scholarly journals Preventing Oxidative Stress in the Liver: An Opportunity for GLP-1 and/or PASK

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 2028
Author(s):  
Verónica Hurtado-Carneiro ◽  
Pilar Dongil ◽  
Ana Pérez-García ◽  
Elvira Álvarez ◽  
Carmen Sanz
Keyword(s):  
Oxidative Stress ◽  
Histone Deacetylases ◽  
Current Knowledge ◽  
Mammalian Target Of Rapamycin ◽  
Antioxidant Response ◽  
Antioxidant Mechanism ◽  
Obesity And Diabetes ◽  
Pas Kinase ◽  
Glucagon Like Peptide 1 ◽  
Functional Inactivation

The liver’s high metabolic activity and detoxification functions generate reactive oxygen species, mainly through oxidative phosphorylation in the mitochondria of hepatocytes. In contrast, it also has a potent antioxidant mechanism for counterbalancing the oxidant’s effect and relieving oxidative stress. PAS kinase (PASK) is a serine/threonine kinase containing an N-terminal Per-Arnt-Sim (PAS) domain, able to detect redox state. During fasting/feeding changes, PASK regulates the expression and activation of critical liver proteins involved in carbohydrate and lipid metabolism and mitochondrial biogenesis. Interestingly, the functional inactivation of PASK prevents the development of a high-fat diet (HFD)-induced obesity and diabetes. In addition, PASK deficiency alters the activity of other nutrient sensors, such as the AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). In addition to the expression and subcellular localization of nicotinamide-dependent histone deacetylases (SIRTs). This review focuses on the relationship between oxidative stress, PASK, and other nutrient sensors, updating the limited knowledge on the role of PASK in the antioxidant response. We also comment on glucagon-like peptide 1 (GLP-1) and its collaboration with PASK in preventing the damage associated with hepatic oxidative stress. The current knowledge would suggest that PASK inhibition and/or exendin-4 treatment, especially under fasting conditions, could ameliorate disorders associated with excess oxidative stress.

scholarly journals Peripheral and central mechanisms involved in the control of food intake by dietary amino acids and proteins

2012 ◽  
Vol 25 (1) ◽  
pp. 29-39 ◽  
Author(s):  
Gilles Fromentin ◽  
Nicolas Darcel ◽  
Catherine Chaumontet ◽  
Agnes Marsset-Baglieri ◽  
Nachiket Nadkarni ◽  
...  
Keyword(s):  
Food Intake ◽  
Arcuate Nucleus ◽  
Peptide Yy ◽  
Current Knowledge ◽  
Mammalian Target Of Rapamycin ◽  
Food Aversion ◽  
Gut Peptides ◽  
Principal Mechanism ◽  
Glucagon Like Peptide 1 ◽  
Diet Intake

The present review summarises current knowledge and recent findings on the modulation of appetite by dietary protein, via both peripheral and central mechanisms. Of the three macronutrients, proteins are recognised as the strongest inhibitor of food intake. The well-recognised poor palatability of proteins is not the principal mechanism explaining the decrease in high-protein (HP) diet intake. Consumption of a HP diet does not induce conditioned food aversion, but rather experience-enhanced satiety. Amino acid consumption is detected by multiple and redundant mechanisms originating from visceral (during digestion) and metabolic (inter-prandial period) sources, recorded both directly and indirectly (mainly vagus-mediated) by the central nervous system (CNS). Peripherally, the satiating effect of dietary proteins appears to be mediated by anorexigenic gut peptides, principally cholecystokinin, glucagon-like peptide-1 and peptide YY. In the CNS, HP diets trigger the activation of noradrenergic and adrenergic neurons in the nucleus of the solitary tract and melanocortin neurons in the arcuate nucleus. Additionally, there is evidence that circulating leucine levels may modulate food intake. Leucine is associated with neural mechanisms involving mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), energy sensors active in the control of energy intake, at least in the arcuate nucleus of the hypothalamus. In addition, HP diets inhibit the activation of opioid and GABAergic neurons in the nucleus accumbens, and thus inhibit food intake by reducing the hedonic response to food, presumably because of their low palatability. Future studies should concentrate on studying the adaptation of different neural circuits following the ingestion of protein diets.

ID: 11: REDOX PROFILING OF CARVEDILOL AND PROPRANOLOL IN A HEART MODEL

2016 ◽  
Vol 64 (4) ◽  
pp. 923.1-923
Author(s):  
P Marathe ◽  
M Thao ◽  
I Benjamin
Keyword(s):  
Oxidative Stress ◽  
Fluorescent Protein ◽  
Antioxidant Response ◽  
Related Factor ◽  
Quinone Oxidoreductase ◽  
Antioxidant Mechanism ◽  
Highly Effective ◽  
Antioxidant Proteins ◽  
Green Fluorescent ◽  
Cellular Compartments

IntroductionClinical trials have shown that carvedilol is highly effective against heart failure (HF). Carvedilol, unlike propranolol, has direct antioxidant effects and is capable of mitigating oxidative stress in HF patients. Moreover, it has been suggested that carvedilol has an indirect antioxidant mechanism that could involve the initial production of non-lethal levels of oxidative stress leading to the regulation of an uncharacterized antioxidant response that later counters oxidative stress.HypothesisWe hypothesized that carvedilol's indirect antioxidant mechanism may involve the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch ECH associating protein 1 (Keap1) pathway, which is a major antioxidant pathway involved in cardiovascular, pulmonary, and neoplastic diseases.MethodsUsing H9C2 rat myoblasts, we confirmed the activation of the Nrf2/Keap1 pathway by detecting levels of downstream protein targets hemeoxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO-1). We transfected H9C2 cells with reductive-oxidative green fluorescent protein (roGFP) fused with human glutaredoxin 1 that targeted mitochondria or cytosol. Redox state changes were quantified by normalized roGFP intensity ratios measured using live-cell imaging.ResultsIn the short term, carvedilol oxidized both cellular compartments while propranolol did not. In the long term, carvedilol upregulated the production of HO-1 and NQO-1 while propranolol downregulated these antioxidant proteins. These results demonstrate that carvedilol's indirect antioxidant effect involves the Nrf2/Keap 1 pathway. This has strong implications as carvedilol is a commonly used, highly effective beta-blocker and elucidating its antioxidant mechanisms can potentially expand the use of carvedilol for the treatment of other diseases, inform the development of new therapeutics, and optimize HF treatment.

Glucagon-like peptide-1 alleviates diabetic kidney disease through activation of autophagy by regulating AMP-activated protein kinase-mammalian target of rapamycin pathway

2020 ◽  
Vol 319 (6) ◽  
pp. E1019-E1030
Author(s):  
Shuangli Yang ◽  
Chuman Lin ◽  
Xiaoyun Zhuo ◽  
Jiyu Wang ◽  
Shitao Rao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Mammalian Target Of Rapamycin ◽  
Renoprotective Effect ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Amp Activated Protein Kinase

Glucagon-like peptide-1 (GLP-1) is a novel antidiabetic agent used in clinical practice. Recently, it was reported to exert a renoprotective effect in the human kidney-2 cells and kidneys of diabetic rats, which was induced by one type of GLP-1 analog, liraglutide, in the presence of high glucose. However, most of the previous findings mainly focused on its indirect effect in inhibiting the advanced glycation end products. Here, besides glycemic control, we also demonstrated a stimulatory role of liraglutide in promoting autophagy and relieving oxidative stress in Zucker diabetic fatty rats. The renoprotective effect of liraglutide has been demonstrated by significantly decreasing urinary albumin ( P < 0.01) and ameliorating renal pathological changes ( P < 0.001) in vivo. Besides that, proliferation of human epithelial kidney cell line HKC-8 and human embryonic kidney-293 cells has increased after treating with exendin-4, a GLP-1 receptor (GLP-1R) agonist. Moreover, GLP-1 could positively improve the progression of autophagy in vivo and in vitro through regulating the autophagy-related protein light chain 3 and p62 via AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway. Simultaneously, it could reverse NF-erythroid 2-related factor 2 (NRF2) translocation into the nuclei and suppress oxidative stress. In terms of mechanism, the renoprotective effect of GLP-1 would be exerted via the GLP-1R-AMPK-mTOR-autophagy-reactive oxygen species signaling axis. The present study not only illustrates the renoprotective effect of GLP-1 in diabetic kidney disease (DKD) rats, but also for the first time elucidates the underlying mechanism that is independent of controlling glucose, which implies that GLP-1 might be a novel therapeutic strategy for the prevention and treatment of DKD.

scholarly journals Natural Phytochemicals as Novel Therapeutic Strategies to Prevent and Treat Parkinson’s Disease: Current Knowledge and Future Perspectives

2021 ◽  
Vol 2021 ◽  
pp. 1-32
Author(s):  
Rengasamy Balakrishnan ◽  
Shofiul Azam ◽  
Duk-Yeon Cho ◽  
In Su-Kim ◽  
Dong-Kug Choi
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Comprehensive Evaluation ◽  
Current Knowledge ◽  
Antioxidant Response ◽  
Experimental Models ◽  
Protein Accumulation ◽  
Related Factor ◽  
Therapeutic Benefits

Parkinson’s disease (PD) is the second-most common neurodegenerative chronic disease affecting both cognitive performance and motor functions in aged people. Yet despite the prevalence of this disease, the current therapeutic options for the management of PD can only alleviate motor symptoms. Research has explored novel substances for naturally derived antioxidant phytochemicals with potential therapeutic benefits for PD patients through their neuroprotective mechanism, targeting oxidative stress, neuroinflammation, abnormal protein accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, neurotrophic factor deficit, and apoptosis. The aim of the present study is to perform a comprehensive evaluation of naturally derived antioxidant phytochemicals with neuroprotective or therapeutic activities in PD, focusing on their neuropharmacological mechanisms, including modulation of antioxidant and anti-inflammatory activity, growth factor induction, neurotransmitter activity, direct regulation of mitochondrial apoptotic machinery, prevention of protein aggregation via modulation of protein folding, modification of cell signaling pathways, enhanced systemic immunity, autophagy, and proteasome activity. In addition, we provide data showing the relationship between nuclear factor E2-related factor 2 (Nrf2) and PD is supported by studies demonstrating that antiparkinsonian phytochemicals can activate the Nrf2/antioxidant response element (ARE) signaling pathway and Nrf2-dependent protein expression, preventing cellular oxidative damage and PD. Furthermore, we explore several experimental models that evaluated the potential neuroprotective efficacy of antioxidant phytochemical derivatives for their inhibitory effects on oxidative stress and neuroinflammation in the brain. Finally, we highlight recent developments in the nanodelivery of antioxidant phytochemicals and its neuroprotective application against pathological conditions associated with oxidative stress. In conclusion, naturally derived antioxidant phytochemicals can be considered as future pharmaceutical drug candidates to potentially alleviate symptoms or slow the progression of PD. However, further well-designed clinical studies are required to evaluate the protective and therapeutic benefits of phytochemicals as promising drugs in the management of PD.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

Combination of Histone Deacetylase Inhibitor with Cu(II) 5,5- diethylbarbiturate Complex Induces Apoptosis in Breast Cancer Stem Cells: A Promising Novel Approach

2020 ◽  
Vol 21 ◽  
Author(s):  
Merve Erkisa ◽  
Nazlihan Aztopal ◽  
Elif Erturk ◽  
Engin Ulukaya ◽  
Veysel T. Yilmaz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Histone Deacetylases ◽  
Caspase 3 ◽  
Cancer Cell Line ◽  
Annexin V ◽  
Tumor Formation ◽  
Dependent Manner

Background: Cancer stem cells (CSC) are subpopulation within the tumor that acts a part in the initiation, progression, recurrence, resistance to drugs and metastasis of cancer. It is well known that epigenetic changes lead to tumor formation in cancer stem cells and show drug resistance. Epigenetic modulators and /or their combination with different agents have been used in cancer therapy. Objective: In our study we scope out the effects of combination of a histone deacetylases inhibitor, valproic acid (VPA), and Cu(II) complex [Cu(barb-κN)(barb-κ2N,O)(phen-κN,N’)]·H2O] on cytotoxicity/apoptosis in a stem-cell enriched population (MCF-7s) obtained from parental breast cancer cell line (MCF-7). Methods: Viability of the cells was measured by the ATP assay. Apoptosis was elucidated via the assessment of caspase-cleaved cytokeratin 18 (M30 ELISA) and a group of flow cytometry analysis (caspase 3/7 activity, phosphatidylserine translocation by annexin V-FITC assay, DNA damage and oxidative stress) and 2ˈ,7ˈ–dichlorofluorescein diacetate staining. Results: The VPA combined with Cu(II) complex showed anti proliferative activity on MCF-7s cells in a dose- and time-dependently. Treatment with combination of 2.5 mM VPA and 3.12 μM Cu(II) complex induces oxidative stress in a time-dependent manner, as well as apoptosis that is evidenced by the increase in caspase 3/7 activity, positive annexin-V-FITC, and increase in M30 levels. Conclusion: The results suggest that the combination therapy induces apoptosis following increased oxidative stress, thereby making it a possible promising therapeutic strategy that further analysis is required.

Activation of GLP-1 and Glucagon Receptors Regulates Bile Homeostasis Independent of Thyroid Hormone

2019 ◽  
Vol 12 (2) ◽  
pp. 139-146
Author(s):  
Vishal J. Patel ◽  
Amit A. Joharapurkar ◽  
Samadhan G. Kshirsagar ◽  
Brijesh K. Sutariya ◽  
Maulik S. Patel ◽  
...  
Keyword(s):  
Single Dose ◽  
Lipid Metabolism ◽  
Thyroid Hormone ◽  
Fibroblast Growth Factor 21 ◽  
Dose Treatment ◽  
Obesity And Diabetes ◽  
Serum T3 ◽  
Serum T4 ◽  
Glucagon Like Peptide 1 ◽  
Glucagon Receptors

Background: Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism. Methods: We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH). Results: Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH. Conclusion: Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.

Let-7e-5p Regulates GLP-1 Content and Basal Release From Enteroendocrine L Cells From DIO Male Mice

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Sandra Handgraaf ◽  
Rodolphe Dusaulcy ◽  
Florian Visentin ◽  
Jacques Philippe ◽  
Yvan Gosmain
Keyword(s):  
Compensatory Mechanism ◽  
L Cells ◽  
Low Fat Diet ◽  
Obesity And Diabetes ◽  
Basal Release ◽  
Glucagon Like Peptide 1 ◽  
Cell Transcriptome ◽  
Microarray Analyses

Abstract Characterization of enteroendocrine L cells in diabetes is critical for better understanding of the role of glucagon-like peptide-1 (GLP-1) in physiology and diabetes. We studied L-cell transcriptome changes including microRNA (miRNA) dysregulation in obesity and diabetes. We evaluated the regulation of miRNAs through microarray analyses on sorted enteroendocrine L cells from control and obese glucose-intolerant (I-HFD) and hyperglycemic (H-HFD) mice after 16 weeks of respectively low-fat diet (LFD) or high-fat diet (HFD) feeding. The identified altered miRNAs were studied in vitro using the mouse GLUTag cell line to investigate their regulation and potential biological functions. We identified that let-7e-5p, miR-126a-3p, and miR-125a-5p were differentially regulated in L cells of obese HFD mice compared with control LFD mice. While downregulation of let-7e-5p expression was observed in both I-HFD and H-HFD mice, levels of miR-126a-3p increased and of miR-125a-5p decreased significantly only in I-HFD mice compared with controls. Using miRNA inhibitors and mimics we observed that modulation of let-7e-5p expression affected specifically GLP-1 cellular content and basal release, whereas Gcg gene expression and acute GLP-1 secretion and cell proliferation were not affected. In addition, palmitate treatment resulted in a decrease of let-7e-5p expression along with an increase in GLP-1 content and release, suggesting that palmitate acts on GLP-1 through let-7e-5p. By contrast, modulation of miR-125a-5p and miR-126a-3p in the same conditions did not affect content or secretion of GLP-1. We conclude that decrease of let-7e-5p expression in response to palmitate may constitute a compensatory mechanism contributing to maintaining constant glycemia in obese mice.

scholarly journals MicroRNAs and Oxidative Stress: An Intriguing Crosstalk to Be Exploited in the Management of Type 2 Diabetes

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 802
Author(s):  
Teresa Vezza ◽  
Aranzazu M. de Marañón ◽  
Francisco Canet ◽  
Pedro Díaz-Pozo ◽  
Miguel Marti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Signaling Pathways ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Dysfunction ◽  
Non Coding Rnas ◽  
And Oxidative Stress ◽  
Molecular Crosstalk

Type 2 diabetes is a chronic disease widespread throughout the world, with significant human, social, and economic costs. Its multifactorial etiology leads to persistent hyperglycemia, impaired carbohydrate and fat metabolism, chronic inflammation, and defects in insulin secretion or insulin action, or both. Emerging evidence reveals that oxidative stress has a critical role in the development of type 2 diabetes. Overproduction of reactive oxygen species can promote an imbalance between the production and neutralization of antioxidant defence systems, thus favoring lipid accumulation, cellular stress, and the activation of cytosolic signaling pathways, and inducing β-cell dysfunction, insulin resistance, and tissue inflammation. Over the last few years, microRNAs (miRNAs) have attracted growing attention as important mediators of diverse aspects of oxidative stress. These small endogenous non-coding RNAs of 19–24 nucleotides act as negative regulators of gene expression, including the modulation of redox signaling pathways. The present review aims to provide an overview of the current knowledge concerning the molecular crosstalk that takes place between oxidative stress and microRNAs in the physiopathology of type 2 diabetes, with a special emphasis on its potential as a therapeutic target.

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