereby providing valuable directions for the prognosis improvement and molecular targeted therapy of HCC in the future.

Associations between dietary patterns and serum uric acid concentrations in children and adolescents: a cross-sectional study.

The serum uric acid (SUA) concentrations in children and adolescents in southeast coastal China are generally high. The relationship between diet and SUA in children and adolescents remains unclear. The objective of the study was to assess the associations between data-driven dietary patterns with SUA concentrations and hyperuricemia in Chinese children and adolescents and to explore the role of food components. This study involved 3383 participants aged 9 to 17 years from a representative nutrition and growth survey conducted in Shenzhen, a southeast coastal city in China. The dietary intake data, obtained from a validated food frequency questionnaire, were categorized into 19 food groups for factor analysis to derive dietary patterns. Weighted least squares regression was performed to examine the associations between dietary patterns and SUA concentrations, logistic regression was used to analyze the relationship between dietary patterns and hyperuricemia, and the relationship between food groups and food components with SUA concentrations was further analyzed. The potential dietary factors contributing to the associations between dietary patterns and SUA concentrations were explored by adjusting various food components. Six dietary patterns were identified by factor analysis, including an ultra-processed diet, plant-based nutritious diet, meat-based diet, soup/seafood/egg diet, vegetarian diet, and mushroom/animal organ diet. After adjusting for confounders, the meat-based diet exhibited a positive correlation with SUA concentrations (ß = 4.89; 95% confidence interval (CI): 0.60-9.18; P = 0.03), while the vegetarian diet could reduce the risk of hyperuricemia (odds ratio = 0.88; 95% CI: 0.80-0.98; P = 0.02). In addition, dietary intake of poultry (g per d) (ß = 0.09, 95% CI: 0.02, 0.16, P = 0.02), animal organs, blood (g per d) (ß = 0.32, 95% CI: 0.12, 0.51, P = 0.002) and hypoxanthine (mg per d) (ß = 0.03, 95% CI: 0.01, 0.06, P = 0.02) showed a significantly positive correlation with SUA concentrations, while that of vegetables (g per d) (ß = -0.02, 95% CI: -0.03, -0.01, P = 0.03) showed a significantly negative correlation. In summary, for children and adolescents, it is recommended to increase vegetable intake and reduce animal-based food intake in order to control SUA concentration and prevent hyperuricemia. This study was registered at the China Clinical Trials Registry (ChiCTR2100051722).

Highly Active Nano-Reactor for Responding Tumor Microenvironment and Antitumor Therapy.

The tumor microenvironment is complex and changeable, so the design of a nano-delivery system for the tumor microenvironment has attracted wide attention. Based on this, we designed an intelligent nano-reactor for the characteristics of acidic pH and hypoxia in the tumor microenvironment. Firstly, the silver nano-balls were synthesized by the biological template method, which exhibited a good photothermal conversion efficiency and can realize the photothermal treatment of tumor sites. Subsequently, the hypoxic prodrug tirapazamine (TPZ) and polydopamine (PDA) for chemotherapy were self-assembled. After PDA arrived at the tumor site (pH 5.5) from the normal physiological environment (pH 7.4), the hypoxic prodrug TPZ was released in pH response by PDA. Subsequently, TPZ selectively induced obvious cell damage under tumor hypoxia stimulation but had no toxic effect on normal cells under normal oxygen. In addition, the nano-converter was loaded with iRGD on the surface, which enhanced the targeted delivery of the nano-reactor to achieve a highly effective antitumor effect. The nano-reactor was capable of combining photothermal/chemotherapy therapy. Importantly, it can selectively kill tumor cells without damaging normal cells based on the characteristics of the tumor microenvironment, with high bio-safety and clinical transformation potential.

LINC00665 up-regulates SIN3A expression to modulate the progression of colorectal cancer via sponging miR-138-5p.

BACKGROUND: Colorectal cancer (CRC) is a malignant tumor affecting people worldwide. Long noncoding RNAs (lncRNAs) is a crucial factor modulating various cancer progression, including CRC. Long intergenic non-protein coding RNA 665 (LINC00665) has been proven as an oncogene in several cancers, but its function in CRC is still unclear. METHODS: QRT-PCR was performed for RNA quantification. Functional assays were designed and carried to test cell phenotype while mechanism experiments were adopted for detecting the interaction of LINC00665, microRNA-138-5p (miR-138-5p) and SIN3 transcription regulator family member A (SIN3A). In vivo experiments were conducted to test LINC00665 function on modulating CRC tumor progression. RESULTS: LINC00665 displayed high expression in CRC tissues and cells, and promoted tumor progression in vivo. MiR-138-5p displayed abnormally low expression in CRC, and was verified to be sponged by LINC00665. Furthermore, SIN3A, as the downstream mRNA of miR-138-5p, exerted promoting impacts on CRC cells. Rescue experiments certified that overexpressed SIN3A or silenced miR-138-5p could offset the repressed function of LINC00665 knockdown on CRC progression. CONCLUSIONS: LINC00665 could sponge miR-138-5p to up-regulate SIN3A expression, thus accelerating CRC progression.

Compressive Strength Prediction of Cemented Backfill Containing Phosphate Tailings Using Extreme Gradient Boosting Optimized by Whale Optimization Algorithm.

Unconfined compressive strength (UCS) is the most significant mechanical index for cemented backfill, and it is mainly determined by traditional mechanical tests. This study optimized the extreme gradient boosting (XGBoost) model by utilizing the whale optimization algorithm (WOA) to construct a hybrid model for the UCS prediction of cemented backfill. The PT proportion, the OPC proportion, the FA proportion, the solid concentration, and the curing age were selected as input variables, and the UCS of the cemented PT backfill was selected as the output variable. The original XGBoost model, the XGBoost model optimized by particle swarm optimization (PSO-XGBoost), and the decision tree (DT) model were also constructed for comparison with the WOA-XGBoost model. The results showed that the values of the root mean square error (RMSE), coefficient of determination (R2), and mean absolute error (MAE) obtained from the WOA-XGBoost model, XGBoost model, PSO-XGBoost model, and DT model were equal to (0.241, 0.967, 0.184), (0.426, 0.917, 0.336), (0.316, 0.943, 0.258), and (0.464, 0.852, 0.357), respectively. The results show that the proposed WOA-XGBoost has better prediction accuracy than the other machine learning models, confirming the ability of the WOA to enhance XGBoost in cemented PT backfill strength prediction. The WOA-XGBoost model could be a fast and accurate method for the UCS prediction of cemented PT backfill.

Blockage of K(Ca)3.1 and Kv1.3 channels of the B lymphocyte decreases the inflammatory monocyte chemotaxis.

OBJECTIVE: To investigate the effects of Ca(2+) activated potassium channel KCa3.1 and voltage-gated potassium channel Kv1.3 of B lymphocyte on inflammatory monocytes chemotaxis and the potential mechanisms. MATERIALS AND METHODS: Thanswell test was used to detect the inflammatory monocyte (Ly-6C(hi)) chemotaxis caused by the B lymphocyte. Enzyme-linked immunosorbent assay (ELISA) was applied to detecting the C-C motif ligand 7 (CCL7) in cultured media. Cell counting kit-8 (CCK) was used to detect the proliferation of B lymphocytes after activation and blockage of both KCa3.1 and Kv1.3 channels. Western blot was used to detect the expression of phosphorylated extracellular signal-regulated kinase (P-ERK) of the B lymphocytes. RESULTS: When activated, B lymphocytes significantly proliferated. After application of KCa3.1 channel-specific inhibitor TRAM-34 and potent Kv1.3 channel inhibitor ShK, both B lymphocytes proliferation and Ly-6C(hi) monocyte chemotaxis were significantly inhibited. The expression of chemotaxis related factor CCL7 decreased remarkably. CONCLUSION: The opening of KCa3.1 and Kv1.3 channels promote B lymphocyte activation, proliferation and Ly-6C(hi) monocyte chemotaxis. The increase of CCL7 secretion by B lymphocyte may explain the pro migration effects.

[Effect of Kv1.3 and KCa3.1 potassium ion channels on the proliferation and migration of monocytes/macrophages].

This study was aimed to investigate the effects of blockade of Ca(2+) activated channel KCa3.1 and voltage-gated potassium channel Kv1.3 of the monocytes/macrophages on inflammatory monocyte chemotaxis. Chemotaxis assay was used to test the inflammatory Ly-6C(hi) monocyte chemotaxis caused by the monocytes/macrophages. The proliferation of monocytes/macrophages was detected by cell counting kit-8 (CCK8). Enzyme-linked immunosorbent assay (ELISA) was applied to detect the C-C motif ligand 7 (CCL7) in cultured media. The results showed that the recruitment of Ly-6C(hi) monocyte induced by monocytes/macrophages was suppressed by the potent Kv1.3 blocker Stichodactyla helianthus neurotoxin (ShK) or the specific KCa3.1 inhibitor TRAM-34. Meanwhile, the proliferation of monocytes/macrophages was significantly inhibited by ShK. The response of Ly-6C(hi) monocyte pretreated with ShK or TRAM-34 to CCL2 was declined. These results suggest that KCa3.1 and Kv1.3 may play an important role in monocytes/macrophages' proliferation and migration.

Blockade of KCa3.1 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction.

BACKGROUND/AIMS: After myocardial infarction (MI), cardiac fibrosis greatly contributes to left ventricular remodeling and heart failure. The intermediate-conductance calcium-activated potassium Channel (KCa3.1) has been recently proposed as an attractive target of fibrosis. The present study aimed to detect the effects of KCa3.1 blockade on ventricular remodeling following MI and its potential mechanisms. METHODS: Myocardial expression of KCa3.1 was initially measured in a mouse MI model by Western blot and real time-polymerase chain reaction. Then after treatment with TRAM-34, a highly selective KCa3.1 blocker, heart function and fibrosis were evaluated by echocardiography, histology and immunohistochemistry. Furthermore, the role of KCa3.1 in neonatal mouse cardiac fibroblasts (CFs) stimulated by angiotensin II (Ang II) was tested. RESULTS: Myocardium expressed high level of KCa3.1 after MI. Pharmacological blockade of KCa3.1 channel improved heart function and reduced ventricular dilation and fibrosis. Besides, a lower prevalence of myofibroblasts was found in TRAM-34 treatment group. In vitro studies KCa3.1 was up regulated in CFs induced by Ang II and suppressed by its blocker.KCa3.1 pharmacological blockade attenuated CFs proliferation, differentiation and profibrogenic genes expression and may regulating through AKT and ERK1/2 pathways. CONCLUSION: Blockade of KCa3.1 is able to attenuate ventricular remodeling after MI through inhibiting the pro-fibrotic effects of CFs.

Fucoidan inhibits the growth of hepatocellular carcinoma independent of angiogenesis.

Some sulphated polysaccharides can bind bFGF but are unable to present bFGF to its high-affinity receptors. Fucoidan, a sulphated polysaccharide purified from brown algae, which has been used as an anticancer drug in traditional Chinese medicine for hundreds of years, exhibits a variety of anticancer effects, including the induction of the apoptosis and autophagy of cancer cells, the inhibition of the growth of cancer cells, the induction of angiogenesis, and the improvement of antitumour immunity. Our research shows that fucoidan dose not inhibit the expressions of VEGF, bFGF, IL-8, and heparanase in HCC cells and/or tumour tissues. Moreover, fucoidan exhibited low affinity for bFGF and could not block the binding of bFGF to heparan sulphated. Although fucoidan had no effect on angiogenesis and apoptosis in vivo, this drug significantly inhibited the tumour growth and the expression of PCNA. These results suggest that fucoidan exhibits an anticancer effect in vivo at least partly through inhibition of the proliferation of HCC cells, although it is unable to suppress the angiogenesis induced by HCC.

Gekko-sulfated glycopeptide inhibits tumor angiogenesis by targeting basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) is a therapeutic target of anti-angiogenesis. Here, we report that a novel sulfated glycopeptide derived from Gekko swinhonis Guenther (GSPP), an anticancer drug in traditional Chinese medicine, inhibits tumor angiogenesis by targeting bFGF. GSPP significantly decreased the production of bFGF in hepatoma cells by suppressing early growth response-1. GSPP inhibited the release of bFGF from extracellular matrix by blocking heparanase enzymatic activity. Moreover, GSPP competitively inhibited bFGF binding to heparin/heparan sulfate via direct binding to bFGF. Importantly, GSPP abrogated the bFGF-stimulated proliferation and migration of endothelial cells, whereas it had no inhibitory effect on endothelial cells in the absence of bFGF. Further study revealed that GSPP prevented bFGF-induced neovascularization and inhibited tumor angiogenesis and tumor growth in a xenograft mouse model. These results demonstrate that GSPP inhibits tumor angiogenesis by blocking bFGF production, release from the extracellular matrix, and binding to its low affinity receptor, heparin/heparan sulfate.

[Expression and significance of macrophage migration inhibitory factor in gastric adenocarcinoma].

OBJECTIVE: To investigate the expression of MIF on the gastric adenocarcinoma, evaluate the relation between the MIF expression and tumor differentiation, lymph node metastasis and other clinical patho-features. METHODS: 120 gastric adenocarcinoma cancer tissues, 40 tissues besides cancer and 40 common mucosa tissues specimens are collected. Detect the expression of MIF with immunohistochemistry method (Streptavidin-Peroxidase). RESULTS: Positive rate of MIF expression in gastric cancer is 80.8% (97/120). Those in poorly differentiated, moderately differentiated and well-differentiated gastric adenocarcinoma are 97.5% (39/40), 82.5% (33/40), 62.5% (25/40), analytical factor of Spearman rank correlation r(s) is 0.458 (χ(2) = 27.046, P < 0.001). Positive rate of MIF expression in tissues besides cancer is 40% (16/40) and that in normal gastric mucosa is 7.5% (3/40). Positive rate of MIF expression in gastric adenocarcinoma without lymph node metastasis is 40% (22/55) and the rate with lymph node metastasis is 67% (44/65). CONCLUSIONS: There is overexpression of MIF in the gastric adenocarcinoma. Expression of MIF in different differentiated cancer is different. Expression in poorly differentiated is higher than that in moderately differentiated and well-differentiated cancer. The level of expression of MIF malignancy has positive correlation with malignancy degree of gastric adenocarcinoma. MIF expression has nothing to do with age, gender, tumor sizes or location.