Research
Glutathione Supplementation of Parenteral Nutrition Prevents Oxidative Stressand Sustains Protein Synthesisin Guinea Pig Model
Abstract:
Peroxides in parenteral nutrition (PN) restrict methionine’s role as a cysteine precursor, causing cysteine deficiency. This deficiency is marked by low glutathione (key for peroxide detoxification) and limited growth in long-term PN recipients vs. the general population.
We hypothesized that glutathione supplementation in PN acts as a pro-cysteine, boosting glutathione levels, enhancing protein synthesis, and reducing PN-induced oxidative stress.
Using 1-month-old guinea pigs (7–8/group), we compared glutathione-enriched PN, non-enriched PN, and enteral nutrition (reference). PN included dextrose, amino acids (Primene), lipid emulsion (Intralipid), multivitamins, and electrolytes, infused for 5 days. We measured glutathione (GSH, GSSG, redox potential) and radioactive leucine incorporation (protein synthesis index) in blood, lungs, liver, and gastrocnemius muscle; data were analyzed via ANOVA (p<0.05 = significant).
Adding glutathione to PN prevented PN-induced oxidative stress in lungs/muscles and supported protein synthesis in liver/muscles. These results potentially support glutathione supplementation in PN and confirm glutathione as a bioavailable cysteine precursor.
Adding glutathione to parenteral nutrition prevents alveolar loss innewborn Guinea pig
Abstract:
Bronchopulmonary dysplasia (BPD), a major prematurity complication, is defined by alveolar hypoplasia. Premature infants have low endogenous glutathione (a key antioxidant) and face high oxidative stress (e.g., ascorbylperoxide from parenteral nutrition [PN]), suggesting oxidative stress triggers BPD.
Hypothesis: Adding glutathione (GSSG) to PN enhances ascorbylperoxide detoxification via glutathione peroxidase, thereby preventing excessive apoptosis and alveolar loss.
Methods: Ascorbylperoxide’s role as a glutathione peroxidase substrate was analyzed via Michaelis-Menten kinetics. Three-day-old guinea pig pups (6 groups) received IV infusions for 4 days: 1) Sham (no infusion); 2) PN(-L) (light-protected PN, low ascorbylperoxide); 3) PN(+L) (unprotected PN, high ascorbylperoxide); 4) 180 μM ascorbylperoxide; 5) PN(+L)+10 μM GSSG; 6) Ascorbylperoxide+10 μM GSSG. Lung samples were analyzed for histology and biochemistry; data via ANOVA (p<0.05 = significant).
Results: Glutathione peroxidase had a Km of 126±6 μM and Vmax of 38.4±2.5 nmol/min/U for ascorbylperoxide. GSSG in IV solutions prevented PN(+L)/ascorbylperoxide-induced effects: high GSSG redox potential, caspase-3 activation (apoptosis marker), and alveolar loss.
Conclusion: Correcting low glutathione in neonates on PN protects lungs from ascorbylperoxide toxicity. This is critical for premature infants (low glutathione) and offers potential for BPD prevention.
Glutathione in liver diseases and hepatotoxicity
Abstract:
Glutathione (GSH) is a major antioxidant as well as redox and cell signaling regulator. GSHguards cells against oxidative injury by reducing H,O, and scavenging reactive oxygen andnitrogen radicals. In addition, GSH-induced redox shift with or without ROS subjects somecellular proteins to varied forms of oxidation, altering the function of signal transductionand transcription factor molecules. Increasing evidence supports the important role ofROS and GSH in modulating multiple signaling pathways. TNF- and Fas signaling, NF-KB, |NK and mitochondrial apoptotic pathways are the focus of this review. The redox regulation either can switch on/off or regulate the threshold for some crucial events in thesepathways. Notably, mitochondrial GSH depletion induces increased mitochondrial ROsexposure which impairs bioenergetics and promotes mitochondrial permeability transitionpore opening which is critical for cell death, Depending on the extent of mitochondriadamage, NF-kB inhibition and jNK activation, hepatocytes may either undergo differentmodes of cell death (apoptosis or necrosis) or be sensitized to cell-death stimuli (i.eTNF-a). These processes have been implicated in the pathogenesis of many liver diseases
Damage During Acute Inflammation
Protective Role of Glutathione against Peroxynitrite-Mediated DNA
Abstract:
Inflammation is an immune response to protect against various types of infections. When unchecked, acuteinfammation can be life-threatening, as seen with the current coronavirus pandemic, Strong oxidants, such as peroxynitrite producedby immune cells, are major mediators of the infammation-associated pathogenesis. Cellular thiols play important roles in mitigatinginflammation-associated macromolecular damage including DNA. Herein, we have demonstrated a role of glutathione (GSH) andother thiols in neutralizing the effect of peroxynitrite -mediated DNA damage through stable GSH-DNA adduct formation. Ourobservation supports the use of thiol supplements as a potential therapeutic strategy against severe COVlD-19 cases and a Phase ll(NC'T04374461) open-abel clinical trial launched in early May 2020 by the Memorial Sloan Kettering Cancer Center.
Glutathione as a Marker for Human Disease
Abstract:
Glutathione (GSH), often referred to as "the master antioxidant," participates not only inantioxidant defense systems, but many metabolic processes, and therefore its rolecannot be overstated. GSH defciency causes cellular risk for oxidative damage andthus as expected, GSH imbalance is observed in a wide range of pathological condi-tions including tuberculosis (TB), HlV, diabetes, cancer, and aging. Consequently, it isnot surprising that GSH has attracted the attention of biological researchers and phar-macologists alike as a possible target for medical intervention. Here, we discuss the roleGSH plays amongst these pathological conditions to illuminate how it can be used as amarker for human disease.
Glutathione-Capped Ag2s Nanoclusters Inhibit CoronavirusProliferation through Blockage of Viral RNA Synthesis and Budding
Abstract:
Development of novel antiviral reagents is of greatimportance for the control of virus spread. Here, Ag2S nanoclusters(NCs)were proved for the first time to possess highly efcient antiviraactivity by using porcine epidemic diarrhea virus (PEDV) as a model ofISG-54coronavirus. Analyses of virus titers showed that Ag2S NCs significantlysuppressed the infection of PEDV by about 3 orders of magnitude at thenoncytotoxic concentration at 12 h postinfection, which was furtherconfrmed by the expression of viral proteins. Mechanism investigationsindicated that Ag2S NCs treatment inhibits the synthesis of viralRNAnegative-strand RNA and viral budding. Ag2S NCs treatment was alsofound to positively regulate the generation of IFN-stimulating genesISGs)and the expression of proinflammation cytokines, which mightprevent PEDV infection. This study suggest the novel underlying of Ag2SNCs as a promising therapeutic drug for coronavirus.
Chronic Glutathione DepletionConfers Protection against Alcohol.induced Steatosis:mplication forRedoxActivation ofAMP-activatedProtein Kinase Pathway
Abstract:
The pathogenesis of alcoholic liver disease (ALD) is not well established. However, oxidative stress andassociated decreases in levels of glutathione (GSH) are known to play a central role in ALD.The presentstudy examines the effect of GSH defciency on alcohol-induced liver steatosis in Gclm knockout (KO)mice that constitutively have <15% normal hepatic levels ofGsH. Following chronic (6 week) feedingwith an ethanol-containing liguid diet, the Gclm KO mice were unexpectedly found to be protectedagainst steatosis despite showing increased oxidative stress (as reflected in elevated levels ofCYP2E1and protein carbonyls). Gclm KO mice also exhibit constitutive activation ofliver AMP-activatedprotein kinase (AMPK) pathway and nuclear factor-erythroid 2-related factor 2 target genes, and showenhanced ethanol clearance, altered hepatic lipid profles in favor of increased levels of polyunsaturatedfatty acids and concordant changes in expression of genes associated with lipogenesis and fatty acidoxidation. in summary, our data implicate a novel mechanism protecting against liver steatosis via anoxidative stress adaptive response that activates the AMPK pathway. We propose redox activation ofthe AMPK mayrepresent a new therapeutic strategyfor preventing ALD.
Allyl Alcohol Liver Injury: Suppression by Ethanol andRelation to Transient Glutathione Depletion
Abstract:
Rats metabolized a sublethal gastric dose (0.73 mmol/kg) of allvl alcohol (AlOH) within 10-15 min. Oxidationof AlOH to acrolein was accompanied by an equally rapid, but only transient depletion of hepatic reduced glutathone(GSH). GSH was restored to levels above normal within 5 hrs. Simultaneously, AlOF provoked marked elevation ofalanine aminotransferase, y-glutamyl transpeptidase, and glutamate dehydrogenase activities in plasma and formation oflesions mainly in the periportal regions of the liver. Inhibition of alcohol dehydrogenase by 4-methyl pyrazole completelcounteracted these effects. On the other hand, attempts to potentiate the toxicity of acrolein by the aldehyde dehydrogenaseinhibitor cyanamide enhanced only the release of alanine aminotransferase. Co-administration of ethanol (3 g/kg) inhibitedthe rate of AlOH oxidation by more than 90%, Although with ethanol GSH remained depleted for several hours, therelease of enzymes was markedly suppressed and the histologic changes completely prevented. These results indicate thatthe rapid rate of acrolein formation, rather than persistently lowered GSH content, is crucial in the hepatotoxicity ofAl0H. They also suggest, that oxidation of acrolein via aldehyde dehydrogenase does not represent a major pathway forits detoxication in vivo.
Glutathione and Transsulfurationin Alcohol-Associated Tissue Injuryand Carcinogenesis
Abstract:
Glutathione (GSH) is the most abundant non-protein thiol, attaining cel.lular concentrations in the millimolar range. GSH functions to protect cells againstendogenous and exogenous electrophiles. In addition, GSH serves as a cofactor forthe GSH peroxidase family of enzymes which metabolize H2O2 as well as lipidperoxides. Through the action of glutathione S-transferase family ofenzymes, GSHis conjugated to a variety of electrophilic endogenous compounds and exogenouschemicals, and thereby facilitates their effcient and safe elimination. Through thetranssulfuration pathway, GSH biosynthesis is metabolically linked with cellularmethylation, which is pivotal for epigenetic gene regulation. Accumulating evi-dence suggests that the underlying mechanisms of alcohol-associated tissue injuryand carcinogenesis involve: (i) generation of the electrophilic metabolite acetalde-hyde, (ii) induction ofCYP2E1 leading to the formation of reactive oxygen speciesand pro-carcinogen activation, and (iii)nutritional deficiencies, such as methylgroups, resulting in enhanced susceptibility to cancer development. In this context.clinical and experimental investigations suggest an intimate involvement of GSHand related enzymes in the development of alcohol-induced pathological conditions.