A novel four­gene biomarker for tobacco smoking -induced colorectal cancer progression.

INTRODUCTION: Cigarette smoking greatly promotes the progression and poor prognosis of colorectal cancer (CRC) patients, with the molecular mechanism still not fully clear. METHODS: In this study, CRC cells were exposed to tobacco specific nitrosamine 4­(methylnitrosamino)­1­(3­pyridyl) 1­butanone (NNK), and the differentially expressed smoking-related genes were identified based on both NNK-induced CRC cells and a total of 763 CRC tissues from TCGA cohort. Cox regression analysis, ROC curve and Kaplan-Meier plot were used to establish the risk score model for CRC prognosis. Moreover, qRT-PCR, western blotting, colony formation, migration and invasion assays were performed to verify the core differentially expressed smoking-related gene and its molecular function in NNK-induced CRC progression. RESULTS: Results indicated NNK significantly enhanced CRC cell proliferation, migration and invasion. Moreover, a four-gene signature containing AKR1B10, CALB2, PLAC1, GNA15 was established as CRC prognosis marker. Among these four genes, AKR1B10 was further validated as the core gene, and its expression was significantly inhibited after NNK exposure in CRC cells. Results of gene enrichment analysis and western blotting suggested AKR1B10 might reduce the malignant progression of NNK-induced CRC cells through inhibiting Wnt signaling pathway by promoting E-Cadherin expression and inhibiting the expression of N-Cadherin, ß-Catenin, Vimentin and Snail. CONCLUSION: In conclusion, a new four smoking-related genes can be jointly used as prognostic markers for CRC. AKR1B10 served as a tumor suppressor, can be used as a potential target to inhibit NNK-induced CRC malignant progression through regulating Wnt signaling pathway. IMPLICATIONS: This study demonstrates tobacco-derived NNK dependence would promote the malignant progression of colorectal cancer through regulating the expressions of AKR1B10/Wnt signaling pathway. And a novel four-gene signature is established for the prognosis prediction of smoking CRC patients. These findings have important translational implications given the continued use of tobacco and the difficulty in smoking cessation worldwide, which can be applied to alleviate the adverse effects induced by tobacco dependence on colorectal cancer patients.

Quadratic associations between cardiovascular stress reactivity and development of cool and hot executive functions in adolescents.

Stress affects executive functions and exploring the association between stress-induced physiological reactivity and executive functions could highlight the potential mechanism of the stress-cognitive function link. Our study examined the linear and nonlinear associations between cardiovascular stress reactivity and cool and hot executive functions among adolescents. In November 2021 (T1), 273 Chinese adolescents between 11 and 14 (Mage = 12.93, SDage = 0.79) underwent a speech task during which their cardiovascular data were recorded, and they completed a Flanker task and an Emotional Stroop task. In May 2023 (T2), 253 adolescents again completed the Flanker and Emotional Stroop tasks. Cool and hot executive functions were assessed using the intra-individual reaction time variability of the Flanker task and Emotional Stroop task, respectively. Results showed that cardiovascular stress reactivity was positively linearly associated with cool executive functions at T1 and quadratically (inverted U-shaped) associated with cool executive functions at T1 and hot executive functions at T1 and T2. These findings suggest that compared to very high and very low cardiovascular reactivity, moderate to high cardiovascular reactivity to a structured social challenge is associated with better cool and hot executive functions.

DNA demethylase TET2-mediated reduction of HADHB expression contributes to cadmium-induced malignant progression of colorectal cancer.

Environmental exposure to the cadmium (Cd) has been shown to be a risk factor for colorectal cancer (CRC) progression, but the exact mechanism has not been fully elucidated. In this study, we found that chronic Cd (3 µM) exposure promoted the proliferation, adhesion, migration, and invasion of CRC cells in vitro, as well as lung metastasis in vivo. RNA-seq and TCGA-COAD datasets revealed that decreased hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta (HADHB) expression may be a crucial factor in Cd-induced CRC progression. Further analysis using qRT-PCR and tissue microarrays from CRC patients showed that HADHB expression was significantly reduced in CRC tissues compared to adjacent normal tissues, and low HADHB expression was associated with adverse clinical features and poor overall survival, either directly or through TNM stage. Furthermore, HADHB was found to play an important role in the Cd-induced malignant metastatic phenotype of CRC cells and lung metastasis in mice. Mechanistically, we discovered that chronic Cd exposure resulted in hypermethylation of the HADHB promoter region via inhibition of DNA demethylase tet methylcytosine dioxygenase 2 (TET2), which then led to decreased HADHB expression and activation of the FAK signaling pathway, and ultimately contributed to CRC progression. In conclusion, this study provided a new potential insight and evaluable biomarker for Cd exposure-induced CRC progression and treatment.

Nonlinear Moderation Effect of Vagal Regulation on the Link between Childhood Trauma and Adolescent Internalizing and Externalizing Symptoms.

Childhood trauma is a leading early adverse environment that increases psychopathological symptoms. Respiratory sinus arrhythmia (RSA) suppression to challenges as a marker of self-regulation is found to linearly moderate the link between early adverse experiences and psychopathological symptoms, but yielding mixed findings. The present study examined the relationships between childhood trauma and internalizing and externalizing symptoms via a 1.5-year longitudinal design and the quadratic moderation effect of RSA suppression on these relationships among adolescents. In November 2021 (T1), the final sample of 275 Chinese adolescents (Mage = 12.94, SDage = 0.79; 49.82% females) completed the short form of Childhood Trauma Questionnaire and the Achenbach Youth Self-Report-2001 and underwent a speech task during which their baseline RSA and stress exposure RSA were obtained. In June 2023 (T2), 251 adolescents completed the Achenbach Youth Self-Report-2001. Results showed that childhood trauma at T1 was positively correlated with internalizing and externalizing symptoms at T1 and T2. RSA suppression to stress quadratically moderated these associations, such that adolescents with moderate rather than higher or lower RSA suppression had the least internalizing and externalizing symptoms at T1 and T2 when exposed to childhood trauma. The findings suggest that moderate RSA suppression to stress as a marker of optimal vagal regulation buffers the risk of developmental psychopathology from early adverse experiences.

Sesamin induces cell cycle arrest and apoptosis through p38/C-Jun N-terminal kinase mitogen-activated protein kinase pathways in human colorectal cancer cells.

Sesamin, a lignan compound, exhibits a variety of biological activities and possesses potent anticancer properties on some human cancers. However, its effect on human colorectal cancer (CRC) remains to be elucidated. To investigate the effects of sesamin on CRC cells and further to explore the mechanisms, cell viability, cell cycle and apoptosis assays were performed in this study. We found that sesamin had a selective antiproliferation of CRC cell line HCT116 in a dose- and time-dependent manner, but no obvious effect on human normal colorectal mucosa epithelial cell FHC. Further study showed that sesamin-induced cell cycle arrest and decreased the expression of Cyclin D1 significantly and dose-dependently in HCT116 cells. Moreover, sesamin dose-dependently triggered apoptosis of HCT116 but not FHC, and promoted the expression levels of proapoptotic biomarkers Bax, cleaved caspase-3 and cleaved PARP-1 and inhibited the expression of antiapoptotic biomarker Bcl-2. Western blot analysis was used to reveal the possible signaling pathways, and we found that sesamin upregulated the phosphorylation expression levels of C-Jun N-terminal kinase (JNK) and p38 except ERK1/2 in a dose-dependent way in both HCT116 and another CRC cell line SW480. Moreover, we found that the apoptosis effect induced by sesamin was partially eliminated by inhibiting JNK or p38 activation. Finally, we showed that sesamin effectively reduced the growth of xenograft tumors derived from cell lines with limited toxicity. Taken together, the potential ability of sesamin to induce cell cycle arrest and apoptosis was shown to be via the p38 and JNK mitogen-activated protein kinase signaling pathways, which may be one of the mechanisms of the anticancer activity of this low-toxic agent.

Nicotine-derived NNK induces the stemness enrichment of CRC cells through regulating the balance of DUSP4-ERK1/2 feedback loop.

Cigarette smoking has been considered as an independent risk factor for colorectal cancer (CRC) initiation and progression. In this study, we found that cigarette smoking was significantly associated with poor CRC differentiation (P = 0.040). Since studies have indicated that poorly differentiated tumors are more aggressive and metastasize earlier, leading to poorer prognosis; and cancer stem cells (CSCs) are largely responsible for tumor differentiation state, here we observed that the exposure of nicotine-derived 4-(methylnitrosamino)- 1-(3-pyridyl)- 1-butanone (NNK) promoted cell sphere formation and the expression of the stem cell markers, CD44, OCT4, C-MYC and NANOG in HCT8 and DLD-1 cells. Further colony formation assay, CCK-8 assay and tumor-bearing experiment showed that NNK exposure significantly increased the proliferative and growth ability of CRC cells. In mechanism, we found that NNK-activated ERK1/2 played an important role in enrichment of CRC stem cells and the up-regulation of DUSP4, a major negative regulator of ERK1/2. Moreover, DUSP4 up-regulation was essential for maintaining NNK-activated ERK1/2 in an appropriate level, which was an required event for NNK-induced stemness enrichment of CRC cells. Taken together, our findings provided a possible mechanistic insight into cigarette smoking-induced CRC progression.

Identification of the urine and serum metabolomics signature of gout.

OBJECTIVE: Gout is the most common inflammatory arthritis and the worldwide incidence is increasing. By revealing the metabolic alterations in serum and urine of gout patients, the first aim of our study was to discover novel molecular biomarkers allowing for early diagnosis. We also aimed to investigate the underlying pathogenic pathways. METHODS: Serum and urine samples from gout patients (n = 30) and age-matched healthy controls (n = 30) were analysed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to screen the differential metabolites and construct a diagnostic model. Next, the model was verified and optimized in the second validation cohort (n = 100). The pathways were illustrated to understand the underlying pathogenesis of gout. RESULTS: In general, serum metabolomics demonstrated a clearer distinction than urine metabolomics. In the discovery cohort, 40 differential serum metabolites were identified that could distinguish gout patients from healthy controls. Among them, eight serum metabolites were verified in the validation cohort. Through regression analysis, the final model consisted of three serum metabolites-pyroglutamic acid, 2-methylbutyryl carnitine and Phe-Phe-that presented optimal diagnostic power. The three proposed metabolites produced an area under the curve of 0.956 (95% CI 0.911, 1.000). Additionally, the proposed metabolic pathways were primarily involved in purine metabolism, branched-chain amino acids (BCAAs) metabolism, the tricarboxylic acid cycle, synthesis and degradation of ketone bodies, bile secretion and arachidonic acid metabolism. CONCLUSION: The metabolomics signatures could serve as an efficient tool for early diagnosis and provide novel insights into the pathogenesis of gout.

The comparison of dyslipidemia and serum uric acid in patients with gout and asymptomatic hyperuricemia: a cross-sectional study.

BACKGROUND: Dyslipidemia often concurs with hyperuricemia. Our study was to discover different lipid levels of gout and asymptomatic hyperuricemia and the predictors of sUA (serum uric acid) levels. METHODS: A cross-sectional study was performed to collect demographic, clinical variables, comorbidities and laboratory testing in patients with gout and asymptomatic hyperuricemia. Group comparison was performed with Student's t-test or Mann Whitney U test for continuous variables and chi-squared tests for categorical variables (Fisher's exact test where appropriate) and to screen potential risk factors. Correlation of sUA levels with demographic and biochemical variables were performed by using correlation analysis. The variable with s p-value less than 0.20 during the group comparison or clinical relevance was introduced into the stepwise multiple regression model. RESULTS: Six hundred fifty-three patients with gout and 63 patients with asymptomatic hyperuricemia (> 420 µmol/L in male and > 360 µmol/L in female) were enrolled, including 553 (84.7%) males. The mean age was 47.8 ± 16.0 years old. Elevated total cholesterol (TC) was observed in 173 (26.5%) cases with gout. Increased triglycerides (TG) and low-density lipoprotein (LDL-C) levels were observed in 242 (37.1%) cases and 270 (41.3%) cases with gout, individually. In contrast, elevated TC, TG and LDL-C levels were observed in 10 (15.9%) cases, 30 (47.6%) cases and 22 (34.9%) cases with hyperuricemia, individually. Significant differences were found in age, serum creatine, TC and erythrocyte sedimentation rate (ESR) between gout and asymptomatic hyperuricemia groups (p < 0.05). In patients with asymptomatic hyperuricemia, 12 (19.0%) patients had hypertension and 5 (7.9%) suffered from coronary heart diseases. Male (B = -112.7, p < 0.001), high-density lipoprotein (HDL-C) (B = -60.797, p = 0.013), body mass index (BMI) (B = 5.168, p = 0.024), age (B = -3.475, p = 0.006), age of hyperuricemia onset (B = 2.683, p = 0.032), and serum creatine (B = 0.534, p < 0.001) were predictors of sUA levels in gout patients (adjusted R2 = 28.7%). CONCLUSIONS: Dyslipidemia is more commonly seen in patients with gout, compared to asymptomatic hyperuricemia. HDL-C is a protective predictor of sUA levels in gout.

JWA suppresses tumor angiogenesis via Sp1-activated matrix metalloproteinase-2 and its prognostic significance in human gastric cancer.

JWA, a multifunctional microtubule-binding protein, plays an important role in regulating tumor metastasis via inhibition of matrix metalloproteinase-2 (MMP-2). Recent investigations suggest that MMP-2 is an angiogenesis-associated molecule. In this study, we provide novel evidence that JWA inhibits tumor angiogenesis in gastric cancer (GC). In two independent retrospective GC cohorts, we found that the expression of JWA was downregulated and that of MMP-2 was upregulated in GC tissues compared with the same in normal gastric mucosa. For patients treated with surgery alone, a strong and independent negative prognostic value was shown for low JWA and high MMP-2 expressions separately, which was even stronger when combined (hazard ratio = 7.75, P < 0.001, in the training cohort; hazard ratio = 2.31, P < 0.001, in the validation cohort). Moreover, we found that loss of JWA expression was strongly correlated with increased GC angiogenesis. In vitro, JWA inhibited MMP-2 at both messenger RNA and protein levels by modulating Sp1 activity. Knockdown of endogenous JWA resulted in enhanced human umbilical vein endothelial cell tube formation and MMP-2 expression. Furthermore, JWA was found to inhibit Sp1 activity via an ubiquitin-proteasome-dependent mechanism and to downregulate the expression of the proangiogenic MMP-2. Our findings imply that JWA and MMP-2 may serve as promising prognostic markers in resectable GC, with JWA as a useful biomarker of angiogenesis in GC and a potential therapeutic target by MMP-2 modulation.

The demethylase ALKBH5 mediates ZKSCAN3 expression through the m6A modification to activate VEGFA transcription and thus participates in MNNG-induced gastric cancer progression.

N-Nitroso compounds (NOCs) are recognized as important factors that promote gastric cancer development, but the specific effects and potential mechanisms by which NOC exposure promotes gastric cancer are still poorly understood. In this study, we explored the effects and potential molecular mechanisms of NOCs on the promotion of gastric cancer using methylnitronitrosoguanidine (MNNG), a classical direct carcinogen of NOC. The results of in vivo and in vitro experiments showed that chronic and low-concentration MNNG exposure significantly promoted the malignant progression of tumors, including cell migration, cell invasion, vasculogenic mimicry (VM) formation, cell spheroid formation, stem cell-like marker expression, and gastric cancer growth and metastasis. Mechanistically, we revealed that demethylase ALKBH5 regulated the level of the N6­methyladenosine (m6A) modification in the 3'UTR and CDS region of the ZKSCAN3 mRNA to promote ZKSCAN3 expression, mediated the binding of ZKSCAN3 to the VEGFA promoter region to regulate VEGFA transcription, and participated in MNNG-induced gastric cancer cell migration, invasion, VM formation, cell spheroid formation, stem cell-like marker expression and ultimately gastric cancer progression. In addition, our study revealed that ALKBH5-ZKSCAN3-VEGFA signaling was significantly activated during MNNG-induced gastric carcinogenesis, and further studies in gastric cancer patients showed that ALKBH5, ZKSCAN3, and VEGFA expression were upregulated in cancers compared with paired gastric mucosal tissues, that ALKBH5, ZKSCAN3, and VEGFA could serve as important biomarkers for determining patient prognosis, and that the molecular combination showed greater prognostic value. These findings provide a theoretical basis for developing gastric cancer interventions for NOCs and for determining gastric cancer progression.

Nicotine-derived NNK promotes CRC progression through activating TMUB1/AKT pathway in METTL14/YTHDF2-mediated m6A manner.

Cigarette smoking substantially promotes tumorigenesis and progression of colorectal cancer; however, the underlying molecular mechanism remains unclear. Among 662 colorectal cancer patients, our investigation revealed a significant correlation between cigarette smoking and factors, such as large tumor size, poor differentiation, and high degree of invasion. Among the nicotine-derived nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) emerged as the most critical carcinogen, which significantly promoted the malignant progression of colorectal cancer both in vivo and in vitro. The results of methylated RNA immunoprecipitation and transcriptome sequencing indicated that NNK upregulated transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) via N6-adenosine methylation, which was regulated by methyltransferase-like 14 (METTL14) and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Elevated TMUB1 levels were associated with a higher risk of cancer invasion and metastasis, leading to a high mortality risk in patients with colorectal cancer. Additionally, TMUB1 promoted lysine63-linked ubiquitination of AKT by interacting with AMFR, which led to the induction of malignant proliferation and metastasis in colorectal cancer cells exposed to NNK. In summary, this study provides a new insight, indicating that targeting TMUB1 expression via METTL14/YTHDF2 mediated N6-adenosine methylation may be a potential therapeutic and prognostic target for patients with colorectal cancer who smoke.

Purple Yam Polyphenol Extracts Exert Anticolitis and Anticolitis-Associated Colorectal Cancer Effects through Inactivation of NF-κB/p65 and STAT3 Signaling Pathways.

Colorectal cancer is a malignancy with high incidence and mortality worldwide, and ulcerative colitis (UC) is strongly associated with colorectal cancer. Purple yam, also known as Dioscorea alata, has been reported to be rich in plant polyphenols that have possessed anti-inflammatory, antioxidant, and antitumor properties. However, it is not clear whether purple yam polyphenol extracts (PYPE) can improve colitis and inhibit colitis-related colorectal tumorigenesis. Therefore, we used dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated colorectal cancer (CAC) models in mice to evaluate the preventive value and possible mechanisms of PYPE. It was found that PYPE effectively alleviated DSS-induced colitis, inhibited macrophage infiltration, and reduced the production of the pro-inflammatory cytokines, such as TNF-α, IL-6, IL-1ß, IL-17A, CXCL1, and MCP-1, and the higher the concentration of PYPE, the better the inhibitory effect. In addition, PYPE dramatically prevented the development of CAC and tumor proliferation in mice. Furthermore, PYPE inactivated NF-κB and STAT3 signaling to exert anti-inflammatory and anticancer effects. Taken together, these findings indicate that PYPE may be used as a promising preventive strategy against UC and CAC.

Meta analysis of the curative effect of acupuncture on post-stroke depression.

OBJECTIVE: To systematically evaluate the curative effect of acupuncture on post-stroke depression (PSD). METHODS: The internet was used to retrieve the Wanfang Medical Data System, Chinese Periodical Net, the Weipu Information Resources System, PubMed and the Cochrane Library Database. Relevant articles, up to September 2010, were manually retrieved. These papers included studies that had performed random and semi-random control trials for the use of acupuncture to treat PSD. Fifteen random control tests involving 1096 patients were included in this study and individual cases, interventional measures and curative effects were extracted from this research. Grade methodological quality evaluation and meta-analysis were performed on these studies. RESULTS: Comparison between the acupuncture group and the Western medicine group for the curative rate on PSD revealed an OR of 1.48, 95% CI = [1.11 1.97] and P = 0.008. Comparison of obviously effective rate shows that OR = 1.39, 95% CI = [1.08 1.80] and P = 0.01. Comparison of effective rate shows that OR = 0.83, 95% CI = [0.631.09] and P = 0.18. CONCLUSION: Comparison between the acupuncture group and Western medicine group in treating PSD revealed that there is a statistical difference in curative rate and remarkably effective rate, but no difference in effective rate.

Identification and validation of a cigarette smoke-related five-gene signature as a prognostic biomarker in kidney renal clear cell carcinoma.

Cigarette smoking greatly promotes the progression of kidney renal clear cell carcinoma (KIRC), however, the underlying molecular events has not been fully established. In this study, RCC cells were exposed to the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, nicotine-derived nitrosamine) for 120 days (40 passages), and then the soft agar colony formation, wound healing and transwell assays were used to explore characteristics of RCC cells. RNA-seq was used to explore differentially expressed genes. We found that NNK promoted RCC cell growth and migration in a dose-dependent manner, and RNA-seq explored 14 differentially expressed genes. In TCGA-KIRC cohort, Lasso regression and multivariate COX regression models screened and constructed a five-gene signature containing ANKRD1, CYB5A, ECHDC3, MT1E, and AKT1S1. This novel gene signature significantly associated with TNM stage, invasion depth, metastasis, and tumor grade. Moreover, when compared with individual genes, the gene signature contained a higher hazard ratio and therefore had a more powerful value for the prognosis of KIRC. A nomogram was also developed based on clinical features and the gene signature, which showed good application. Finally, AKT1S1, the most crucial component of the gene signature, was significantly induced after NNK exposure and its related AKT/mTOR signaling pathway was dramatically activated. Our findings supported that NNK exposure would promote the KIRC progression, and the novel cigarette smoke-related five-gene signature might serve as a highly efficient biomarker to identify progression of KIRC patients, AKT1S1 might play an important role in cigarette smoke exposure-induced KIRC progression.

Integrative blood-derived epigenetic and transcriptomic analysis reveals the potential regulatory role of DNA methylation in ankylosing spondylitis.

BACKGROUND: The currently known risk loci could explain a small proportion of the heritability of ankylosing spondylitis (AS). Epigenetics might account for the missing heritability. We aimed to seek more novel AS-associated DNA methylation alterations and delineate the regulatory effect of DNA methylation and gene expression with integrated analysis of methylome and transcriptome. METHODS: Epigenome-wide DNA methylation and mRNA expression were profiled in peripheral blood mononuclear cells (PBMCs) from 45 individuals (AS: health controls (HCs) = 30:15) with high-throughput array. The methylome was validated in an independent cohort (AS: HCs = 12:12). Pearson correlation analysis and causal inference tests (CIT) were conducted to determine potentially causative regulatory effects of methylation on mRNA expression. RESULTS: A total of 4794 differentially methylated positions (DMPs) were identified associated with AS, 2526 DMPs of which were validated in an independent cohort. Both cohorts highlighted T cell receptor (TCR) signaling and Th17 differentiation pathways. Besides, AS patients manifested increased DNA methylation variability. The methylation levels of 158 DMPs were correlated with the mRNA expression levels of 112 genes, which formed interconnected network concentrated on Th17 cell differentiation and TCR signaling pathway (LCK, FYN, CD3G, TCF7, ZAP70, CXCL12, and PLCG1). We also identified several cis-acting DNA methylation and gene expression changes associated with AS risk, which might regulate the cellular mechanisms underlying AS. CONCLUSIONS: Our studies outlined the landscapes of epi-signatures of AS and several methylation-gene expression-AS regulatory axis and highlighted the Th17 cell differentiation and TCR signaling pathway, which might provide innovative molecular targets for therapeutic interventions for AS.

Sesamin inhibits hypoxia-stimulated angiogenesis via the NF-κB p65/HIF-1α/VEGFA signaling pathway in human colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths. Tumor angiogenesis plays a critical role in CRC metastasis, and hypoxia, which widely existed in the tumor mass, drives tumor angiogenesis. Sesamin, a phytochemical derived from sesame seeds, has been reported to inhibit tumor cell growth and metastasis, however, the role of sesamin in CRC angiogenesis and its underlying mechanism have not been investigated yet. Here, an in vitro tube formation assay and an in vivo angiogenesis assay were used to explore the role of sesamin in CRC angiogenesis. In this study, we found that sesamin significantly inhibited hypoxia-stimulated CRC angiogenesis in a dose-dependent manner in vitro. Moreover, oral intake of sesamin dramatically suppressed neovessel formation of matrigel plugs with CRC cells in nude mice. In mechanism, sesamin reduced the expression of VEGFA to inhibit hypoxia-induced CRC angiogenesis. In addition, sesamin inhibited the phosphorylation of IκBα and thus restrained NF-κB p65 to activate HIF-1α transcription under hypoxic conditions. Finally, our results indicated that sesamin inhibited hypoxia-induced CRC angiogenesis via the NF-κB/HIF-1α/VEGFA signaling pathway. Our study might provide a theoretical and experimental basis for the use of sesamin in the prevention and treatment of CRC.

ING4 Promotes Stemness Enrichment of Human Renal Cell Carcinoma Cells Through Inhibiting DUSP4 Expression to Activate the p38 MAPK/type I IFN-Stimulated Gene Signaling Pathway.

Renal cell carcinoma (RCC) recurs frequently due to high metastatic spread, resulting in a high mortality. Cancer stem cells play a critical role in initiating the tumor metastasis. Inhibitor of growth 4 (ING4) is a member of the ING family, but its impact on cancer stem cells in RCC is still unknown. In this study, we found that ING4 significantly promoted the sphere-forming size and number of RCC cells under an ultralow-attachment culture condition in vitro, tumor growth and metastasis in vivo, and the expression of some stem-like or pluripotent biomarkers CD44, MYC, OCT4, and NANOG, indicating that ING4 increased the stemness enrichment of RCC cells. Mechanistically, the ING4-activated p38 MAPK pathway possibly upregulated the expression of type I IFN-stimulated genes to promote the formation of RCC stem cells. ING4 could inhibit the expression of DUSP4 to activate p38 MAPK. In addition, selective pharmacological p38 MAPK inhibitors could significantly inhibit stemness enrichment only in ING4-overexpressed RCC cells, suggesting that the p38 MAPK inhibitors might be effective in patients with high ING4 expression in RCC tissue. Taken together, our findings proposed that ING4 might serve as a potential therapeutic target for metastatic RCC, particularly RCC stem cells.

Comorbidities and factors influencing frequent gout attacks in patients with gout: a cross-sectional study.

OBJECTIVES: The objective was to identify the comorbidities of gout, to compare gender difference and independent factors of frequent gout attacks (> 20 times). METHOD: Demographic, clinical variables, self-reported comorbidities, and biochemical variables (i.e., initial serum uric acid (UA) and UA at visit) were collected in this cross-sectional study. Gout attack times were recorded as ≤ 5, 6-10, 11-20, and > 20. Adjusted odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated to explore the association between selected risk factors and frequent gout attacks. RESULTS: Six hundred fifty-three gout patients with a mean age of 48.3 ± 15.8 years were included, 84.7% of whom were males. The median gout duration was 6.0 (3.0-12.0) years. The most common comorbidities involved hypertension (166, 25.4%), coronary artery disease (CAD) (67, 10.3%), chronic kidney disease (66, 10.1%), and hyperlipidemia (57, 8.7%). Abnormalities including nephrolithiasis (29.4%), hydronephrosis (3.2%), and gallstones (11.9%) were also found. Although female patients had a longer disease duration and more CAD, they had a lower level of UA, creatine, and C-reactive protein (CRP) but higher high-density lipoprotein cholesterol (HDL-C) (p < 0.05). A positive correlation between UA and triglycerides was found in females (p = 0.039). Patients with renal insufficiency or nephrolithiasis had longer disease duration and more gout attacks (p < 0.001). In multivariable regression analysis, only gout duration (OR = 7.89, p < 0.001) and UA (OR = 1.48, p < 0.001) was independent factors of frequent gout attacks. CONCLUSIONS: Comorbidity screening involving dyslipidemia is often neglected in gout patients. Gout duration and UA are the risk factors of frequent gout attacks. Key Points • Comorbidities can be overlooked if the screening for lipid levels, cardiovascular disease, and kidney disease is not completed. • There are differences in comorbidities and biochemical findings between male and female patients with gout. • Gout duration and serum uric acid level are independent risk factors of frequent gout attacks.

Dynamics of Adaptive Immune Cell and NK Cell Subsets in Patients With Ankylosing Spondylitis After IL-17A Inhibition by Secukinumab.

Background: Anti-IL-17A therapy is generally effectively applied in patients with Ankylosing Spondylitis (AS) to achieve and maintain remission. However, the influence of anti-IL-17A on the composition of the immune system is not apparent. Our prospective study was to explore the changes in immune imbalance regarding T cell, B cell and natural killer (NK) cell subsets after secukinumab treatment in AS patients. Methods: Immune cell distribution of 43 AS patients treated with secukinumab for 12 weeks and 47 healthy controls (HC) were evaluated. Flow cytometry using monoclonal antibodies against 25 surface markers was accomplished to explore the frequencies of lineage subsets. The differences between HC, AS pre-treatment, and post-treatment were compared using the paired Wilcoxon test, Mann-Whitney U test, and ANOVA. Results: AS patients had altered immune cell distribution regarding T cell and B cell subsets. Apart from activated differentiation of CD4+ T cell, CD8+ T cell and B cell, higher levels of cytotoxic T (Tc) two cells and Tc17 cells were noted in AS patients. We confirmed that helper T (Th) one cell became decreased; however, Th17 cells and T follicular helper (Tfh) 17 cells went increased in AS. After 12 weeks of secukinumab therapy, CRP and ASDAS became significantly decreased, and meanwhile, the proportions of Th1 cells, Tfh17 cells and classic switched B cells were changed towards those of HC. A decreased CRP was positively correlated with a decrease in the frequency of naïve CD8+ T cells (p = 0.039) and B cells (p = 0.007) after secukinumab treatment. An elevated level of T cells at baseline was detected in patients who had a good response to secukinumab (p = 0.005). Conclusion: Our study confirmed that AS patients had significant multiple immune cell dysregulation. Anti-IL-17A therapy (Secukinumab) could reverse partial immune cell imbalance.