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Open AccessArticle

Structural Features Governing the Metabolic Stability of Tetraethyl-Substituted Nitroxides in Rat Liver Microsomes

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Antioxidants 2023, 12(2), 402; https://doi.org/10.3390/antiox12020402 - 07 Feb 2023

Viewed by 704

Abstract

Nitroxides are potent tools for studying biological systems by electron paramagnetic resonance (EPR). Whatever the application, a certain stability is necessary for successful detection. Since conventional tetramethyl-substituted cyclic nitroxides have insufficient in vivo stability, efforts have recently been made to synthesize more stable, [...] Read more.

Nitroxides are potent tools for studying biological systems by electron paramagnetic resonance (EPR). Whatever the application, a certain stability is necessary for successful detection. Since conventional tetramethyl-substituted cyclic nitroxides have insufficient in vivo stability, efforts have recently been made to synthesize more stable, tetraethyl-substituted nitroxides. In our previous study on piperidine nitroxides, the introduction of steric hindrance around the nitroxide moiety successfully increased the resistance to reduction into hydroxylamine. However, it also rendered the carbon backbone susceptible to modifications by xenobiotic metabolism due to increased lipophilicity. Here, we focus on a new series of three nitroxide candidates with tetraethyl substitution, namely with pyrrolidine, pyrroline, and isoindoline cores, to identify which structural features afford increased stability for future probe design and application in in vivo EPR imaging. In the presence of rat liver microsomes, pyrrolidine and pyrroline tetraethyl nitroxides exhibited a higher stability than isoindoline nitroxide, which was studied in detail by HPLC-HRMS. Multiple metabolites suggest that the aerobic transformation of tetraethyl isoindoline nitroxide is initiated by hydrogen abstraction by P450-Fe^V = O from one of the ethyl groups, followed by rearrangement and further modifications by cytochrome P450, as supported by DFT calculations. Under anaerobic conditions, only reduction by rat liver microsomes was observed with involvement of P450-Fe^II. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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Open AccessArticle

Comprehensive Effect of Carbon Tetrachloride and Reversal of Gandankang Formula in Mice Liver: Involved in Oxidative Stress, Excessive Inflammation, and Intestinal Microflora

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Antioxidants 2022, 11(11), 2234; https://doi.org/10.3390/antiox11112234 - 12 Nov 2022

Cited by 1 | Viewed by 950

Abstract

Aim: To systematically evaluate the effect of Gandankang (GDK) aqueous extract in alleviating acute and chronic liver injury. Forty-one chemical compounds were identified by ultra-high performance liquid chromatography-linear trap quadrupole-orbitrap-tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS) from GDK. All dosages of GDK and Biphenyl diester (BD) [...] Read more.

Aim: To systematically evaluate the effect of Gandankang (GDK) aqueous extract in alleviating acute and chronic liver injury. Forty-one chemical compounds were identified by ultra-high performance liquid chromatography-linear trap quadrupole-orbitrap-tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS) from GDK. All dosages of GDK and Biphenyl diester (BD) improved CCl₄-induced acute and chronic liver injury. GDK curbed liver fibrosis and blocked the NF-κB pathway to effectively inhibit the hepatic inflammatory response. Additionally, GDK treatment reduced the abundance of Phascolarctobacterium, Turicibacter, Clostridium_xlva, Atoprostipes, and Eubacterium, in comparison with those in the CCl₄ mice and elevated the abundance of Megamonas and Clostridium_IV as evident from 16S rDNA sequencing. Correlation analysis showed that the abundance of Eubacterium and Phascolarctobacterium was positively correlated with inflammation, fibrosis, and oxidation indexes. This indicates that GDK ameliorates chronic liver injury by mitigating fibrosis and inflammation. Nrf2 pathway is the key target of GDK in inhibiting liver inflammation and ferroptosis. Eubacterium and Phascolarctobacterium played a vital role in attenuating liver fibrosis. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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Open AccessArticle

Effect of Empagliflozin on Thioacetamide-Induced Liver Injury in Rats: Role of AMPK/SIRT-1/HIF-1α Pathway in Halting Liver Fibrosis

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Antioxidants 2022, 11(11), 2152; https://doi.org/10.3390/antiox11112152 - 30 Oct 2022

Cited by 3 | Viewed by 1300

Abstract

Hepatic fibrosis causes severe morbidity and death. No viable treatment can repair fibrosis and protect the liver until now. We intended to discover the empagliflozin’s (EMPA) hepatoprotective efficacy in thioacetamide (TAA)-induced hepatotoxicity by targeting AMPK/SIRT-1 activity and reducing HIF-1α. Rats were treated orally [...] Read more.

Hepatic fibrosis causes severe morbidity and death. No viable treatment can repair fibrosis and protect the liver until now. We intended to discover the empagliflozin’s (EMPA) hepatoprotective efficacy in thioacetamide (TAA)-induced hepatotoxicity by targeting AMPK/SIRT-1 activity and reducing HIF-1α. Rats were treated orally with EMPA (3 or 6 mg/kg) with TAA (100 mg/kg, IP) thrice weekly for 6 weeks. EMPA in both doses retracted the serum GGT, ALT, AST, ammonia, triglycerides, total cholesterol, and increased serum albumin. At the same time, EMPA (3 or 6 mg/kg) replenished the hepatic content of GSH, ATP, AMP, AMPK, or SIRT-1 and mitigated the hepatic content of MDA, TNF-α, IL-6, NF-κB, or HIF-1α in a dose-dependent manner. Likewise, hepatic photomicrograph stained with hematoxylin and eosin or Masson trichrome stain of EMPA (3 or 6 mg/kg) revealed marked regression of the hepatotoxic effect of TAA with minimal injury. Similarly, in rats given EMPA (3 or 6 mg/kg), the immunohistochemically of hepatic photomicrograph revealed minimal stain of either α-SMA or caspase-3 compared to the TAA group. Therefore, we concluded that EMPA possessed an antifibrotic effect by targeting AMPK/SIRT-1 activity and inhibiting HIF-1α. The present study provided new insight into a novel treatment of liver fibrosis. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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Open AccessArticle

A Greater Improvement of Intrahepatic Fat Contents after 6 Months of Lifestyle Intervention Is Related to a Better Oxidative Stress and Inflammatory Status in Non-Alcoholic Fatty Liver Disease

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Margalida Monserrat-Mesquida

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Magdalena Quetglas-Llabrés

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Antioxidants 2022, 11(7), 1266; https://doi.org/10.3390/antiox11071266 - 27 Jun 2022

Cited by 3 | Viewed by 1445

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by the excessive accumulation of lipids in the liver parenchyma. To date, there is no effective pharmacological treatment against NAFLD. Objective: To assess the relationship between the improvement of the intrahepatic fat content (IFC) [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by the excessive accumulation of lipids in the liver parenchyma. To date, there is no effective pharmacological treatment against NAFLD. Objective: To assess the relationship between the improvement of the intrahepatic fat content (IFC) in patients with NAFLD and metabolic syndrome and biomarkers of oxidative stress and inflammation after 6 months of lifestyle intervention. Patients diagnosed with NAFLD (n = 60 adults; 40–60 years old) residing in the Balearic Islands, Spain, were distributed in tertiles attending the improvement of IFC calculated by magnetic resonance imaging (MRI). Anthropometrics, blood pressure, maximal oxygen uptake, and pro/antioxidant and inflammatory biomarkers were determined in plasma before and after the lifestyle intervention. The improvement in IFC levels was higher in tertile 3 with respect to tertiles 2 and 1. The greatest improvement in IFC is related to cardiorespiratory fitness and adherence to the Mediterranean diet (ADM). Higher reductions in weight, body mass index (BMI), and alanine aminotransferase (ALT) were observed in tertile 3 with respect to tertile 1 after 6 months of intervention. The improvement in catalase, irisin, and cytokeratin 18 plasma levels were higher in tertile 3, whereas no differences were observed in superoxide dismutase activity. Malondialdehyde and protein carbonyl levels, as biomarkers of oxidative damage, remained unchanged in all groups. The present data show that the reduction of IFC is associated with an improvement in pro/antioxidant and pro-inflammatory status and a better cardiorespiratory fitness in NAFLD patients. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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Open AccessArticle

18β-Glycyrrhetinic Acid Protects against Cholestatic Liver Injury in Bile Duct-Ligated Rats

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Antioxidants 2022, 11(5), 961; https://doi.org/10.3390/antiox11050961 - 12 May 2022

Cited by 2 | Viewed by 2011

Abstract

18β-Glycyrrhetinic acid is a nutraceutical agent with promising hepatoprotective effects. Its protective mechanisms against cholestatic liver injury were further investigated in a rodent model of extrahepatic cholestasis caused by Bile Duct Ligation (BDL) in rats. The daily oral administration of 18β-Glycyrrhetinic acid improved [...] Read more.

18β-Glycyrrhetinic acid is a nutraceutical agent with promising hepatoprotective effects. Its protective mechanisms against cholestatic liver injury were further investigated in a rodent model of extrahepatic cholestasis caused by Bile Duct Ligation (BDL) in rats. The daily oral administration of 18β-Glycyrrhetinic acid improved liver histology, serum biochemicals, ductular reaction, oxidative stress, inflammation, apoptosis, impaired autophagy, and fibrosis. 18β-Glycyrrhetinic acid alleviated the BDL-induced hepatic and systemic retention of bile acids, matrix-producing cell activation, hepatic collagen deposition, Transforming Growth Factor beta-1/Smad activation, malondialdehyde elevation, glutathione reduction, High Mobility Group Box-1/Toll-Like Receptor-4 activation, NF-κB activation, inflammatory cell infiltration/accumulation, Interleukin-1β expression, Signal Transducer and Activator of Transcription-1 activation, Endoplasmic Reticulum stress, impairment autophagy, and caspase 3 activation. Conversely, the protein expression of Sirt1, Farnesoid X Receptor, nuclear NF-E2-Related Factor-2, Transcription Factor EB, bile acid efflux transporters, and LC3-II, as well as the protein phosphorylation of AMP-Activated Protein Kinase, was promoted in 18β-Glycyrrhetinic acid-treated BDL rats. The hepatoprotective effects of 18β-Glycyrrhetinic acid in the present investigation correlated well with co-activation and possible interactions among Sirt, FXR, and Nrf2. The concurrent or concomitant activation of Sirt1, FXR, and Nrf2 not only restored the homeostatic regulation of bile acid metabolism, but also alleviated oxidative stress, inflammation, apoptosis, impaired autophagy, and fibrosis. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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Open AccessArticle

Metabolic Disorders in Patients with Chronic Hepatitis B Virus Infection: Coffee as a Panacea? (ANRS CO22 Hepather Cohort)

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Ventzislava Petrov-Sanchez

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Tarik Asselah

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Elisabeth Delarocque-Astagneau

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Dominique Larrey

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Jean-Charles Duclos-Vallée

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Fabrice Carrat

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Patrizia Carrieri

and on behalf of the ANRS/AFEF Hepather Study Group

Antioxidants 2022, 11(2), 379; https://doi.org/10.3390/antiox11020379 - 14 Feb 2022

Cited by 1 | Viewed by 1810

Abstract

People living with chronic hepatitis B virus (HBV) infection are at high risk of liver disease progression, which is positively associated with metabolic disorders, but inversely associated with dyslipidemia. Diet, including dietary antioxidants, is a lever of metabolic disorder management. In particular, elevated [...] Read more.

People living with chronic hepatitis B virus (HBV) infection are at high risk of liver disease progression, which is positively associated with metabolic disorders, but inversely associated with dyslipidemia. Diet, including dietary antioxidants, is a lever of metabolic disorder management. In particular, elevated coffee consumption is associated with different metabolic outcomes in the general population. We aimed to test whether such associations occur in HBV-infected people. Based on cross-sectional data from the ANRS CO22 Hepather cohort, we performed logistic regression models with (i) dyslipidemia, (ii) hypertension, and (iii) diabetes as outcomes, and with demographic, clinical, and socio-behavioral (including coffee consumption) data as explanatory variables. Among 4746 HBV-infected patients, drinking ≥3 cups of coffee per day was associated with a higher risk of dyslipidemia (adjusted odds ratio [95% confidence interval] 1.49 [1.10–2.00], p = 0.009) and a lower risk of hypertension (0.64 [0.50–0.82], p = 0.001). It was not associated with diabetes. Elevated coffee consumption was associated with a higher risk of dyslipidemia and a lower risk of hypertension in HBV-infected patients, two effects expected to be associated with favorable clinical outcomes. Further studies should test whether such metabolic benefits translate into reduced mortality risk in this population. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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Review

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Open AccessReview

Beneficial Effects of Opuntia spp. on Liver Health

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Irene Besné-Eseverri

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Jenifer Trepiana

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Saioa Gómez-Zorita

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Marilena Antunes-Ricardo

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M. Pilar Cano

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María P. Portillo

Antioxidants 2023, 12(6), 1174; https://doi.org/10.3390/antiox12061174 - 29 May 2023

Viewed by 103

Abstract

The genus Opuntia spp. includes plants capable of growing in arid, temperate and tropical climates. The vast majority of wild species grow in Mexico, but O. ficus-indica (prickly pear or nopal) is cultivated around the world and it is one of the most [...] Read more.

The genus Opuntia spp. includes plants capable of growing in arid, temperate and tropical climates. The vast majority of wild species grow in Mexico, but O. ficus-indica (prickly pear or nopal) is cultivated around the world and it is one of the most studied. This review shows the currently available knowledge concerning the action of O. ficus-indica and other Opuntia species (Opuntia vulgaris, Opuntia robusta, Opuntia streptacantha, Opuntia microdasys, Opuntia dillenii and Opuntia dejecta) on liver health. The available data demonstrate the positive effects of extracts, vinegar, juices or seed oil of the Opuntia genus on the alterations induced in the liver by inadequate feeding patterns or the administration of chemicals. In this regard, the potential beneficial effects of nopal are related to the attenuation of triglyceride accumulation, oxidative stress and/or inflammation. Nevertheless, there is no information concerning the bioactive compound’s characterisation in most of these studies; consequently, it is not possible to link the therapeutic effects of these plants to the presence of specific compounds in the nopal extracts. Therefore, further research is needed to confirm if the positive effects observed in animal models are also found in humans, in order to determine whether Opuntia can represent an effective tool to prevent and/or manage hepatic alterations. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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Open AccessReview

Genetic Factors Associated with Response to Vitamin E Treatment in NAFLD

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Mehtap Civelek

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Maren C. Podszun

Antioxidants 2022, 11(7), 1284; https://doi.org/10.3390/antiox11071284 - 28 Jun 2022

Cited by 3 | Viewed by 1224

Abstract

Non-alcoholic fatty liver disease (NAFLD) is becoming the predominant liver disease worldwide, and vitamin E has been clinically shown to improve histological parameters in a subset of patients. In this narrative review, we investigate whether genetic factors may help to explain why some [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is becoming the predominant liver disease worldwide, and vitamin E has been clinically shown to improve histological parameters in a subset of patients. In this narrative review, we investigate whether genetic factors may help to explain why some patients show histological improvements upon high-dose alpha-tocopherol (αT) treatment while others do not. In summary, we identified two factors that are associated with treatment response, including genetic variations in haptoglobin as well as fatty acid desaturase 1/2 (FADS1/FADS2). Other genetic variants such as in alpha-tocopherol transfer protein (αTTP), tocopherol associated protein (TAP), transmembrane 6 superfamily 2 (TM6SF2), cluster of differentiation 36 (CD36), and proteins involved in lipoprotein metabolism may also play a role, but have not yet been investigated in a clinical context. We propose to further validate these associations in larger populations, to then use them as a clinical tool to identify the subset of patients that will benefit the most from vitamin E supplementation. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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Open AccessReview

Cell Models and Omics Techniques for the Study of Nonalcoholic Fatty Liver Disease: Focusing on Stem Cell-Derived Cell Models

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María Pelechá

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Estela Villanueva-Bádenas

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Enrique Timor-López

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María Teresa Donato

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Laia Tolosa

Antioxidants 2022, 11(1), 86; https://doi.org/10.3390/antiox11010086 - 30 Dec 2021

Cited by 2 | Viewed by 2228

Abstract

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in western countries. The molecular mechanisms leading to NAFLD are only partially understood, and effective therapeutic interventions are clearly needed. Therefore, preclinical research is required to improve knowledge about [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in western countries. The molecular mechanisms leading to NAFLD are only partially understood, and effective therapeutic interventions are clearly needed. Therefore, preclinical research is required to improve knowledge about NAFLD physiopathology and to identify new therapeutic targets. Primary human hepatocytes, human hepatic cell lines, and human stem cell-derived hepatocyte-like cells exhibit different hepatic phenotypes and have been widely used for studying NAFLD pathogenesis. In this paper, apart from employing the different in vitro cell models for the in vitro assessment of NAFLD, we also reviewed other approaches (metabolomics, transcriptomics, and high-content screening). We aimed to summarize the characteristics of different cell types and methods and to discuss their major advantages and disadvantages for NAFLD modeling. Full article

(This article belongs to the Special Issue Oxidative Stress and Chronic Liver Diseases)

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