Umbilical Cord Mesenchymal Stem Cells Combined with Fufang Xueshuantong Capsule Attenuate Oxidative Stress and Vascular Lesions in Diabetic Rats by Activating Nrf-2/HO-1 Signaling Pathway.

BACKGROUND: Macrovascular lesions are the main cause of death and disability in diabetes mellitus, and excessive accumulation of cholesterol and lipids can lead to long-term and repeated damage of vascular endothelial cells. Umbilical cord mesenchymal stem cells (UCMSCs) can attenuate vascular endothelial damage in type 1 diabetic mice, while Fufang Xueshuantong capsule (FXC) has a protective effect on endothelial function; however, whether FXC in combination with UCMSCs can improve T2DM macrovascular lesions as well as its mechanism of action are not clear. Therefore, the aim of this study was to reveal the role of FXC + UCMSCs in T2DM vasculopathy and their potential mechanism in the treatment of T2DM. METHODS: The control and T2DM groups were intragastrically administered with equal amounts of saline, the UCMSCs group was injected with UCMSCs (1×106, resuspended cells with 0.5 mL PBS) in the tail vein, the FXC group was intragastrically administered with 0.58 g/kg FXC, and the UCMSCs + FXC group was injected with UCMSCs (1×106) in the tail vein, followed by FXC (0.58 g/kg), for 8 weeks. RESULTS: We found that FXC+UCMSCs effectively reduced lipid levels (TG, TC, and LDL-C) and ameliorated aortic lesions in T2DM rats. Meanwhile, Nrf2 and HO-1 expression were upregulated. We demonstrated that inhibition of Nrf-2 expression blocked the inhibitory effect of FXC+UCMSCs-CM on apoptosis and oxidative stress injury. CONCLUSION: Our data suggest that FXC+UCMSCs may attenuate oxidative stress injury and macroangiopathy in T2DM by activating the Nrf-2/HO-1 pathway.

Palmitic acid-activated GPRs/KLF7/CCL2 pathway is involved in the crosstalk between bone marrow adipocytes and prostate cancer.

BACKGROUND: Obesity-induced abnormal bone marrow microenvironment is one of the important risk element for bone metastasis in prostate cancer (PCa). The present study aimed to determine whether obesity-induced elevation in palmitic acid (PA), which is the most abundant of the free fatty acids (FFAs), increased CCL2 via the GPRs/KLF7 pathway in bone marrow adipocytes (BMA) to facilitate PCa growth and metastasis. METHODS: We constructed a bone-tumor bearing mouse model with obesity through high-fat diet, and observed the tumor formation ability of PCa cells. In vitro, observe the effect of PA on the expression level of CCL2 in BMA through GPRs/KLF7 signaling pathway. After co-culture of BMA and PCa cells, CCK8 assay and transwell experiment were used to detect the changes in biological behavior of PCa cells stimulated by BMA. RESULTS: The BMA distribution in the bone marrow cavity of BALB/c nude mice fed with the high-fat diet (HFD) was evidently higher than that in the mice fed with the normal diet (ND). Moreover, HFD-induced obesity promoted KLF7/CCL2 expression in BMA and PCa cell growth in the bone marrow cavity of the mice. In the vitro experiment, a conditioned medium with increased CCL2 obtained from the BMA cultured with PA (CM-BMA-PA) was used for culturing the PCa cell lines, which evidently enhanced the proliferation, invasion, and migration ability. KLF7 significantly increased the CCL2 expression and secretion levels in BMA by targeting the promoter region of the CCL2 gene. In addition, GPR40/120 engaged in the PA-induced high KLF7/CCL2 levels in BMA to facilitate the malignant progression of PC-3 cells. CONCLUSIONS: PA-activated GPRs/KLF7/CCL2 pathway in BMA facilitates prostate cancer growth and metastasis.

Caprylic Acid (FFA C8:0) promotes the progression of prostate cancer by up-regulating G protein-coupled receptor 84/ Krüppel-like factor 7.

BACKGROUND: In previous study, we found that the content of medium-chain fatty acid Caprylic Acid (FFA C8:0) may be an important risk factor of obesity induced prostate cancer (PCa). However, the relationship between FFA C8:0 and PCa has not been reported. In this study, we explored whether the FFA C8:0 can promotes the progression of PCa by up-regulating Krüppel-like factor 7 (KLF7). METHODS: We collected tissues from PCa patients and Benign Prostate Hyperplasia (BPH), constructed a primary-tumor bearing mouse model with obesity through high-fat diet, and observed the tumor formation ability of PCa cells. In vitro, CCK8 assay, plate cloning, Transwell and scratch experiment were used to detect the changes in biological behavior of PCa cells stimulated by FFA C8:0. RESULTS: First, we found that the expression level of KLF7 is higher in PCa tissues of patients, and the expression of KLF7 is positively correlated with tumour-promoting gene IL-6, while it is negative correlated with another tumour-suppressor gene p21. Then, this study found that PCa cells were more likely to form tumors in diet induced obese mice. Compared with the normal diet group (ND), the expression levels of KLF7 in tumor tissues in high-fat diet group (HFD) were higher. Futhermore, we verified that high concentrations of FFA C8:0 can promote the biological behavior of PCa cells by activating KLF7/IL-6/p21 signaling pathway, which is mediated by the GPR84. CONCLUSIONS: Our research may provide a potential target for clinical prevention and treatment of PCa which induced by obesity.

miR-548ag functions as an oncogene by suppressing MOB1B in the development of obesity-related endometrial cancer.

Obesity is a high-risk factor in the development of endometrial cancer (EC). Our previous study observed that miR-548ag was significantly overexpressed in the sera of obese individuals. Here, we report the function of miR-548ag and its mechanism in promoting the obesity-related progression of EC. The content of miR-548ag was increased in the serum of obese EC individuals. Bioinformatics analysis indicated that the survival rate of EC patients with a higher expression of miR-548ag was significantly reduced. The Mps One Binder Kinase Activator 1B (MOB1B, the core member of the Hippo signaling pathway) is a direct target gene of miR-548ag, which is inversely correlated with the expression of miR-548ag. The overexpression of miR-548ag enhances the proliferation, invasion, and migration, and inhibits apoptosis by downregulating the expression of MOB1B, leading to the deactivation of the Hippo pathway in EC cell lines and contributing to tumor progression in vivo. Our study has established that miR-548ag functions as an oncogene by suppressing MOB1B in the development of obesity-related EC.

[RS102895 inhibits the proliferation, invasion, and migration of PC-3 prostate cancer cells by blocking CCL2/CCR2 pathway].

Objective To investigate the effect of RS102895, a specific C-C motif chemokine receptor 2 (CCR2) antagonist, on the biological behavior of prostate cancer (PCa) cells with different degrees of malignancy. Methods Non-androgen-dependent prostate cancer cells PC-3 and androgen-dependent prostate cancer cells 22RV1 were cultured in vitro. A control group, a recombinant C-C motif chemokine ligand 2 (rCCL2) treatment group, and a rCCL2 combined with RS102895 treatment group were established. Cell proliferation ability was detected by CCK-8 assay, cell invasion and migration abilities were detected by TranswellTM assay, mRNA expressions of cell antigen KI-67 (ki67) and matrix metalloproteinase 2 (MMP2) were detected by real-time quantitative PCR, and protein expression levels of ki67 and MMP2 were detected by Western blotting. Results The proliferation, invasion, and migration abilities of PC-3 cells were significantly enhanced by rCCL2, and the proliferation ability of 22RV1 cells was significantly increased as well. Meanwhile, the mRNA and protein expression levels of ki67 and MMP2 in PC-3 cells were significantly up-regulated by rCCL2. After RS102895 treatment, the above effects of rCCL2 were reversed. Conclusion RS102895 can inhibit the proliferation, invasion, and migration of PC-3 prostate cancer cells by specifically blocking the CCL2/CCR2 pathway and down-regulating the expressions of ki67 and MMP2.

Potential biomarker in serum for predicting susceptibility to type 2 diabetes mellitus: Free fatty acid 22:6.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is closely linked to increased levels of free fatty acids (FFAs) in obese individuals, although which FFA is most associated with type 2 diabetes mellitus is unclear. This study aimed to identify the specific FFAs that best predict the occurrence of type 2 diabetes mellitus in obese individuals, and assess their potential application value. MATERIALS AND METHODS: Participants were divided into three groups: a normal weight group (n = 20), an obese group (n = 10) and a type 2 diabetes mellitus group (n = 10). FFAs in serum samples were determined by ultra-high-pressure liquid chromatography-mass spectrometry, and orthogonal partial least squares discriminant analysis models were used to study the FFA profile among the three groups. RESULTS: Compared with the normal weight group, 14 FFAs (C8:0/10:0/14:0/16:1/18:1/20:2/ 20:3 /20:4/ 20:5/ 22:6/7:0/9:0/11:0 and C13:0) were significantly increased in the obese group, and nine FFAs (C14:0, C18:1, C20:1, C 18:2, C20:2, C20:3, C18:3, C20:5 and C22:6) were significantly increased in the type 2 diabetes mellitus group. Subsequently, the Venn diagram results showed that six FFAs (C14:0, C18:1, C20:2, C20:3, C20:5 and C22:6) were significantly increased in both the obese and type 2 diabetes mellitus groups. Among these six, C22:6 was finally identified as an independent risk factor for type 2 diabetes mellitus, and had a great potential to predict the susceptibility to type 2 diabetes mellitus (area under the curve 0.803). CONCLUSIONS: C22:6 can be an independent risk factor for type 2 diabetes mellitus, and it has a great potential to predict the susceptibility to type 2 diabetes mellitus.

Dihydroartemisinin alleviates high glucose-induced vascular smooth muscle cells proliferation and inflammation by depressing the miR-376b-3p/KLF15 pathway.

Inflammation and the proliferation of vascular smooth muscle cells (VSMCs) are seen to play critical roles in the development of vascular complications induced by diabetes and hyperglycemia. Dihydroartemisinin (DHA) has been identified as a semi-synthetic derivative of artemisinin that exhibits broad protective effects. However, the effect of DHA on high glucose (HG)-induced inflammation and proliferation of VSMCs remains unknown. Therefore, this study aims to show that DHA significantly inhibited the proliferation of VSMCs and that expression of the inflammatory cytokines IL-1ß and TNF-α was induced by HG in a dose-dependent manner. Additionally, we were able to determine that KLF15 played a critical role in HG-induced VSMC proliferation and inflammation, confirming its protective effects observed after DHA treatment in the HG-induced inflammatory response of VSMCs. DHA was observed to directly depress the HG-induced expression of miR-376b-3p, which targeted the 3'-UTR of KLF15 and inhibited its expression. These results suggested that DHA plays a protective role in HG-induced VSMC proliferation and associated inflammation by inhibiting the miR-376b-3p/KLF15 axis. Our findings provide new evidence of the mechanisms of DHA and its critical role in treating the pathogenesis of diabetic vascular complications.