scholarly journals The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE−/−Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Weiling Leng ◽  
Xinshou Ouyang ◽  
Xiaotian Lei ◽  
Mingxia Wu ◽  
Liu Chen ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Therapeutic Potential ◽  
Fat Metabolism ◽  
Sglt2 Inhibitor ◽  
Inhibitory Effect ◽  
High Fat ◽  
Protein Levels ◽  
Sodium Glucose Cotransporter ◽  
The Stability

Background. Our study aimed to observe the effect of sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin on diabetic atherosclerosis and investigate the subsequent mechanism.Methods. Aortic atherosclerosis was induced in streptozotocin induced diabetic ApoE−/−mice by feeding with high-fat diet, and dapagliflozin was administrated intragastrically for 12 weeks as treatment. Effects of dapagliflozin on indices of glucose and fat metabolism, IL-1β, IL-18, NLRP3 protein levels, and the reactive oxygen species (ROS) were measured. The atherosclerosis was evaluated by oil red O and hematoxylin-eosin staining. The effects of dapagliflozin on the IL-1βproduction in culturing primary macrophages of wild type and NLRP3−/−knockout mice were investigated for mechanism analyses.Results. Dapagliflozin treatment showed favorable effects on glucose and fat metabolism, partially reversed the formation of atherosclerosis, inhibited macrophage infiltration, and enhanced the stability of lesion. Also, reduced production of IL-1β, IL-18, NLRP3 protein, and mitochondrial ROS in the aortic tissues was detected with dapagliflozin treatment. In vitro, NLRP3 inflammasome was activated by hyperglucose and hyperlipid through ROS pathway.Conclusions. Dapagliflozin may be of therapeutic potential for diabetic atherosclerosis induced by high-fat diet, and these benefits may depend on the inhibitory effect on the secretion of IL-1βby macrophages via the ROS-NLRP3-caspase-1 pathway.

scholarly journals Ipragliflozin Ameliorates Diabetic Nephropathy Associated with Perirenal Adipose Expansion in Mice

2021 ◽  
Vol 22 (14) ◽  
pp. 7329
Author(s):  
Hideyuki Okuma ◽  
Kentaro Mori ◽  
Suguru Nakamura ◽  
Tetsuo Sekine ◽  
Yoshihiro Ogawa ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Fat Diet ◽  
Urinary Albumin Excretion ◽  
Sglt2 Inhibitor ◽  
Urinary Albumin ◽  
Standard Diet ◽  
Adipocyte Size ◽  
High Fat ◽  
Sodium Glucose Cotransporter

Sodium glucose cotransporter-2 (SGLT2) inhibitors inhibit the development of diabetic nephropathy (DN). We determined whether changes in perirenal fat (PRAT) by a SGLT2 inhibitor ipragliflozin (Ipra) contribute to the suppression of DN development. High-fat diet (HFD)-fed mice were used as a DN model and were treated with or without Ipra for 6 weeks. Ipra treatment reduced urinary albumin excretion (UAE) and glomerular hypertrophy in HFD-fed mice. In the PRAT of Ipra-treated mice, adipocyte size was increased, and inflammation, fibrosis, and adipocyte death were suppressed. In conditioned medium made from PRAT (PRAT-CM) of Ipra-treated mice, the concentration of leptin was significantly lower than PRAT-CM of mice without Ipra treatment. Serum leptin concentration in renal vein positively correlated with UAE. PRAT-CM from HFD-fed mice showed greater cell proliferation signaling in mouse glomerular endothelial cells (GECs) than PRAT-CM from standard diet-fed mice via p38MAPK and leptin-dependent pathways, whose effects were significantly attenuated in PRAT-CM from Ipra-treated mice. These findings suggest that Ipra-induced PRAT expansion may play an important role in the improvement of DN in HFD-fed mice. In vitro experiments suggest that reduced PRAT-derived leptin by Ipra could inhibit GECs proliferation, possibly contributing to the suppression of DN development.

scholarly journals Influence ofOreocnide integrifolia(Gaud.) Miq on IRS-1, Akt and Glut-4 in Fat-Fed C57BL/6J Type 2 Diabetes Mouse Model

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Ansarullah ◽  
Selvaraj Jayaraman ◽  
Anandwardhan A. Hardikar ◽  
A. V. Ramachandran
Keyword(s):  
Signaling Pathway ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Therapeutic Potential ◽  
Insulin Signaling Pathway ◽  
High Fat ◽  
Isolated Pancreatic Islets ◽  
Glut 4

Oreocnide integrifolia(OI) leaves are used as folklore medicine by the people of northeast India to alleviate diabetic symptoms. Preliminary studies revealed hypoglycemic and hypolipidemic potentials of the aqueous leaf extract. The present study was carried out to evaluate whether the OI extract induces insulin secretionin vivoandin vitroand also whether it is mediated through the insulin-signaling pathway. The experimental set-up consisted of three groups of C57BL/6J mice strain: (i) control animals fed with standard laboratory diet, (ii) diabetic animals fed with a high-fat diet for 24 weeks and (iii) extract-supplemented animals fed with 3% OI extract along with high-fat diet for 24 weeks. OI-extract supplementation lowered adiposity and plasma glucose and insulin levels. Immunoblot analysis of IRS-1, Akt and Glut-4 protein expressions in muscles of extract-supplemented animals revealed that glucoregulation was mediated through the insulin-signaling pathway. Moreover, immunostaining of pancreas revealed increased insulin immunopositive cells in OI-extract-treated animals. In addition, the insulin secretogogue ability of the OI extract was demonstrated when challenged with high glucose concentration using isolated pancreatic isletsin vitro. Overall, the present study demonstrates the possible mechanism of glucoregulation of OI extract suggestive of its therapeutic potential for the management of diabetes mellitus.

scholarly journals Inhibiting myeloperoxidase prevents onset and reverses established high-fat diet-induced microvascular insulin resistance

2019 ◽  
Vol 317 (6) ◽  
pp. E1063-E1069 ◽  
Author(s):  
Weidong Chai ◽  
Kevin Aylor ◽  
Zhenqi Liu ◽  
Li-Ming Gan ◽  
Erik Michaëlsson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Disease Risk ◽  
Therapeutic Potential ◽  
Cardiovascular Disease Risk ◽  
Sprague Dawley ◽  
High Fat

A high-fat diet (HFD) can rapidly recruit neutrophils to insulin target tissues and within days induce microvascular insulin resistance (IR). Myeloperoxidase (MPO) is highly enriched in neutrophils, can inhibit nitric oxide-mediated vasorelaxation in vitro and is associated with increased cardiovascular disease risk. AZD5904 irreversibly inhibits MPO and in human clinical trials. MPO knockout, or chemical inhibition, blunts HFD-induced metabolic IR in mice. Whether MPO affects microvascular IR or muscle metabolic insulin sensitivity in vivo is unknown. We used contrast-enhanced ultrasound and the euglycemic insulin clamp to test whether inhibiting MPO could prevent the development or reverse established HFD-induced metabolic and/or microvascular IR in Sprague-Dawley rats. Two weeks of HFD feeding blocked insulin-mediated skeletal muscle capillary recruitment, inhibited glucose utilization, and insulin signaling to muscle. Continuous subcutaneous AZD5904 infusion during the 2 wk selectively blocked HFD’s microvascular effect. Furthermore, AZD5904 infusion during the last 2 of 4 wk of HFD feeding restored microvascular insulin sensitivity but not metabolic IR. We conclude that inhibiting MPO selectively improves vascular IR. This selective microvascular effect may connote a therapeutic potential for MPO inhibition in the prevention of vascular disease/dysfunction seen in IR humans.

scholarly journals Inhibitory Effects of Six Types of Tea on Aging and High-Fat Diet-Related Amyloid Formation Activities

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1513
Author(s):  
Juan Wan ◽  
Meiyan Feng ◽  
Wenjing Pan ◽  
Xin Zheng ◽  
Xinya Xie ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
High Fat Diet ◽  
Inhibitory Effect ◽  
Premature Aging ◽  
High Fat ◽  
Amyloid A ◽  
Significant Inhibitory Effect ◽  
Lipid Metabolism Disorders ◽  
Age Related

Aging and lipid metabolism disorders promote the formation and accumulation of amyloid with β-sheet structure, closely related to cardiovascular disease, senile dementia, type 2 diabetes, and other senile degenerative diseases. In this study, five representative teas were selected from each of the six types of tea, and a total of 30 teas were selected to evaluate the inhibitory activities on the formation of aging-related amyloid in vitro. The results showed that the 30 teas had a significant inhibitory effect on the formation activity on aging-related amyloid at the protein level in vitro. Although the content of catechins is relatively low, black tea and dark tea still have significant antioxidant activity and inhibit the formation of amyloid. A high-fat diet established the model of lipid metabolism disorder in premature aging SAMP8 mice, and these mice were gavaged different tea water extracts. The results showed that different tea types have a significant inhibitory effect on the formation of β-amyloid and Aβ42 mediated by age-related lipid metabolism disorders, and the in vivo activity of fully fermented teas was better than that of green tea. The action mechanism was related to antioxidation, anti-inflammatory, and improving lipid metabolism.

Intermedin1-53 Ameliorates Homocysteine-Promoted Atherosclerotic Calcification by Inhibiting Endoplasmic Reticulum Stress

2019 ◽  
Vol 25 (3) ◽  
pp. 251-264 ◽  
Author(s):  
Jin-Ling Ren ◽  
Yue-Long Hou ◽  
Xian-Qiang Ni ◽  
Qing Zhu ◽  
Yao Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
High Fat Diet ◽  
Peritoneal Macrophages ◽  
Human Aorta ◽  
High Fat ◽  
Protein Levels ◽  
Cardiovascular Morbidity And Mortality ◽  
Mouse Peritoneal Macrophages

Aim: Vascular calcification (VC) is thought to be an independent predictor of cardiovascular morbidity and mortality. Intermedin1-53 (IMD) is a cardiovascular protective peptide and can inhibit vascular medial calcification in rats. In this study, we investigated the effect of IMD on atherosclerotic calcification induced by a high-fat diet plus homocysteine (Hcy) and the potential mechanisms. Methods: ApoE−/− mice were fed a high-fat diet with Hcy in drinking water to induce atherosclerotic calcification. Results: As compared to the high-fat diet alone, Hcy treatment significantly increased atherosclerotic lesion areas and the number of calcified nodules in aortic roots and was reduced by IMD infusion or 4-phenylbutyric acid (PBA) treatment. In vitro, as compared to calcifying medium alone, Hcy treatment further increased alkaline phosphatase activity, calcium content, and calcium nodule number in human aorta vascular smooth muscle cells (HA-VSMCs), all blocked by IMD or PBA pretreatment. Mechanistically, IMD or PBA significantly alleviated endoplasmic reticulum stress (ERS) activation compared with Hcy treatment. In parallel, IMD or PBA attenuated the messenger RNA levels of osteogenic markers and inflammatory cytokines in aortas and their protein levels in lesions of aortic roots. In vitro, Hcy treatment significantly increased the protein levels of osteoblast-like cell markers in primary rat VSMCs and inflammation markers in mouse peritoneal macrophages, all decreased with IMD or PBA pretreatment. Intermedin1-53 pretreatment also markedly reduced the protein levels of ERS markers in rat VSMCs and mouse peritoneal macrophages. Conclusions: Intermedin1-53 protects against Hcy-promoted atherosclerotic calcification in ApoE−/− mice by inhibiting ERS.

Anti-obesity effects of instant fermented teas in vitro and in mice with high-fat-diet-induced obesity

2019 ◽  
Vol 10 (6) ◽  
pp. 3502-3513 ◽  
Author(s):  
Yue Sun ◽  
Yuwan Wang ◽  
Pengpeng Song ◽  
Haisong Wang ◽  
Na Xu ◽  
...  
Keyword(s):  
Pancreatic Lipase ◽  
High Fat Diet ◽  
Inhibitory Effect ◽  
High Fat ◽  
Related Factors ◽  
Diet Induced Obesity

IDT exerted better anti-obesity effects than PET in HFD-fed mice, as evidenced by reduced BW and regulated obesity-related factors. IDT also showed inhibitory effect on pancreatic lipase in vitro.

scholarly journals (-)-Epicatechin Prevents High Fat Diet-Induced Bile-Associated Intestinal Permeabilization Both In Vivo and In Vitro

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 487-487
Author(s):  
Ziwei Wang ◽  
Corina Litterio ◽  
Michael Müller ◽  
David Vauzour ◽  
Patricia Oteiza
Keyword(s):  
Nadph Oxidase ◽  
High Fat Diet ◽  
Cell Monolayer ◽  
Intestinal Barrier ◽  
Mek Inhibitor ◽  
High Fat ◽  
Protein Levels ◽  
Fecal Bile Acids

Abstract Objectives This work investigated the capacity of (-)-epicatechin (EC) to prevent high fat diet (HFD)-induced intestinal permeabilization and the underlying mechanisms both in rodents and in Caco-2 cells. Methods Male C57BL/6J mice (7 mice/group) (20–25 g) were fed for 15 w control or HFD, supplemented without or with 20 mg EC/kg body weight. Tissues and feces were collected and stored at −80 °C for further analysis. Caco-2 cells were differentiated into intestinal epithelial cells, which were incubated in the absence or the presence of deoxycholic acid (DCA), with or without EC, NADPH oxidase (NOX) inhibitors (apocynin and VAS-2870) and MEK inhibitor (U0126). After the corresponding incubations, monolayer permeability and the activation of signaling pathways and events involved in tight junction (TJ) opening/disruption were evaluated. Results Consumption of a HFD caused intestinal permeabilization which was associated with decreased expression of ileal TJ proteins in mice. Supplementation with EC mitigated all these adverse effects. However, EC did not prevent neither the increase nor the altered profile of fecal bile acids caused by HFD consumption. DCA content was particularly elevated. In vitro, EC inhibited DCA-induced Caco-2 cell monolayer permeabilization. EC also prevented DCA-mediated increase in oxidant production and the parallel increase in NOX4 expression, which were both prevented by EC. Inhibition of the ERK1/2 pathway with U0126 prevented DCA-induced monolayer permeabilization, stressing the key involvement of NADPH oxidase and ERK1/2 in this process. DCA-mediated ERK1/2 activation was also inhibited by EC, apocynin and VAS-2870. DCA increased myosin light chain (MLC) phosphorylation levels, which was related to ERK1/2-mediated MLC phosphatase inactivation. DCA also decreased TJ protein levels, in part via Matrix Metallopeptidase-2 (MMP2) activation. Both events were prevented by EC, apocynin, VAS-2870 and U0126. Conclusions EC protects the intestinal barrier from HFD-induced TJ alterations, and associated intestinal permeability both in vivo and in vitro. This is in part to mediated by EC's capacity to inhibit bile-induced NADPH oxidase, ERK1/2, and MMP2 activation, resulting in the preservation of TJ structure. Funding Sources This work was supported by HE Jastro awards to ZW, and grant NIFA-USDA (CA-D-NTR-7244-H) to P.O.

scholarly journals High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

2021 ◽  
Vol 22 (7) ◽  
pp. 3746
Author(s):  
Ilaria Zuliani ◽  
Chiara Lanzillotta ◽  
Antonella Tramutola ◽  
Eugenio Barone ◽  
Marzia Perluigi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
High Fat Diet ◽  
Mitochondrial Activity ◽  
High Fat ◽  
Hexosamine Biosynthetic Pathway ◽  
Neurodegenerative Process ◽  
The Brain

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.

scholarly journals Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model

2021 ◽  
Author(s):  
P. Comeglio ◽  
E. Sarchielli ◽  
S. Filippi ◽  
I. Cellai ◽  
G. Guarnieri ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
High Fat Diet ◽  
Metabolic Regulation ◽  
Therapeutic Potential ◽  
Rabbit Model ◽  
Free Testosterone ◽  
Preclinical Model ◽  
High Fat ◽  
Liver Health ◽  
Metabolic Dysfunctions

Abstract Purpose Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. Methods Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson’s trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. Results Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. Conclusions Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

scholarly journals Differential organ-specific inflammatory response to progranulin in high-fat diet-fed mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maki Murakoshi ◽  
Tomohito Gohda ◽  
Eri Adachi ◽  
Saki Ichikawa ◽  
Shinji Hagiwara ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Tubular Damage ◽  
Standard Diet ◽  
Mrna Levels ◽  
High Fat ◽  
Organ Specific

AbstractProgranulin (PGRN) has been reported to bind tumor necrosis factor (TNF) receptor and to inhibit TNFα signaling. We evaluated the effect of augmentation of TNFα signaling by PGRN deficiency on the progression of kidney injury. Eight-week-old PGRN knockout (KO) and wild-type (WT) mice were fed a standard diet or high-fat diet (HFD) for 12 weeks. Albuminuria, markers of tubular damage, and renal mRNA levels of inflammatory cytokines were higher in HFD-fed KO (KO-HFD) mice than in HFD-fed WT (WT-HFD) mice. Body weight, vacuolization in proximal tubules, and systemic and adipose tissue inflammatory markers were lower in the KO-HFD mice than in the WT-HFD mice. The renal megalin expression was lower in the KO mice than in the WT mice regardless of the diet type. The megalin expression was also reduced in mouse proximal tubule epithelial cells stimulated with TNFα and in those with PGRN knockdown by small interfering RNA in vitro. PGRN deficiency was associated with both exacerbated renal inflammation and decreased systemic inflammation, including that in the adipose tissue of mice with HFD-induced obesity. Improved tubular vacuolization in the KO-HFD mice might partially be explained by the decreased expression of megalin in proximal tubules.

Sign in / Sign up

Export Citation Format

Share Document