Lower Glutathione Research Articles

BRAIN GLUTATHIONE, MITOCHONDRIA, GLUCOSE METABOLISM, AND COGNITION IN AGED MICE: IMPACT OF GLYNAC SUPPLEMENTATION

Abstract Alzheimer’s disease (AD) remains unsolved, and is associated with brain defects including impaired glucose uptake, mitochondrial dysfunction, inflammation and glutathione deficiency. These defects also occur in age-related cognitive decline (ACD). Because mice do not naturally develop AD, mouse models of AD have been developed and studied. However, such mouse models are highly artificial because defects do not occur naturally and are artificially induced in mice. To understand the mechanistic basis of cognitive decline in aging, it is important to investigate these defects directly in the brain, which is only possible in animal models as performing brain biopsies in humans is not practical. To overcome these challenges, we studied glutathione deficiency, oxidative stress, glucose uptake, mitochondrial function, inflammation, genomic damage and neurotropic factors directly in the brains of old-mice (OM, 90-weeks)) and young-mice (YM, 20-weeks), and also measured cognition (maze-running). Compared to YM, OM had the following defects in the brain: (a) lower glutathione concentrations; (b) elevated oxidative stress (TBARS); (c) lower immunoblot expressions of: GLUT1 and GLUT3 (brain and neuronal glucose uptake); PGC1a; electron-chain complexes and PINK1 (mitochondria), TSPO (inflammation), pH2AX (genomic damage), and BDNF, GDNF and NGF (neurotrophic factors); (d) impaired mitochondrial respiration (high-resolution respirometry); (e) poor cognition (maze-running time). After 8-weeks of supplementation with GlyNAC (combination of glutathione precursors glycine and N-acetylcysteine), all of these defects improved/corrected in the brains of OM and cognitive performance improved significantly. The results of this study have important implications for improving brain health and cognition in human aging and in AD.

Glutathione Involvement in Potato Response to French Marigold Volatile Organic Compounds.

To elucidate the involvement of glutathione in the mitigation of induced oxidative changes and the sequestration of perceived volatiles in cells, we exposed potato plants to French marigold essential oil. The formation of short-lived radicals, the determination of scavenging activity towards ascorbyl and DPPH radicals, and the assessment of the potato plants' overall intra/extracellular reduction status were performed using electron paramagnetic resonance spectroscopy (EPR). The results showed the presence of hydroxyl radicals in potatoes, with significantly reduced accumulation in exposed plants compared to the control group after 8 h. However, the kinetics of EPR signal intensity change for the pyrrolidine spin probe (3CP) in these plants showed very low reducing potential, suggesting that the antioxidant system acts lethargically and/or the probe has been reoxidized. Total glutathione and its reduced/oxidized form ratio, determined spectrophotometrically, showed that the exposed plants initially had lower glutathione levels with diminutive, reduced form compared to the control. Still, after 8 h, both characteristics were similar to those of the control. RT-qPCR analysis revealed that the volatiles altered the expression of glutathione metabolism-involved genes, especially that of glutathione-S-transferase, after 8 h. Glutathione metabolism was affected by volatiles in the initial response of potato plants exposed to French marigold essential oil, and glutathione molecules were involved in the mitigation of induced oxidative burst.

Detecting structural and functional mitochondrial abnormalities in periodontal tissues using an experimental periodontitis model

Background: Recent research indicates that mitochondrial dysfunction plays a significant role in the development and progression of oral inflammation, such as periodontitis and pulpitis. Aim: To assess structural and functional mitochondrial abnormalities in periodontal tissues using an experimental periodontitis model in rats. Materials and methods: The study used male Wistar rats aged 4 months, with a body weight of 221.0±7.5 g. Simple randomization was used to divide the animals into two groups (n=10 each). Group 1 (control) consisted of intact animals, while Group 2 consisted of animals with experimentally induced periodontitis. A ligature-induced periodontitis model was used, with a non-absorbable polyfilament thread sutured into the gum near the mandibular incisors. Histological examinations were used to validate the experimental periodontitis model. The following molecular genetic and biochemical parameters were assessed: nuclear DNA and mitochondrial DNA (mtDNA) damage, abundance and heteroplasmy of mtDNA, mitochondrial gene expression, and levels of hydrogen peroxide (H2O2), malondialdehyde, and reduced glutathione. Results: The resulting experimental periodontitis model revealed histological changes in periodontal tissues, indicating periodontitis in the animals. On day 14 after ligation, histological findings showed that Group 2 had more significant mtDNA damage and heteroplasmy in periodontal tissues than Group 1 (control). Moreover, Group 2 showed a decrease in the expression of mtDNA genes involved in adenosine triphosphate synthesis. This group also had lower glutathione levels and higher H2O2 and malondialdehyde levels than the control group. Conclusion: The experimental periodontitis model in rats revealed structural and functional mitochondrial abnormalities in periodontal tissues. New approaches to assessing mitochondrial function in periodontitis may facilitate the diagnosis and treatment of the disease and its complications.

Coordination-Driven in Situ Grown Copper Peroxide in Mesoporous Dopamine with Self-Supplied H2O2 for Synergistic Enhanced PTT/CDT Antibacterial Treatment and Wound Healing.

As antibiotic resistance increases, alternative antimicrobial methods become essential. Chemical dynamics therapy (CDT) utilizing copper peroxide (CuO2) nanodots shows significant potential in antibacterial applications due to its ability to self-supply hydrogen peroxide (H2O2) on its own. This characteristic effectively addresses the challenges of low H2O2 levels and high glutathione (GSH) expression in the bacterial infection microenvironment. However, its tendency to aggregate and instability greatly affect its effectiveness. Therefore, this study developed a coordination-driven strategy to prepare copper peroxide-loaded mesoporous polydopamine nanomaterials (CuO2@MPDA) through in situ growth of CuO2 in mesoporous polydopamine utilizing the chelating interaction between amino and catechol structures of MPDA with copper ions. This strategy not only ensures that copper peroxide is evenly distributed within the pores of mesoporous polydopamine but also protects it through the shielding effect of pores, greatly enhancing its dispersibility and stability. More notably, the loading of CuO2 enhances the photothermal performance of MPDA by broadening its light absorption range, and MPDA-mediated photothermal therapy (PTT) can accelerate CuO2 to produce more hydroxyl radicals by speeding up chemical reactions, resulting in a combined boost in PTT and CDT. The developed CuO2@MPDA nanomaterials at very low concentrations exhibit improved antibacterial efficiency both in vitro and in vivo. Overall, this study provides an innovative strategy to construct an antibacterial nanoplatform for synergistically enhanced PTT/CDT dual-mode antibacterial treatment, exhibiting great potential for future biomedical applications.

Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span

Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss, and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with naturally short-lived animals exhibit a loss of dopamine neurons without generalized neurodegeneration, while animals from long-lived strains retain dopamine neurons across age. Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress, and vulnerability to silencing the familial PD gene parkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (Gcl) overexpression is sufficient to normalize ROS levels, extend life span, and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity. These findings may be relevant to human PD pathogenesis, where glutathione depletion is reported to occur in the idiopathic PD patient brain through unknown mechanisms. Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in the human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.

Pseudomonas aeruginosa LasR-deficient mutants have increased methylglyoxal and hydrogen peroxide sensitivity due to low intracellular glutathione.

The electrophile methylglyoxal (MG) is produced by microorganisms and host cells through central metabolic pathways. MG is a highly reactive electrophile, so it must be rapidly detoxified to prevent damaging modifications to macromolecules. Pseudomonas aeruginosa, a pathogen of concern due to its ability develop multidrug resistance, causes many types of infections that have been associated with elevated MG levels, including cystic fibrosis (CF). P. aeruginosa isolates commonly have mutations that lead to LasR loss-of-function (LasR-) and we found that lasR mutations confer sensitivity to MG in multiple strain backgrounds. LasR- strains have increased activity of the CbrAB two-component system which represses Crc regulation of metabolism. Here, we show that higher CbrAB activity and low Crc activity renders cells sensitive to MG. We found that P. aeruginosa LasR- strains are more sensitive to MG and have lower intracellular reduced glutathione (GSH) compared to their LasR+ comparators. Consistent with published reports, mutants lacking gloA3, which encodes a MG-glyoxalase, and mutants lacking GSH biosynthesis enzymes (gshA or gshB) were sensitive to MG. Exogenous GSH rescued MG sensitivity in LasR- strains and gshA or gshB mutants, but not in a gloA3 mutant strain. We propose that low GSH levels in LasR- strains contribute to increased sensitivity to MG and H2O2.

Persistent Post COVID-19 Endothelial Dysfunction and Oxidative Stress in Women.

The assessment of endothelial dysfunction and free radical homeostasis parameters were performed in 92 women, aged 45 to 69 years, divided into the following groups: women without COVID-19 (unvaccinated, no antibodies, control); women with acute phase of COVID-19 infection (main group, COVID-19+); 12 months post COVID-19+; women with anti-SARS-CoV-2 IgG with no symptoms of COVID-19 in the last 12 months (asymptomatic COVID-19). Compared to the control, patients of the main group had lower glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, decreased advanced glycation end products (AGEs) level, higher glutathione reductase (GR) activity, and higher glutathione S transferases pi (GSTpi), thiobarbituric acid reactants (TBARs), endothelin (END)-1, and END-2 concentrations (all p ≤ 0.05). The group with asymptomatic COVID-19 had lower 8-OHdG and oxidized glutathione (GSSG) levels, decreased total antioxidant status (TAS), and higher reduced glutathione (GSH) and GSH/GSSG levels (all p ≤ 0.05). In the group COVID-19+, as compared to the group without clinical symptoms, we detected lower GPx and SOD activities, decreased AGEs concentration, a higher TAS, and greater GR activity and GSTpi and TBARs concentrations (all p ≤ 0.05). The high content of lipid peroxidation products 12 months post COVID-19+, despite decrease in ENDs, indicates long-term changes in free radical homeostasis. These data indicate increased levels of lipid peroxidation production contribute, in part, to the development of free radical related pathologies including long-term post COVID syndrome.

Redox-responsive CpG-dextran conjugate enhances anti-tumour immunity following intratumoral administration

Conjugation of a therapeutic agent to a polymer for enhanced delivery into target cells followed by its intracellular triggered release has proved to be an effective drug delivery approach. This approach is applied to the delivery of the immune–stimulatory unmethylated cytosine-phosphate-guanine (CpG) oligonucleotide for an anti-tumour immune response after intratumoral administration. On average four CpG-1668 molecules were covalently linked to a 40-kDa amino-functionalised dextran polymer via either a non-reversible (CpG-dextran) or an intracellular redox-responsive disulfide linkage (CpG-SS-dextran). Dynamic light scattering analysis showed that both conjugates had a similar particle size and surface charge of 17 nm and −10 mV, respectively. Agarose gel electrophoresis analysis showed that CpG-SS-dextran was stable in the extracellular low glutathione (GSH) concentration range (i.e. 10–20 μM) and was cleaved at the higher intracellular GSH concentration (5 mM), while CpG-dextran was stable in both GSH concentrations. Uptake and activation assays on bone-marrow-derived dendritic cells showed no significant difference between free CpG, CpG-dextran and CpG-SS-dextran. In a mouse subcutaneous colorectal tumour model the CpG-SS-dextran showed a statistically significantly greater inhibition of tumour growth (p < 0.03) and prolonged survival (p < 0.001) compared to CpG-dextran or free CpG. These results demonstrate that the redox-triggered intracellular release of CpG from a dextran polymer carrier has promise for intratumoral therapeutic vaccination against cancer.

Jasmonic acid priming and foliar application of spermidine up-regulates the tolerance mechanisms to alleviate the damaging effects of cadmium stress on growth and photosynthesis in wheat

The study examined the effects of jasmonic acid (100 nmol, JA) priming and foliar application of spermidine (1 mM, Spd), both individually and combined, on mitigating cadmium (100 µM, Cd) stress-induced oxidative damage in wheat. Cadmium stress reduced plant height and dry mass, but JA priming and/or Spd treatment increased resistance. Cd stress significantly decreased carotenoids, total chlorophylls, glutamate 1-semialdehyde (GSA), and δ-aminolevulinic acid (ALA), but JA and Spd treatments counteracted these reductions. Photosynthetic parameters improved under JA and Spd treatments, with combined treatment showing greater alleviation. Cd exposure increased lipid peroxidation, hydrogen peroxide, electrolyte leakage, and superoxide, but these oxidative stress indicators were significantly reduced after JA and Spd treatment. Antioxidant enzyme activity was upregulated by JA priming and Spd application, both under unstressed and Cd-stressed conditions. JA and/or Spd treatments also increased ascorbic acid, lowered glutathione concentration, and upregulated glyoxylase activity, reducing methylglyoxal accumulation. Additionally, secondary compounds (phenols and flavonoids) and osmolytes (proline and glycine betaine) levels improved. Proline oxidase activity decreased, indicating controlled proline buildup, while γ-glutamyl kinase activity increased. JA and/or Spd treatments significantly reduced Cd accumulation in seedlings. The study concluded that JA and Spd treatments enhance the plant's defensive mechanisms against oxidative stress by boosting antioxidant enzymes and secondary metabolism.

Decreased glutathione synthesis in granulosa cells, but not oocytes, of growing follicles decreases fertility in mice†.

Prior studies showed that mice deficient in the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in synthesis of the thiol antioxidant glutathione, have decreased ovarian glutathione concentrations, chronic ovarian oxidative stress, poor oocyte quality resulting in early preimplantation embryonic mortality and decreased litter size, and accelerated age-related decline in ovarian follicle numbers. Global deficiency of the catalytic subunit of this enzyme, Gclc, is embryonic lethal. We tested the hypothesis that granulosa cell- or oocyte-specific deletion of Gclc recapitulates the female reproductive phenotype of global Gclm deficiency. We deleted Gclc in granulosa cells or oocytes of growing follicles using Gclc floxed transgenic mice paired with Amhr2-Cre or Zp3-Cre alleles, respectively. We discovered that granulosa cell-specific deletion of Gclc in Amhr2Cre;Gclc(f/-) mice recapitulates the decreased litter size observed in Gclm-/- mice but does not recapitulate the accelerated age-related decline in ovarian follicles observed in Gclm-/- mice. In addition to having lower glutathione concentrations in granulosa cells, Amhr2Cre;Gclc(f/-) mice also had decreased glutathione concentrations in oocytes. By contrast, oocyte-specific deletion of Gclc in Zp3Cre;Gclc(f/-) mice did not affect litter size or accelerate the age-related decline in follicle numbers, and these mice did not have decreased oocyte glutathione concentrations, consistent with transport of glutathione between cells via gap junctions. The results suggest that glutathione deficiency at earlier stages of follicle development may be required to generate the accelerated follicle depletion phenotype observed in global Gclm null mice.

Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.

The role of metals in hypothiocyanite resistance in Escherichia coli.

Hypothiocyanite (HOSCN) is an antimicrobial oxidant produced by the innate immune system. The molecular mechanisms by which host-associated bacteria defend themselves against HOSCN have only recently begun to be understood. The results in this paper are significant because they show that the low molecular weight thiol glutathione and enzyme glutathione reductase are critical components of the Escherichia coli HOSCN response, working by a mechanism distinct from that of the HOSCN-specific defenses provided by the RclA, RclB, and RclC proteins and that metal ions (including nickel, copper, and zinc) may impact the ability of bacteria to resist HOSCN by inhibiting specific defensive enzymes (e.g., glutathione reductase or RclA).

Glutathione Levels and Lipid Oxidative Damage in Selected Organs of Obese Koletsky and Lean Spontaneously Hypertensive Rats.

Koletsky rats, the genetically obese strain of spontaneously hypertensive rats (SHROB), are the well-accepted animal model of human metabolic syndrome. They are characterized by early onset obesity, spontaneous hypertension, hyperinsulinemia, hyperlipidemia, proteinuria and shortened life-span. One of the factors in the pathogenesis of metabolic syndrome is oxidative stress. The aim of the present study was to compare two parameters related to oxidative stress: the levels of the main intracellular antioxidant, reduced glutathione as well as the indirect indicator of lipid peroxidation damage, thiobarbituric acid-reactive substances (TBARS) in heart, renal cortex and medulla and liver in male lean spontaneously hypertensive rats (SHR) and obese Koletsky rats. We did not find any significant differences in these markers in heart and kidneys. However, we found significantly lower glutathione level in Koletsky rat liver compared with SHR (5.03+/-0.23 vs. 5.83+/-0.14 µmol/g tissue, respectively). On the contrary, we observed significantly higher TBARS levels in Koletsky rat liver compared with SHR (28.56+/-2.15 vs. 21.83+/-1.60 nmol/mg protein, respectively). We conclude that the liver is the most sensitive tissue to oxidative damage with the significantly decreased concentration of glutathione and the significantly increased concentration of TBARS in obese Koletsky rats in comparison with lean control SHR.

Haplotypes of ATP-Binding Cassette CaABCC6 in Chickpea from Kazakhstan Are Associated with Salinity Tolerance and Leaf Necrosis via Oxidative Stress.

Salinity tolerance was studied in chickpea accessions from a germplasm collection and in cultivars from Kazakhstan. After NaCl treatment, significant differences were found between genotypes, which could be arranged into three groups. Those that performed poorest were found in group 1, comprising five ICC accessions with the lowest chlorophyll content, the highest leaf necrosis (LN), Na+ accumulation, malondialdehyde (MDA) content, and a low glutathione ratio GSH/GSSG. Two cultivars, Privo-1 and Tassay, representing group 2, were moderate in these traits, while the best performance was for group 3, containing two other cultivars, Krasnokutsky-123 and Looch, which were found to have mostly green plants and an exact opposite pattern of traits. Marker-trait association (MTA) between 6K DArT markers and four traits (LN, Na+, MDA, and GSH/GSSG) revealed the presence of four possible candidate genes in the chickpea genome that may be associated with the three groups. One gene, ATP-binding cassette, CaABCC6, was selected, and three haplotypes, A, D1, and D2, were identified in plants from the three groups. Two of the most salt-tolerant cultivars from group 3 were found to have haplotype D2 with a novel identified SNP. RT-qPCR analysis confirmed that this gene was strongly expressed after NaCl treatment in the parental- and breeding-line plants of haplotype D2. Mass spectrometry of seed proteins showed a higher accumulation of glutathione reductase and S-transferase, but not peroxidase, in the D2 haplotype. In conclusion, the CaABCC6 gene was hypothesized to be associated with a better response to oxidative stress via glutathione metabolism, while other candidate genes are likely involved in the control of chlorophyll content and Na+ accumulation.

Inflamma-miRs Profile in Myelodysplastic Syndrome Patients.

Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation (inflamma-miRs), including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and the 5-AZA group. Inflammation increases miRNs and, specifically, miR-18a, miR-21 and miR-34a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRN profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRN expression levels. Relating to prognostic risk factors, high-risk MDS groups (high Revised International Prognostic Scoring System (IPSS-R), high cytogenetic risk, high molecular risk (HMR) mutations) tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRN expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRN deregulation involved in MDS development that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRN expression levels in MDS patients.

Menopausal women with moderate and asymptomatic COVID-19: antioxidant defense system biomarkers

The aim. The research was conducted to assess the total antioxidant and glutathione status, superoxide dismutase activity in menopausal women with moderate and asymptomatic COVID-19.Materials and methods. Ninety two women 45 to 69 years old were divided into groups: women without COVID-19, not vaccinated, with no antibodies to SARS-CoV-2 (IgG) – control; women with moderate COVID-19 – main group; women with anti-SARS-CoV-2 IgG in blood but who deny any symptoms of COVID-19 in the last 12 months – asymptomatic COVID-19.Results. A lower glutathione peroxidase (GPx), superoxide dismutase (SOD) activities and a higher glutathione reductase (GR) activity, glutathione S-transferase pi (GSTpi) concentrations were detected in the patients with moderate COVID-19 as compared to control. There were statistically lower oxidized glutathione (GSSG) levels, total antioxidant status (TAS) and higher reduced glutathione (GSH) levels, as well as GSH/GSSG ratio in the group with asymptomatic COVID-19 as compared to control. Significantly a lower GPx, SOD activities and a higher TAS, GR activity, GSTpi concentrations were detected in the patients with symptomatic COVID-19 as compared to group without clinical symptoms. ROC analysis shows the diagnostic significance of TAS (AUC = 0.714; p = 0.048), GSH (AUC = 0.714; p = 0.030), GSSG (AUC = 0.712; p = 0.031), GSH/GSSG (AUC = 0.837; p &lt; 0.001) for group with asymptomatic COVID-19 compared with controls; TAS (AUC = 0.709; p = 0.020), SOD (AUC = 0.760; p &lt; 0.001), GSH/GSSG (AUC = 0.658; p = 0.039), GPx (AUC = 0.774; p &lt; 0.001), GSTpi (AUC = 0.864; p &lt; 0.001) and GR (AUC = 0.871; p &lt; 0.001) for group with moderate COVID-19 compared asympotmatic COVID-19.Conclusions. Antioxidant defense system activity in menopausal women depends on the COVID-19 course.

The influence of newly synthesized tellurium-containing cyanine dyes on the intensity of oxidative processes in the bodies of mammals

The purpose of this work was to study the influence of new synthesized organotellurium compounds (TOCs) on the intensity of oxidative processes in the body of mammals – in this case, the blood and liver of rats.The experiments were performed on white outbred rats, which were given a single dose of various TOC derivatives (0.01 g/kg). The next day, the animals were decapitated, blood was collected and the liver was isolated. The content of products of oxidative modification of lipids and proteins, as well as the low molecular weight antioxidant glutathione, was determined in blood plasma, erythrocytes and liver homogenate.It was found that all TOC derivatives studied significantly increase the intensity of lipid peroxidation in erythrocytes and hepatocytes, as evidenced by a multiple increase in the concentration of malondialdehyde (MDA) in them. At the same time, TOC suppresses the levels of oxidative damage to liver proteins, which is expressed in a significant decrease in the content of carbonyl groups. A study of glutathione content in the rat erythrocytes showed the absence of any significant effects of TOS on this antioxidant in erythrocytes.However, changes in its concentration were found in the liver, which depend on the nature of TOS (for TOS1 and TOS3 a decrease and for TOS2 a slight increase). Newly synthesized TOC demonstrate pronounced prooxidant properties, significantly increasing the intensity of oxidative processes in lipids, which makes them promising agents for antibacterial, antiviral and antitumor therapy.

Abstract 3378: Acinar cell susceptibility for tumor development in the pancreas: Targeting the critical regulators for therapy

Abstract Acinar to ductal metaplasia (ADM) or acinar cell dedifferentiation is one of the most notable features of chronic pancreatitis. It is also considered the initial step of pancreatic cancer development when oncogenic mutations accumulate. However, its precise mechanism and regulatory pathways remain unclear. This study profiled the transcriptome of dedifferentiated acinar cells from both humans and mice. Differential expression analysis integrated with a systematic literature search revealed several potential regulators (e.g., GDF15, GFRA1, MXRA5, CXCL17), of which the expression pattern over time was validated by qRT-PCR. We also focused on multiple conserved pathways of cell survival, among which SLC7A11 (xCT) is transiently upregulated in both species. The xCT subunit, integral to the cystine/glutamate antiporter system xc-, plays a critical role in cell survival across various cell types. To elucidate its role in acinar dedifferentiation, we employed gene silencing, pharmacological inhibition, and a knock-out mouse model. Acinar cells with diminished xCT function exhibit increased ferroptosis linked to lipid peroxidation. Antioxidants such as N-acetylcysteine and ferroptosis inhibitors like Ferrostatin-1 can mitigate lower glutathione levels and lipid ROS accumulation. Similarly, in mouse acute pancreatitis, xCT prevents lipid peroxidation. Our findings indicate that xCT fuels the glutathione pool and maintains ROS balance during ADM, thereby preventing pancreatic acinar cells from ferroptosis, a form of cell death rarely reported in relation to ADM. Next to xCT, a future and similar comprehensive study of the aforementioned genes could provide valuable insights into the dynamic changes that occur during acinar cell dedifferentiation and pave the way to the discovery of new intervention targets to suppress tumorigenesis in chronic pancreatitis. Citation Format: Zhaolong Pan, Jan-Lars Van den Bossche, Eva Rodriguez-Aznar, Pauline Janssen, Olaya Lara, Gamze Ates, Ann Massie, Diedert Luc De Paep, Isabelle Houbracken, Marco Mambretti, Ilse Rooman. Acinar cell susceptibility for tumor development in the pancreas: Targeting the critical regulators for therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3378.

Artesunate induces ferroptosis by regulating MT1G and has an additive effect with doxorubicin in diffuse large B-cell lymphoma cells

Diffuse Large B-cell lymphoma (DLBCL) is a highly aggressive disease with heterogeneous outcomes and marked variability in the response to chemotherapy. DLBCL comprises two major subtypes: germinal centre B-cell-like (GCB) and activated B-cell-like (ABC). Our study highlights the extensive antitumour activity of artesunate (ART) against both major DLBCL subtypes. Transcriptome analysis suggests the potential involvement of ferroptosis in artesunate-induced cell death. Because of low glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels, along with the accumulation of free iron (Fe2+), artesunate induces the excessive production of reactive oxygen species (ROS), ultimately leading to ferroptosis, a form of cell death driven by phospholipid peroxidation. A putative target of artesunate, metallothionein 1G (MT1G), was selected for further analysis. Subsequent studies revealed that inhibiting MT1G expression in vitro significantly impedes the ferroptosis-promoting activity of artesunate by reducing lipid peroxidation and iron accumulation. We also showed that the combination of artesunate and doxorubicin had a marked additive inhibitory effect on GCB and ABC DLBCL cells. In conclusion, artesunate induces ferroptotic death in GCB and ABC DLBCL cells by attenuating the GPX4/GSH antioxidant defence system and increasing intracellular iron levels, indicating its therapeutic potential for relapsed or refractory DLBCL.

Review of Alzheimer’s Disease’s Animal Model with it’s Pathophysiology and Drug Discovery

Alzheimer disease (AD) chronic neurodegenerative disease. Beta amyloid and tau neuropathy associated with this disease. New drug therapy deals with AREA, DIED etc. The in vitro and in vivo study shows Aducanumab was the first treatment to address an underlying cause of the disease. This removes sticky depositions of amyloid plaques. Alzheimer's neuropathology the superfrontal cortex suffer from atrophy and loss of neurones, which occurs inflammation and deposition of amyloid plaques and bundles of connective tissue and abnormal set of protein fragments. The monoclonal part of the drug attacks the aggregated depositions. Gantenerumab &amp; Solanezumab also are tested for curing for this disease. There much model like 2D and 3D and various cultural model by which the AD cure process can be reached. A neuron is unit of the brain function, which contains an excess amount of polyunsaturated (fatty) acids. It can react with ROS, which can deals with lipid peroxidation response and cell apoptosis, in addition, low glutathione to neurons and is major causes of oxidative stress injure Modelling has been formed by stem cells, vascularised organ. Advanced models are used to understand better neurodegeneration, and potential therapies. In this review we can say that the current progress of new therapeutics like lipid metabolism, inflammation, and disease customize genes to AD in preclinical and clinical research. It’seeming that higher dose are worked in AD patients but lower dose causes AREA. ARIA can successfully cured in most of the patients who engaged themselves in important tests without stopping the treatment.