Search

Background: Extraintestinal metastasis is the main therapeutic challenge for colorectal cancer, the third most common cancer worldwide. Various components of the tumor microenvironment, especially cancer-associated fibroblasts (CAFs), play important roles in tumor metastasis. NAMPT is often overexpressed in tumor tissues and is associated with poorer prognosis. However, the specific roles of NAMPT as well as NAD+ in tumor metastasis are relatively unknown. Therefore, we investigated the role of NAMPT and related NAD+ metabolism in cancer-associated fibroblasts mediated colorectal cancer metastasis. Objective: This study sought to explore the molecular mechanism of FK866 in CAFs cell and colorectal cancer proliferation and metastasis. Methods: The expression of NAMPT in clinical tissues were detected by immunohistochemically analysis. To investigate the role of NAMPT and NAD+ in the interactions between cancer cells and cancer-associated fibroblasts in tumor microenvironment, we isolated CAFs from normal and cancer tissues of clinical colorectal cancer patients. CAFs were treated with different concentrations of FK866, inhibitor of NAMPT, then the NAD+ content was detected using kits, the expression of CAFs activity and stemness indexes was assessed by Western blot and immunofluorescence. The secreted factors of these cells were analyzed by cellular inflammatory factor microarrays. The migration of SW480 after co-cultured with FK866-treated CAFs was detected by Transwell. Finally, high-throughput sequencing was performed to identify the proteins that are associated with the effect of altered NAD+ in CAFs on the migration of cancer cells. Results: NAMPT expression is significantly higher in colorectal cancer tissues, especially in metastatic cancer patients, than that in normal tissues. Inhibition of NAMPT by FK866 in CAFs decreases the expression of activity indicators (α-SMA, PDGFRβ), stemness indicators (BMI-1, OCT4), inflammatory factors and chemokines. Meanwhile, FK866 treatment inhibits the migration ability of SW480 cells co-cultured with CAFs. Finally, high-throughput sequencing reveals that PITX3 are down-regulated after NAD+ reduction in CAFs, which could be reversed by adding NAM, a raw material for NAD+ synthesis. Conclusion: Inhibition of the NAMPT-mediated NAD+ synthesis by FK866 may decrease the activation and stemness of CAFs, reduce the secretion of inflammatory and chemokines by suppressing the expression of PITX3, resulting in the suppression of colorectal cancer metastasis. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a metabolic disease caused by a combination of genetic and environmental factors. The importance of the inflammatory response occurring in the pancreas and adipose tissue in the occurrence and progression of diabetes has been gradually accepted. Excess blood glucose and free fatty acids produce large amounts of inflammatory cytokines and chemokines through oxidative stress and endoplasmic reticulum stress. There is sufficient evidence that proinflammatory mediators, such as interleukin (IL)-1β, IL-6, macrophage chemotactic protein-1, and tumor necrosis factor-α, are engaged in insulin resistance in peripheral adipose tissue and the apoptosis of pancreatic β-cells. IL-36, IL-37, and IL-38, as new members of the IL-1 family, play an indispensable role in the regulation of immune system homeostasis and are involved in the pathogenesis of inflammatory and autoimmune diseases. Recently, the abnormal expression of IL-36, IL-37, and IL-38 in diabetes has been reported. In this review, we discuss the emerging functions, potential mechanisms, and future research directions on the role of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To study the correlation between non-alcoholic fatty liver disease (NAFLD) and glycosylated hemoglobin (HbA1c) in middle-aged and aged population., Methods: A total of 4 127 in-service workers and retirees aged 45 years old or above from one petrochemical enterprise in Ningbo were enrolled in our study. The waistline, body mass index, blood pressure, fasting blood-glucose, blood lipid profile, glutamyltranspeptidase, HbA1c and epigastrium B ultrasound were investigated. According to the quartile of HbA1c level, participants were divided into four groups, namely, Q1 group ≤5.2%, Q2 group >5.2%-5.4%, Q3>5.4%-5.6% and Q4 group>5.6%. The prevalence of NAFLD and clinical characteristics of each group were analyzed. Logistic regression was used to predict independent risk factors of NAFLD., Results: The morbidity of NAFLD was 27.2% with 31.9% in male and 21% in female, which was significantly higher in men. In Q1, Q2, Q3 and Q4 group, the prevalence of NAFLD were 18.5% (178/961), 22.8% (185/812), 25.6% (280/1 095), 38.1% (480/1 259) respectively. With the increase of HbA1c level, the morbidity of NAFLD increased synchronously. The age, systolic pressure, total cholesterol, low density lipoprotein cholesterin and fasting blood-glucose were all elevated according to the increase of HbA1c in 1 123 NAFLD patients. Multi-factor logistic regression analysis indicated that high HbAlc level was the risk factor of NAFLD (OR=1.67, 95%CI 1.15-2.43, P=0.007)., Conclusion: HbA1c is an independent risk factor of NAFLD and both of these are closely related to blood lipid metabolism disorder.