Publications by authors named "Theodomir Dusabimana"

8 Publications

  • Page 1 of 1

P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice.

Int J Mol Sci 2021 May 24;22(11). Epub 2021 May 24.

Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea.

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid β-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.
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http://dx.doi.org/10.3390/ijms22115528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197197PMC
May 2021

Geniposide Improves Diabetic Nephropathy by Enhancing ULK1-Mediated Autophagy and Reducing Oxidative Stress through AMPK Activation.

Int J Mol Sci 2021 Feb 6;22(4). Epub 2021 Feb 6.

Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea.

Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response and a decrease of AKT activity to block oxidative stress, inflammation and fibrosis in diabetic kidney. In addition, geniposide increased the activities of PKA and GSK3β, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction and ameliorating the progression of DN. Conclusively, geniposide enhances ULK1-mediated autophagy and reduces oxidative stress, inflammation and fibrosis, suggesting geniposide as a promising treatment for DN.
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http://dx.doi.org/10.3390/ijms22041651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915505PMC
February 2021

Fermentation of Sprouted Ginseng () Increases Flavonoid and Phenolic Contents to Attenuate Alcoholic Hangover and Acute Liver Injury in Mice.

Am J Chin Med 2021 26;49(1):131-146. Epub 2020 Dec 26.

Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea.

Alcoholic liver damage is caused by ethanol and its oxidized intermediates, and endotoxin-induced acute liver failure is mediated by apoptosis and inflammation. We investigated whether extracts of sprouts of (SG) attenuate alcohol or endotoxin-induced acute liver injury in mice. Whole SG contains eight times more ginsenosides than the root and, because it grows quickly ([Formula: see text]30 days) without using pesticides, the whole-plant can be harvested. The extracts were enriched in phenolics and flavonoids and showed high radical scavenging activities. Mice received oral administration of SG or fermented SG (FSG) extracts 1 h before an injection of either ethanol or lipopolysaccharide and D-galactosamine (LPS/GalN). The latency of righting reflex was monitored to examine the effect of extracts on relieving hangover symptoms. The results indicate that FSG significantly reduced the latency of righting reflex, SG and FSG increased the activity and expression of ethanol-metabolizing enzymes, and FSG decreased hepatic necrosis and plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). During the ethanol metabolism, cytochrome P450 2E1 expression was increased, but 4-hydroxynonenal levels were decreased by the extracts due to their anti-oxidant activity. LPS/GalN-induced liver injury was reduced by SG and FSG; plasma ALT and AST levels, hepatic necrosis, and apoptotic and inflammatory markers were all decreased. In conclusion, SG extracts attenuated ethanol-induced hangover and endotoxin-induced acute liver injury, and fermentation enhanced the efficacy with regard to relieving hangover.
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http://dx.doi.org/10.1142/S0192415X21500075DOI Listing
December 2020

P2Y2R contributes to the development of diabetic nephropathy by inhibiting autophagy response.

Mol Metab 2020 12 25;42:101089. Epub 2020 Sep 25.

Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea; Department of Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University Graduate School, Jinju 52727, Republic of Korea. Electronic address:

Objective: Diabetic nephropathy (DN) is one of the most common complications of diabetes and a critical risk factor for developing end-stage renal disease. Activation of purinergic receptors, including P2Y2R has been associated with the pathogenesis of renal diseases, such as polycystic kidney and glomerulonephritis. However, the role of P2Y2R and its precise mechanisms in DN remain unknown. We hypothesised that P2Y2R deficiency may play a protective role in DN by modulating the autophagy signalling pathway.

Methods: We used a mouse model of DN by combining a treatment of high-fat diet and streptozotocin after unilateral nephrectomy in wild-type or P2Y2R knockout mice. We measured renal functional parameter in plasma, examined renal histology, and analysed expression of autophagy regulatory proteins.

Results: Hyperglycaemia and ATP release were induced in wild type-DN mice and positively correlated with renal dysfunction. Conversely, P2Y2R knockout markedly attenuates albuminuria, podocyte loss, development of glomerulopathy, renal tubular injury, apoptosis and interstitial fibrosis induced by DN. These protective effects were associated with inhibition of AKT-mediated FOXO3a (forkhead box O3a) phosphorylation and induction of FOXO3a-induced autophagy gene transcription. Furthermore, inhibitory phosphorylation of ULK-1 was decreased, and the downstream Beclin-1 autophagy signalling was activated in P2Y2R deficiency. Increased SIRT-1 (sirtuin-1) and FOXO3a expression in P2Y2R deficiency also enhanced autophagy response, thereby ameliorating renal dysfunction in DN.

Conclusions: P2Y2R contributes to the pathogenesis of DN by impairing autophagy and serves as a therapeutic target for treating DN.
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http://dx.doi.org/10.1016/j.molmet.2020.101089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568185PMC
December 2020

Honokiol Protects the Kidney from Renal Ischemia and Reperfusion Injury by Upregulating the Glutathione Biosynthetic Enzymes.

Biomedicines 2020 Sep 15;8(9). Epub 2020 Sep 15.

Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea.

Glutathione (GSH) is an endogenous antioxidant found in plants, animals, fungi, and some microorganisms that protects cells by neutralizing hydrogen peroxide. Honokiol, an active ingredient of , is known for antioxidant, anti-inflammatory, and anti-bacterial properties. We investigated the protective mechanism of honokiol through regulating cellular GSH in renal proximal tubules against acute kidney injury (AKI). First, we measured cellular GSH levels and correlated them with the expression of GSH biosynthetic enzymes after honokiol treatment in human kidney-2 (HK-2) cells. Second, we used pharmacological inhibitors or siRNA-mediated gene silencing approach to determine the signaling pathway induced by honokiol. Third, the protective effect of honokiol via GSH biosynthesis was investigated in renal ischemia-reperfusion (IR) mice. Honokiol significantly increased cellular GSH levels by upregulating the subunits of glutamate-cysteine ligase (Gcl)-Gclc and Gclm. These increases were mediated by activation of nuclear factor erythroid 2-related factor 2, via PI3K/Akt and protein kinase C signaling. Consistently, honokiol treatment reduced the plasma creatinine, tubular cell death, neutrophil infiltration and lipid peroxidation in IR mice and the effect was correlated with upregulation of Gclc and Gclm. Conclusively, honokiol may benefit to patients with AKI by increasing antioxidant GSH via transcriptional activation of the biosynthetic enzymes.
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http://dx.doi.org/10.3390/biomedicines8090352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555803PMC
September 2020

Fermented Extracts Attenuate Endotoxin-Induced Acute Liver Injury in Mice.

Nutrients 2020 Sep 13;12(9). Epub 2020 Sep 13.

Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea.

Endotoxin-induced acute liver injury is mediated by an excessive inflammatory response, hepatocellular oxidative stress, and apoptosis. Traditional medicinal plants have been used to treat various disorders. (PG) has been shown to be beneficial in relieving cough and asthma and to have anti-tumor, anti-inflammatory, anti-diabetic activities. The pharmacological action of PG is mainly due to saponins, flavonoids, phenolic, and other compounds. However, raw PG exhibits some side effects at high doses. Here, we extracted raw PG with varying fermentation methods and examined its anti-inflammatory effect and associated signaling kinases in Raw264.7 cells. Then, we investigated the effect of fermented black PG (FBPG) on endotoxin-induced liver injury. Mice were administered FBPG orally at 1 h before the lipopolysaccharide and D-galactosamine (LPS/GalN) injection and sacrificed after 5 h. Black PG (BPG) and FBPG showed a significant reduction in pro-inflammatory cytokines and extracellular nitric oxide (NO); p-38 and ERK signaling was involved in reducing inducible NO synthase in Raw264.7 cells. Consistently, FBPG attenuates LPS/GalN-induced liver injury; plasma ALT and AST, hepatic necrosis, pro-inflammatory cytokines, apoptosis, and lipid peroxidation were all reduced. In conclusion, PG extracts, particularly FBPG, play anti-inflammatory, antioxidant, and anti-apoptotic roles, alleviating endotoxin-induced acute liver injury. Processing raw PG into FBPG extract may be clinically useful by improving the pharmacologically active ingredients and reducing the required dosage.
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http://dx.doi.org/10.3390/nu12092802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551015PMC
September 2020

Nobiletin ameliorates hepatic ischemia and reperfusion injury through the activation of SIRT-1/FOXO3a-mediated autophagy and mitochondrial biogenesis.

Exp Mol Med 2019 04 26;51(4):1-16. Epub 2019 Apr 26.

Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, 52727, Republic of Korea.

Hepatic ischemia and reperfusion injury are characterized by impaired autophagy, mitochondrial dysfunction, and subsequent compromise of cellular homeostasis following hepatic surgery or transplantation. Nobiletin, a natural flavonoid, is a beneficial antioxidant that possesses anti-inflammatory and anti-cancer activities. We investigated the effect of nobiletin on hepatic IR injury and described the underlying mechanisms. C57BL/6 mice were subjected to 60 min of partial hepatic ischemia, treated with nobiletin (5 mg/kg) or vehicle at the start of reperfusion, and killed at 5 h of reperfusion. Hepatic ischemia and reperfusion increased hepatocellular oxidative damage, inflammation, and cell death, but these changes were alleviated upon nobiletin treatment. Nobiletin increased the expression of proteins that control autophagy, mitochondrial dynamics, and biogenesis. Specifically, the SIRT-1/FOXO3a and PGC-1α pathways were activated by nobiletin. IR-induced AKT activation was associated with FOXO3a phosphorylation, which resulted in a significant reduction in the nuclear FOXO3a levels and potentially attenuated autophagy-regulatory gene expression. Nobiletin increased FOXO3a expression and its nuclear translocation via the inhibition of AKT. Specific inhibition of SIRT-1 abolished the protective effect of nobiletin, causing decreased FOXO3a expression, followed by autophagy induction and decreased PGC-1α expression and mitochondrial dynamics. Taken together, our data indicate that SIRT-1 directly mediates the protective effect of nobiletin against hepatic ischemia and reperfusion injury. The activation of autophagy and mitochondrial function through the SIRT-1/FOXO3a and PGC-1α pathways indicate that nobiletin could have therapeutic potential for treating hepatic ischemia and reperfusion injury.
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http://dx.doi.org/10.1038/s12276-019-0245-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486618PMC
April 2019

Supplementation of Ameliorates Diabetic Nephropathy and Hepatic Steatosis by Activating Autophagy in Mice.

Nutrients 2018 Nov 7;10(11). Epub 2018 Nov 7.

Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727, Korea.

Diabetic nephropathy (DN) is a diabetic complication marked by albuminuria and a decline of the glomerular filtration rate. Diabetic kidneys are defective in the autophagy process and mitochondrial function and their enhancement of activity alleviates the pathology. In this paper, we developed a mouse model of DN by a combined treatment of a high-fat diet and streptozotocin after unilateral nephrectomy and supplementation with flower or leaf extracts of (AM) were tested. The preventive effects of the extracts on DN pathology and changes on autophagy and mitochondrial proteins were investigated. DN mice showed a significant increase in fasting blood glucose, plasma creatinine, blood urea nitrogen, and urinary albumin levels. Periodic acid⁻Schiff and Sirius red staining of the diabetic kidney presented a significant change in glomerular and tubular structures that was associated with podocyte loss and fibrotic protein accumulation. These changes were attenuated by AM extract treatment in DN mice. In addition, hepatic injury, proinflammatory cytokines, and lipid accumulation were decreased by AM extracts in DN mice. As a protective mechanism, AM extracts significantly increased the expression of proteins by regulating autophagy and mitochondrial dynamics, which potentially prevented the kidney and liver from accumulating pathogenic proteins and dysfunctional mitochondria, which alleviated the progression of DN.
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http://dx.doi.org/10.3390/nu10111703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266484PMC
November 2018