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Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
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Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
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Department of Pharmacology, College of Graduate Studies, Midwestern University, Downers Grove, Illinois, USA
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Graphical abstract
Abstract
Binge drinking is a growing health concern among all age groups. The ability of individuals to handle ethanol in their systems differs not due to differences in enzyme expression but also due to other factors. Vital organs including brain, liver, heart, and kidneys are at high risk following repeated exposure to high concentrations of ethanol from binge drinking. The impact of chronic binge drinking on kidneys is not well studied. Using a mouse model of chronic binge drinking, we have identified major metabolic alterations that could set the stage for detrimental effects in the kidneys of male and female mice. We have deciphered that even though there are pathway overlaps, the different sexes exhibited unique and divergent metabolic pathway dysregulations as per the metabolite panels following binge drinking. We have reported that binge drinking could negatively influence renal redox homeostasis in both sexes through the regulation of different metabolite clusters. In male mice by downregulation of pantothenic acid and riboflavin synthesis, and in female mice by upregulation of α-aminoadipic acid and formyl kynurenine level. Interestingly, the uric acid biosynthesis pathway has been upregulated independent of the sex-specific effects, portraying the significance of uric acid as a potential marker for binge drinking-induced injury in both sexes. Thus, by altering renal metabolome, binge drinking sets the stage for renal damage by disturbing renal redox balance. Our data has high translational potential and will aid in finding ideal therapeutics in a sex-specific manner for subjects exposed to binge drinking- induced renal injury.
Search for other papers by Opeyemi S Ademowo in
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Search for other papers by Irundika H K Dias in
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Despite decades of research, the cause and series of events underlying the advancement of Alzheimer’s disease (AD) have not yet been established. Lipid, especially cholesterol, levels have been proposed to be implicated in AD. Several studies have been undertaken and many are ongoing in different directions looking at the importance of circulating cholesterols and oxidised cholesterols in AD with inconsistent methods and results. This meta-analysis aims to systematically analyse available data describing the involvement of oxidised cholesterols in mild cognitive impairment (MCI) and AD. We conducted a systematic literature search of six databases MEDLINE (PubMed), BIOSIS (Web of Science), EMBASE (Elsevier), PsycNET, Scopus and Cochrane library for studies measuring oxysterols (24-hydroxycholesterol (24OHC); 26-hydroxycholesterol (26OHC) and 7-oxycholesterols) in serum or plasma from MCI/AD patients compared to age- and gender-matched cognitively normal controls. Data were analysed using the inverse variance and standard mean difference with random-effect analysis model at 95% CI for association between oxysterols and MCI/AD in Review Manager (RevMan) software version 5.4.1. Between January 2000 and April 2022, 175 studies were identified by two independent researchers out of which 14 met the inclusion criteria and were analysed with a total of 957 controls, 469 MCI cases and 509 AD cases. The standard mean differences between MCI/AD participants and controls did not show any difference in the oxysterol levels except for 26OHC level which was higher in AD but not statistically significant.
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Background
The side chain 27-hydroxycholesterol has been reported to inhibit the replication of several pathogen viruses, including herpes simplex virus, rhinovirus, rotavirus and SARS-CoV-2, in in vitro and ex vivo models.
Objective
In view of a future potential therapeutic use of 27-hydroxycholesterol, a pilot pharmacokinetic study was set up.
Methods
This active substance was complexed with 2-hydroxypropyl-β-cyclodextrin and orally administered in a single dose to CD1 male mice; its recovery in plasma and a few tissues up to 24 h post-treatment was evaluated.
Results
The absorption of the oxysterol by the small intestine was moderate, due to its physicochemical properties, but still relevant and rapid, showing a peak at 1 h after supplementation and being almost completed 24 h after treatment. 27-Hydroxycholesterol appeared to be a high hepatic extraction drug, possibly with an extrahepatic component contributing to the total clearance.
Conclusions
Following the oral 25 mg/kg dosing, plasma levels of 27-hydroxycholesterol showed an average steady-state concentration similar to that shown to be able to inhibit the replication of all viruses tested so far in in vitro models.
Significance statement
The first pharmacokinetic data relative to a natural oxysterol administered p.o. are reported. Data should contribute to further elucidate oxysterol pathophysiology and guide non-clinical studies aiming at investigating possible therapeutic use of 27-hydroxycholesterol or its analogs.
Search for other papers by Yoshiro Saito in
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Graphical abstract
Abstract
The essential trace element selenium plays a significant role in redox homeostasis in the human body. Selenium is very reactive and has a potent toxicity; however, the living body cleverly utilizes its reactivity for redox reactions. The biological function of selenium is mainly mediated by selenoproteins, which contain selenocysteine, a cysteine analogue that possesses selenium instead of sulphur. Twenty-five types of human selenoproteins have been identified, including glutathione peroxidase (GPX; for the reduction of hydrogen peroxide and lipid hydroperoxide) and thioredoxin reductase (for redox regulation). Selenoprotein P (SELENOP), which is a major selenoprotein in the plasma, is mainly synthesized in the liver and secreted into the plasma. As a multifunctional protein with selenium-transporting activity, GPX-like activity, and metal-binding properties, SELENOP plays a vital role in selenium metabolism and redox regulation. This review focuses on the relationship between selenium metabolism and redox regulation, particularly on the physiological role of selenoproteins and the pathophysiological implications of its disorder. Furthermore, the significant roles of selenium in infectious diseases and its utility for phylaxis are discussed.
Search for other papers by Ebenezer Tunde Olayinka in
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Department of Environmental Health Science, Ajayi Crowther University, Oyo, Nigeria
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Graphical abstract
Abstract
Objectives
Renal failure has been reported in patients treated with teicoplanin (TEIC), a widely used antibiotic. Hesperetin, a flavonoid in citrus fruits, has been reported to possess nephroprotective effects. This study investigated the protective effect of hesperetin on TEIC-induced nephrotoxicity in rats.
Methods
Male Wistar rats (n = 32, 144–180 g) were grouped into four groups of eight rats each. The control, group 1 received water, group 2 received 50 mg/kg of hesperetin orally, group 3 received 10 mg/kg of TEIC intraperitoneally and group 4 received 50 mg/kg of hesperetin and 10 mg/kg of TEIC. Administration was done for 21 days. Rats were sacrificed 24 h after the last administration, and the kidney was excised and used for biochemical assays.
Results
Administration of TEIC resulted in kidney injury that was characterized by significant increase in plasma urea and creatinine level relative to control group (P < 0.05). Additionally, a significant increase in the biomarkers of inflammation (NO, myeloperoxidase, TNF-α) and lipid peroxidation (malondialdehyde) of TEIC-treated rats was observed when compared to the control group. Furthermore, altered antioxidant status was observed following TEIC treatment. Activities of enzymic antioxidants (SOD, CAT, GPx, GST) and concentration of non-enzymic antioxidants (GSH and ascorbic acid) were downregulated. In comparison to the TEIC-treated group, the administration of hesperetin with TEIC significantly reduced all changes in the markers of kidney injury, inflammation and oxidative stress. Histopathological examination revealed that rats given TEIC showed increased glomerular size and considerable hydropic changes in the proximal convoluted tubules, whereas rats given HESP and TEIC showed only mildly enhanced glomerular size and hydropic modifications.
Conclusion
Hesperetin preserved the histo-architecture of the kidney. From this study, hesperetin offered a protective effect against TEIC-induced nephrotoxicity in rats.
Significance statement
One of the known hazards of TEIC, a frequently used antibiotic, has been renal failure, among others. This study sheds fresh light on the efficacy of hesperetin, a flavonoid found in many citrus fruits, for preventing TEIC-induced kidney damage by reducing oxidative stress and inflammation. Also, hesperetin should be considered as an alternate supplement against TEIC-induced kidney impairment. Furthermore, the data reported in this study will provide useful information for future research into the therapeutic benefits of hesperetin as an alternative therapy for renal damage.
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In a Western or Westernized diet, the abundant cholesterol is invariably associated with the presence of biochemically reactive oxysterols, the amount of which mainly depends upon the autoxidation degree of cholesterol itself, during food harvesting, production and storage. Oxysterols, in the average amount and composition detected in a high-cholesterol diet, display remarkable pro-inflammatory and cytotoxic effects on the gut epithelium. Moreover, in a low micromolar range, they may change the physiological level and membrane localization of tight junctions of the intestinal epithelial barrier, which then become leaky and permeable to microbiota. This combination of toxic effects possibly exerted by dietary oxysterols likely contributes to the impairment of the microbiota–gut–brain axis, through both direct and indirect mechanisms hereby reviewed. Importantly, dietary oxysterols are absorbed like cholesterol and circulate in the bloodstream, mainly within LDLs, rendering these micelles more oxidized and dangerous. Last but not the least, dietary oxysterols may deeply interfere with correct gut–brain signalling because of the redox pathways they are hyper-regulating and sustaining. In conclusion, protective dietary measures should be adopted, including restricted consumption of cholesterol-rich food and reduction of cholesterol autoxidation in food production and storage, for instance by supplementation of food with flavonoids and/or other bioactive substances with strong anti-oxysterol properties.
Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain
INSERM UMR1141, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
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Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain
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Department of Physiology, University of Valencia, Burjassot, Spain
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Brain is an oxyregulator organ, however extremely vulnerable to oxygen. Both high and low oxygen concentrations generate free radicals and may cause oxidative stress and damage because of an insufficient response of the antioxidant system. Hypoxic preconditioning (HP) exerts neuroprotective effects and may be a protecting tool against oxygen fluctuations, thus preventing neuronal damage in events such as ischaemia, acute hypoxia, stroke, or traumatic brain injury, among others. This review aims to discuss the molecular mechanisms involved in the neuroprotective action of HP against oxidative stress and subsequently upon the brain under pro-oxidant conditions. Activation of the antioxidant defences represents the first line to neutralize oxidative stress and is characterized by low reactive oxygen species, reduced oxidative damage biomarkers, and increased level of reduced glutathione. These protective mechanisms decrease cell death activating anti-apoptotic signalling pathways and reducing neuroinflammation by the inactivation of microglia and astroglia cells. HP could be considered a new approach to reduce oxidative stress derived damage caused by a great variety of brain pathologies. Despite our intriguing findings, further experiments are needed for a better understanding of the molecular mechanisms involved in the neuroprotective actions of HP.
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In the last decade, non-alcoholic fatty liver disease (NAFLD) and particularly its evolution to nonalcoholic steatohepatitis (NASH) have become a leading cause of chronic liver disease and cirrhosis as well as an important risk factor for hepatocellular carcinoma. Oxidative stress is a common feature of NAFLD/NASH and plays a key role in the complex of metabolic and cellular derangements that are involved in the development of liver steatosis, as well as in the transition to steatohepatitis. This review deals with the contribution of oxidative stress in promoting hepatic inflammation which represents a key factor in NAFLD evolution to liver fibrosis/cirrhosis. We discuss in detail recent data involving oxidative stress products as triggers for hepatic innate immunity and as a source of antigens implicated in sustaining lymphocyte-mediated adaptive immune responses. Attention is also paid to emerging evidence linking oxidative stress and extra-hepatic complications of NAFLD/NASH.
Biomedical Research Institute INCLIVA, Valencia, Spain
Department of Physiology, Medicine and Dentistry School, University of Valencia, Valencia, Spain
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Biomedical Research Institute INCLIVA, Valencia, Spain
Department of Physiology, Medicine and Dentistry School, University of Valencia, Valencia, Spain
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Biomedical Research Institute INCLIVA, Valencia, Spain
Department of Physiology, Medicine and Dentistry School, University of Valencia, Valencia, Spain
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Biomedical Research Institute INCLIVA, Valencia, Spain
Department of Physiology, Medicine and Dentistry School, University of Valencia, Valencia, Spain
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Oxidative stress is an important contributor to sepsis and one of the most important causes of death in intensive care units. Even though sepsis pathogenesis remains obscure due to its heterogenicity and complexity, there is increasing evidence that oxidants and antioxidants play a key role in its onset and progression. Recent evidence suggests that pyroptosis is required for defense against bacterial infection, and it is active in several cell types during sepsis. One of the most relevant mediators of pyroptosis is the NLRP3 inflammasome, and the oxidative stress/NLRP3 signaling pathway is one of the main upstream signals involved in its activation. So, it is of special relevance to clarify how oxidative stress and antioxidants can modulate pyroptosis signals and therefore decrease the deleterious effects that both oxidative stress and pyroptosis-related cytokines can induce in the tissues during sepsis. Recent studies evaluating several antioxidants are promising, but further trials are needed to confirm their potential role as agents to block NLRP3 and mitigate the exacerbated inflammasome-related responses during sepsis.
