Diabetic retinopathy (DR) is a progressive microvascular complication of diabetes mellitus and is characterised by excessive inflammation and oxidative stress. Urolithin A (UA), a major metabolite of ellagic acid, exerts anti-inflammatory and antioxidant functions in various human diseases. This study, for the first time, uncovered the role of UA in DR pathogenesis. Streptozotocin-induced diabetic rats were used to determine the effects of UA on blood glucose levels, retinal structures, inflammation, and oxidative stress. High glucose (HG)-induced human retinal endothelial cells (HRECs) were used to elucidate the anti-inflammatory and antioxidant mechanisms of UA in DR in vitro. The in vivo experiments demonstrated that UA injection reduced blood glucose levels, decreased albumin and vascular endothelial growth factor concentrations, and ameliorated the injured retinal structures caused by DR. UA administration also inhibited inflammation and oxidative damage in the retinal tissues of diabetic rats. Similar anti-inflammatory and antioxidant effects of UA were observed in HRECs induced by HG. Furthermore, we found that UA elevated the levels of nuclear Nrf2 and HO-1 both in vivo and in vitro. Nrf2 silencing reversed the inhibitory effects of UA on inflammation and oxidative stress during DR progression. Together, our findings indicate that UA can ameliorate DR by repressing inflammation and oxidative stress via the Nrf2/HO-1 pathway, which suggests that UA could be an effective drug for clinical DR treatment.
Thyroid carcinoma (TC) is the most common endocrine malignancy. The incidence rate of thyroid cancer has increased rapidly in recent years. The occurrence and development of thyroid cancers are highly related to the massive genetic and epigenetic changes. Therefore, it is essential to explore the mechanism of thyroid cancer pathogenesis. Genome-Wide Association Studies (GWAS) have been widely used in various diseases. Researchers have found multiple single nucleotide polymorphisms (SNPs) are significantly related to TC. However, the biological mechanism of these SNPs is still unknown. In this paper, we used one GWAS dataset and two eQTL datasets, and integrated GWAS with expression quantitative trait loci (eQTL) in both thyroid and blood to explore the mechanism of mutations and causal genes of thyroid cancer. Finally, we found rs1912998 regulates the expression of IGFALS (P = 1.70E-06) and HAGH (P = 5.08E-07) in thyroid, which is significantly related to thyroid cancer. In addition, KEGG shows that these genes participate in multiple thyroid cancer-related pathways.
Background. The development of tissue engineering provides a new method for the clinical treatment of bone defects, but the problems of slow formation and slow vascularization of tissue engineered bone have always existed. Studies have shown that the combined culture system of vascular endothelial cells and adipose stem cells is superior to single cell in repairing bone defects. With the excellent proliferation ability, secretion of synthetic collagen and a variety of regulatory factors and fibroblasts can differentiate into osteoblasts and have the potential to be excellent seed cells involved in tissue engineering bone construction. Objective. To investigate the effects of combined culture of fibroblasts, vascular endothelial cells, and adipose stem cells on proliferation and osteogenic differentiation of adipose stem cells. Methods. The cells were divided into 4 groups: adipose stem cell group, adipose stem cell+vascular endothelial cell coculture group, adipose stem cell+fibroblast coculture group, and adipose stem cell+vascular endothelial cell+fibroblast coculture group. The morphological changes of the cells were observed under an inverted microscope. After 1, 3, 5, 7, and 9 days of coculture, the proliferation of adipose stem cells in each group was detected by a CCK-8 method and the growth curve was plotted. Adipose stem cells in each group were stained with alizarin red and alkaline phosphatase at days 7, 14, 21, and 28. At the third week of coculture, Western blot was used to detect the expression level of bone morphogenetic protein 2 of adipose stem cells in each group. Results and Conclusions. (1) After 14 days of culture, some cells in the adipose stem cell+vascular endothelial cell+fibroblast coculture group fused into clumps and distributed in nests, while the adipose stem cells in the adipose stem cell group had a single cell morphology and no cell clusters were observed. (2) The cell growth curves were basically the same in each group, and the absorbance value increased gradually. The absorbance value of the adipocyte+vascular endothelial cell+fibroblast coculture group was the highest, followed by the adipocyte+fibroblast coculture group and then the adipocyte+fibroblast coculture group. (3) Alizarin red staining showed negative reaction in each group on the 7th day, and a small number of red positive cells gradually appeared in each group as time went on. On the 28th day, red positive cells were found in all groups, and most of them were in the coculture group of adipose stem cells+vascular endothelial cells+fibroblasts, showing red focal. The coculture group of adipose stem cells+vascular endothelial cells and adipose stem cells+fibroblasts was less, and the adipose stem cell group was the least. On day 28 of alkaline phosphatase staining, cells in each group had red positive particles, and the adipose stem cell+vascular endothelial cell+fibroblast coculture group and adipose stem cell+fibroblast coculture group had the most, followed by the adipose stem cell+vascular endothelial cell coculture group and then the adipose stem cell group. (4) Bone morphogenetic protein 2 was expressed in all groups, especially in adipose stem cell+fibroblast coculture group and adipose stem cell+vascular endothelial cell+ fibroblast coculture group. (5) Fibroblast could promote adipose stem cell osteogenic differentiation better than vascular endothelial cells, but the proliferation effect was not as good as vascular endothelial cells. The coculture system of fibroblast combined with vascular endothelial cells and adipose stem cells promoted the proliferation of adipose stem cells and the rapid and efficient differentiation of adipose stem cells into osteoblasts.
Objective: To investigate the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on diabetic retinopathy (DR) in diabetic rats, and to study the mechanism of hUCMSCs in treating diabetic retinopathy by tert-butylhydroquinone (tBHQ) regulation of the Nrf2/HO-1 pathway.Methods: The diabetic rat model was induced by intraperitoneal injection of streptozotocin (STZ). The experimental animals were divided into six groups: Normal, diabetes mellitus (DM), hUCMSCs, tBHQ, combined tBHQ-hUCMSCs, and all-trans-retinoid acid (ATRA)-hUCMSCs combined group. Visual function experiments and histological analyses were performed eight weeks post intravitreal injection. Biochemical and molecular analyses were used to assess the hUCMSCs composition and its biological effects.Results: Improvements in systemic oxidative stress and inflammation were found in the tBHQ group. Although hUCMSCs had no significant effect on oxidative stress, retinal structure was improved, visual defects reduced and expression of local retinal inflammatory factors were inhibited following its application. The effect of combined therapy was better than that of single therapy. Inhibition of the Nrf2/HO-1 pathway can promote the expression of systemic inflammatory factors and inhibit the therapeutic effect of hUCMSCs in the retina.Conclusions: Intravitreal administration of hUCMSCs triggers an effective cytoprotective microenvironment in the retina of diabetic mice. Alone, however, it may not significantly improve the systemic inflammatory response of diabetes. In combination with tBHQ it may promote Nrf2expression, systemic antioxidant stress and therapeutic effects of hUCMSCs.
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