3-8-dihydroxy-6h-dibenzo(b-d)pyran-6-one and Diabetes-Mellitus--Type-2

This study aims to investigate the effect and mechanism of Urolithin A (UA) on neuronal stress damage on cognitive impairment in type 2 diabetes mellitus (T2DM) mouse model induced by high-fat diet (HFD) and streptozotocin (STZ).. T2DM mice fed with UA display an attenuated cognitive impairment along with suppressed endoplasmic reticulum (ER) stress and Tau hyperphosphorylation in brain. Similar restraint effect of UA on Tau hyperphosphorylation and ER stress is also observed in high glucose-treated primary hippocampal neurons. Moreover, UA ameliorates oxidative stress, ER stress, aberrant energy metabolism, and apoptosis in 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced HT22 cells. Atp2a3 is identified as a potential target gene of UA which is closely related to intracellular calcium homeostasis, ER stress, and apoptosis, so that UA significantly down-regulated Atp2a3 expression in DMNQ-induced cells. Furthermore, the protection effect of UA against ER stress and apoptosis is abolished by Atp2a3 over-expression in HT22 cells. Taken together, these data suggest that UA performs anti-stress effect by suppressing the expression of Atp2a3 in damaged neuronal cells and thus attenuates diabetes-associated cognitive impairment in T2DM mice.. The study implies UA as a potential novel pharmaceutic target for neurodegeneration and stress damage through regulating the expression of Atp2a3.

Topics: Animals; Apoptosis; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Mice; Neurons

This study aims to investigate the effect of Urolithin A (UA) on diabetes-associated cognitive impairment in type 2 diabetes mellitus (T2DM) mouse model induced by high-fat diet (HFD) and streptozotocin (STZ).. The UA-treated T2DM mice display an attenuated cognitive impairment as well as reduced levels of metabolic endotoxemia and proinflammatory cytokines in serum. A systemic restraint of gut/brain inflammation in UA-treated T2DM mice is also observed as the downregulation of TLR4 and Myd88 in colon along with the inhibition of GFAP, Iba-1, NLRP3, and inflammation-related genes in brain. Moreover, UA ameliorates gut barrier dysfunction by upregulating tight-junction proteins levels. Furthermore, UA restores the hyperglycemia-mediated downregulation of genes involved in N-glycan biosynthesis both in vivo and in vitro, which plays a crucial role in barrier integrity. Although UA shares similar beneficial effects on diabetes with metformin, unlike metformin, the effect of UA is independent of gut microbiome and short chain fatty acids. Taken together, these data suggest that feeding UA can attenuate diabetes-associated cognitive impairment by ameliorating systemic inflammation and intestinal barrier dysfunction via N-glycan biosynthesis pathway. The study implies UA as a potential novel pharmaceutic target for diabetes therapy via manipulating gut-brain axis and N-glycan metabolism.

Topics: Animals; Cognitive Dysfunction; Coumarins; Diabetes Mellitus, Type 2; Diet, High-Fat; Inflammation; Intestinal Diseases; Metformin; Mice; Mice, Inbred C57BL; Polysaccharides

Urolithin A (UroA), the main intestinal microflora metabolite of ellagic acid of berries, pomegranate,and some other traditional chinese herbals such as emblica officinalis,etc,has been reported to exhibit anti-inflammatory, anti-oxidative, anti-tumor and pro-autophagy effects.. This study evaluated the anti-diabetic and pancreas-protective effects of UroA using a mice model of type 2 diabetes and preliminarily explored its effect on autophagy as well as the mechanism involved.. Type 2 diabetes model was induced by high-fat diet (HFD; 60% energy as fat) and low-dose streptozotocin (85 mg/kg) injection. Mice were administered with UroA (50 mg/kg/d) alone or UroA-chloroquine (autophagy inhibitor) combination for 8 weeks.. UroA improved symptoms of diabetic mice such as high water intake volume, high urine volume, significantly decreased fasting blood glucose (FBG), after-glucose-loading glucose, glycated hemoglobin (GHb) levels, plasma C-peptide, malondialdehyde (MDA) and interleukin-1 β level, increased reduced glutathione (GSH), interleukin-10 content, and glucose tolerance. UroA also improved pancreatic function indexes such as HOMA-β as evidenced by improved pathological and ultrastructural features of the pancreas assessed by light microscopy and transmission electron microscopy (TEM). Accordingly, UroA decreased mitochondrial swelling and myelin-like cytoplasmic inclusions. UroA significantly upregulated the protein levels of microtubule-associated protein 1 light chain 3-II (LC3II) and beclin1, downregulated sequestosome 1 (p62) accompanied by decreased expression of apoptotic protein cleaved caspase3 in pancreas of diabetic mice. In addition, it increased the phosphorylation level of protein kinase B (p-Akt) and mammalian target of rapamycin (p-mTOR). Most of these effects of UroA were reversed by treatment with autophagy inhibitor chloroquine.. Our findings reveal that the pancreas protective effects of UroA against diabetes were partially mediated by its regulation of autophagy and AKT/mTOR signal pathway.

Topics: Animals; Autophagy; Blood Glucose; Chloroquine; Coumarins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Male; Mice; Mice, Inbred C57BL; Pancreas; Proto-Oncogene Proteins c-akt; Signal Transduction; Streptozocin; TOR Serine-Threonine Kinases