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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,639 records · Page 91
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Fibroblast growth factor 19 protects the heart from oxidative stress-induced diabetic cardiomyopathy via activation of AMPK/Nrf2/HO-1 pathway

Highlights: • FGF19 Improves Cardiac Dysfunction and Fibrosis in Diabetic Cardiomyopathy. • FGF19 Prevent Cardiac Oxidative Stress in the Diabetic Heart. • FGF 19 induces expression Nrf2/HO-1 signaling axis through activation of AMPK. Diabetes affects cardiac structure and function, where it leads to diabetic cardiomyopathy. Reactive oxygen species (ROS) produced by oxidative stress play an important role in the development of diabetic cardiomyopathy. Fibroblast growth factor (FGF) 19, an enterokine, is synthesized and released into the ileum. In the present study, we revealed that FGF19 induced an antioxidant response through stimulating the expression of nuclear erythroid factor 2 (NE-F2)-related factor 2 (Nrf2) and as well as reducing ROS production through the AMPK signaling pathway. Additionally, AMPK inhibition by the AMPK-specific inhibitor compound C decreased Nrf2 and heme oxygenase-1 (HO-1) protein expression. Taken together, these results suggested that FGF19, through the anti-oxidative defense system, attenuated the development of diabetic cardiomyopathy and restored cardiac function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Pharmacological inhibition of Rac1 exerts a protective role in ischemia/reperfusion-induced renal fibrosis

Acute kidney injury induced by renal ischemia-reperfusion (IR) is a prominent risk factor in the development towards renal fibrosis. Ras-related C3 botulinum toxin substrate 1(Rac1) has been involved in the pathophysiology of fibrotic disorders. But the role of Rac1 in the pathogenesis of IR-induced renal fibrosis is still unknown. Here, we examined the effects of NSC23766, an inhibitor of Rac1, on the progression of renal fibrosis after IR injury. In mice, IR induced Rac1 activation in kidneys. Rac1 inhibition alleviated renal damage and dysfunction. Mice treated with NSC23766 displayed diminished collagen area in the kidneys compared with IR controls, which was associated with reduction of extracellular matrix (ECM) proteins and α-SMA. Furthermore, Rac1 inhibition reduced profibrotic molecules levels in the kidneys of mice with IR. Finally, Rac1 inhibition impaired the accumulation of bone marrow-derived M2 macrophages and the transition of M2 macrophages to myofibroblasts. In cultured mouse monocytes, IL-4 treatment activated Rac1, which was abrogated by NSC23766. Moreover, application with IL-4 induced polarization of monocytes to M2 phenotype and increased the levels of ECM proteins and α-SMA, which was abolished by NSC23766. In summary, Rac1 plays a crucial role in the pathogenesis of renal fibrosis after IR via regulation of expressions of profibrotic molecules, bone-marrow derived M2 macrophages recruitment, and M2 macrophages-myofibroblasts transition.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

PPARγ provides anti-inflammatory and protective effects in intrahepatic cholestasis of pregnancy through NF-κB pathway

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific hepatic disorder with potentially deleterious consequences of fetuses. Although the intimate relationship between ICP and peroxisome proliferator-activated receptor γ (PPARγ) has been previously reported in physiological and pathological conditions, the detailed mechanisms in the process of intrahepatic cholestasis of pregnancy has been unclear. The aims of this study are to assess the role of PPARγ regulating the reactive oxygen species (ROS) and inflammation in the process of the ICP.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Liraglutide protects non-alcoholic fatty liver disease via inhibiting NLRP3 inflammasome activation in a mouse model induced by high-fat diet

Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue that has recently become the first-line treatment for type 2 diabetes mellitus (T2DM), has also been reported to decrease fatty degeneration of the liver. The purpose of this study is to explore whether liraglutide improves high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) in mice through inhibiting the NLRP3 inflammasome in the liver. After daily intraperitoneal injection of liraglutide (0.6 mg/kg body weight) for four weeks, the liver, liver/body weight, serum levels of ALT, AST, total cholesterol, triglycerides and LDL were significantly decreased in a high-fat diet-induced NAFLD mouse model. The hepatic steatosis among sections of H&E and Oil Red O staining was also markedly reduced after treatment with liraglutide. The expressions of NLRP3 inflammasome components (including NLRP3, ASC, and caspase-1) in the liver of mice after treatment with liraglutide were decreased substantially. In vitro studies found that the mitochondrial dysfunction in Kupffer cells induced by palmitic acid was attenuated, and the protein levels of NLRP3, ASC and caspase-1 were also decrease markedly. These results demonstrate that liraglutide was able to alleviate high-fat diet-induced hepatic steatosis via inhibiting NLRP3 inflammasome activation, suggesting that liraglutide is a potent drug that can reverse the pathological hallmarks of NAFLD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The long noncoding RNA XIST protects cardiomyocyte hypertrophy by targeting miR-330-3p

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in numerous kinds of cardiovascular diseases, and their vital role in regulating cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA X-inactive specific transcript (XIST) was upregulated in hypertrophic cardiac of mice and phenylephrine (PE)-treated cardiomyocytes. Next, we observed that inhibition of XIST induced hypertrophic response of cardiomyocyte and overexpression of XIST attenuated cardiomyocyte hypertrophy induced by PE. Furthermore, through online predictive tools and functional experiments, we demonstrated that XIST and S100B were targets of miR-330-3p. XIST and miR-330-3p suppressed each other in a reciprocal way in cardiomyocytes. Additionally, XIST promoted S100B expression through harboring the complementary binding sites with miR-330-3p, eventually prevented cardiac hypertrophy. In conclusion, our findings revealed a novel molecular mechanism that XIST/miR-330-3p/S100B pathway modulates the progression of cardiomyocyte hypertrophy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Leukocytic toll-like receptor 2 knockout protects against diabetes-induced cardiac dysfunction

Highlights: • TLR2 KO promotes the functional recovery of myocardium. • TLR2 KO maintains the balance of calcium. • TLR2 KO reduces cell apoptosis induced by oxidative stress. • TLR2 KO decreases the fibrosis of heart tissues in diabetic cardiomyopathy mice. Diabetic cardiomyopathy is characterized by the deterioration of the myocardial function. Emerging evidences have indicated that leukocytic toll-like receptor 2 (TLR2) played an important role in the development of diabetic cardiomyopathy. Our study aimed to investigate whether TLR2 knockout (KO) exerted a cardioprotective effect in vivo. The establishment of diabetes model was set up in mice via intraperitoneal injection of streptozotocin (STZ). Results demonstrated that blocking of TLR2 significantly suppressed the enhanced left ventricular end-diastolic dimension (LVEDD), left ventricular end systolic diameter (LVESD) and the reduced the heart rate in diabetic cardiomyopathy mice. The decreased resting cell length, PS, TPS and + dL/dt while increased TR90 and - dL/dt caused by diabetic cardiomyopathy were remarkably inhibited by TLR2 KO. Besides that, the alleviated ΔFFI (360/380), decreased SERCA2a and p-NFATc3 expressions, extended Ca{sup 2+} decay time and elevated Calcineurin A induced by diabetic cardiomyopathy were vastly repressed by TLR2 KO in cardiocytes. Moreover, TLR2 gene silence could ameliorate oxidative stress-induced apoptosis, evidences were the up-regulated superoxide generation and Bax/Bcl-2 expression while restrained GSH/GSSG ratio caused by diabetic cardiomyopathy were tremendously repressed in TLR2 KO mice. Furthermore, blocking of TLR2 remarkably attenuated the augmented fibrosis areas of heart tissues in mice with diabetic cardiomyopathy. The result of the enhanced α-SMA and collagenⅠ caused by diabetic cardiomyopathy were suppressed in heart tissues of TLR2 KO mice further validate it. All in all, our study demonstrated that diabetes-induced cardiac dysfunction could be attenuated by TLR2 KO.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Rnf112 deletion protects brain against intracerebral hemorrhage (ICH) in mice by inhibiting TLR-4/NF-κB pathway

Highlights: • Rnf112{sup −/−} mice exhibits accelerated brain injury and neuroinflammation. • Rnf112{sup −/−} promotes inflammation by enhancing TLR-4/NF-κB pathway. • Over-expressing Rnf112 attenuates brain injury after intracerebral hemorrhage. Intracerebral hemorrhage (ICH) is reported as a common and often fatal type of stroke accompanied with high morbidity and mortality, and it frequently results in long-lasting neurological dysfunctions. However, the pathogenesis that contributes to ICH has not been fully understood. Rnf112, also known as Znf179, is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is modulated during brain progression and development. The study aimed to explore the role of Rnf112 in brain injury after ICH, as well as the underlying molecular mechanisms. The results indicated that ICH led to a significant decrease in Rnf112, which was confirmed in oxyhemoglobin (oxyHb)-incubated astrocytes and microglial cells. Moreover, the Rnf112 knockout (Rnf112{sup −/−}) mice and wild type (WT) mice induced by ICH were further employed. Compared to the WT/ICH group, Rnf112{sup −/−} mice exhibited accelerated brain injury, as evidenced by the increased brain water contents and neurological deficit scores (NDS). In comparison to WT/ICH group, a remarkable up-regulation in the release of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, was observed in perihematoma tissues of Rnf112{sup −/−} mice on day 3 post-ICH. The process was along with promoted glial fibrillary acidic protein (GFAP) and Iba1 expression and reduced NeuN levels. Furthermore, ICH-induced increases in toll-like receptor (TLR)-4 and myeloid differentiation primary response protein (MyD88) expression were exacerbated by the loss of Rnf112. The phosphorylated expression of IKKα, inhibitor of NF-κB (IκBα) and nuclear factor-kappa B (NF-κB) induced by ICH in perihematoma tissues of mice was markedly enhanced in Rnf112{sup −/−} mice. Rnf112 repression-induced inflammatory response was verified in lipopolysaccharide (LPS)-incubated glial cells. In contrast, over-expressing Rnf112 markedly attenuated ICH-induced brain injury by restraining inflammation via inactivating TLR-4/NF-κB pathway. In summary, our findings suggested that Rnf112 expression was highly involved in the progression of ICH, and targeting Rnf112 signaling might be a promising therapeutic strategy against ICH development.

60 APPLIED LIFE SCIENCES↗