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Ischemia-reperfusion injury, a critical pathophysiological phenomenon in multiple organ systems, remains a formidable therapeutic challenge in clinical practice. As the third endogenously produced gaseous signaling molecule, hydrogen sulfide (H2S) has emerged as a pivotal regulator of diverse physiological processes and pathological cascades. Accumulating evidence indicates that H2S exerts cytoprotective effects against cerebral, cardiac, hepatic, renal, and pulmonary ischemia-reperfusion injuries through multifaceted mechanisms involving mitigation of inflammatory responses, suppression of oxidative stress, modulation of autophagic processes, and inhibition of apoptotic pathways. This comprehensive review systematically examines the endogenous biosynthesis and metabolic regulation of H2S, while elucidating the molecular mechanisms underlying its organ protective effects during ischemia-reperfusion injury. Particular emphasis is placed on the therapeutic potential of H2S synthase isoforms and bioactive metabolites in ischemic pathophysiology. Notably, recent advances in H2S pharmacology have catalyzed the development of novel H2S donors and slow-releasing compounds, including HSDF-NH2, S-allyl cysteine, S-propargyl cysteine, and S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-L-cysteine. These pharmacological innovations demonstrate enhanced tissue specificity and controlled release kinetics, paving the way for clinical translation of H2S-based therapeutics in ischemia-reperfusion injury management. Future research directions should focus on optimizing drug delivery systems and elucidating the spatiotemporal dynamics of H2S signaling in organ-specific ischemia-reperfusion pathologies.
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Gasotransmisores , Sulfuro de Hidrógeno , Daño por Reperfusión , Sulfuro de Hidrógeno/metabolismo , Humanos , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Gasotransmisores/metabolismo , AnimalesRESUMEN
Objective: The aim of this study is to find potential biomarkers and drugs in intrahepatic cholestasis of pregnancy (ICP) by combining bioinformatics and experimental validation strategies. Method: Differentially expressed genes were obtained by analyzing the GSE282182 GEO dataset, after which the weighted gene co-expression network analysis was performed. The intersection of these two analyses yielded core genes. The MCODE module was used to analyze and identify key genes for further study, including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and immune infiltration analysis. Potential target drugs for the above target genes were obtained from the Comparative Toxicogenomics Database. Finally, external database validation and cell experiment validation were performed. Results: A total of 10 core genes (RPS15A, RPL37A, RPL34, RPL32, RPS27, RPL23, RPS7, RPS27A, TPT1) were selected. GO and KEGG pathway analysis showed that they mainly participate in DNA repair, oxidative stress. The drug database showed that aspirin is linked to most genes. Verification of the external database proved that RPL34 was highly expressed in ICP, with statistically significant differences. In vitro cell experiments have confirmed that the expression levels of RPL34 and the activity of mitochondrial complex I were significantly reduced in human trophoblast cells by taurine intervention. Different concentrations of aspirin intervention can rescue apoptosis, restored mitochondrial complex I activity, and upregulated RPL34 expression via modulation of oxidative stress pathways. Conclusion: This study identified 10 core genes, and the relationship between RPL34 and ICP was found to warrant further investigation. As a drug targeting RPL34, aspirin may represent a potential therapeutic agent for treating ICP.
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Breast cancer remains a major public health challenge globally, with its etiology influenced by a complex interplay of genetic, hormonal, and environmental factors. While traditional risk factors such as age, reproductive history, and family predisposition are well-recognized, emerging evidence points to heavy metal exposure - particularly iron - as a potential contributor to carcinogenesis. Iron is a vital micronutrient required for cellular metabolism; however, excess iron has been shown to catalyze oxidative stress and deoxyribonucleic acid damage, both of which are implicated in tumor initiation and progression. Occupational and environmental iron exposure is increasingly prevalent due to industrial expansion, especially in metal-processing industries such as welding, mining, and steel manufacturing. Workers in these sectors, as well as individuals living near industrial zones, may experience chronic low-level exposure to iron through inhalation, ingestion, or dermal absorption. When iron accumulates beyond the body's regulatory capacity, it may foster a pro-oxidative and pro-inflammatory milieu conducive to breast tumorigenesis. Furthermore, iron's interaction with estrogen metabolism may have unique implications for hormonally sensitive tissues like the breast.
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Introduction and importance: Paraquat is a highly toxic herbicide commonly used in low- and middle-income countries. Ingestion, even in small amounts, can lead to multiorgan failure, with acute kidney injury (AKI) being a common and often fatal complication. Although paraquat poisoning is more frequently reported in adults, adolescent cases are underreported. Case presentation: We report the case of a 15-year female who presented with intentional ingestion of paraquat. Initial symptoms included throat pain and irritability. Laboratory investigations revealed rapidly worsening renal function within 24 hours of ingestion. The patient was managed with supportive therapy including fluid resuscitation guided by point-of-care ultrasound. Intravenous antioxidants, N-acetylcysteine, corticosteroids, and furosemide were given. Due to persistent anuria and rising creatinine levels, hemodialysis was initiated. Clinical discussion: Serum creatinine increased from 0.5 to 9.9 mg/dL over 5 days. Despite initial transient improvement, she required two sessions of hemodialysis. Following the second session, her urine output improved significantly, exceeding 2 L/day, and her serum creatinine decreased steadily. She was discharged in stable condition with ongoing improvement in renal function. No respiratory failure was observed, and corticosteroid therapy may have contributed to this outcome. Conclusion: This case underscores the severe nephrotoxicity associated with paraquat poisoning and the potential for renal recovery with timely, supportive interventions, even in adolescents. Early use of adjunctive therapies and hemodialysis, although not curative for paraquat toxicity, plays a critical role in managing complications of AKI. Point-of-care tools and a multidisciplinary approach, including psychiatric support, are essential in optimizing outcomes in such poisoning cases.
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Hepatic encephalopathy (HE), which develops as a result of liver failure, is an important neurological disorder involving inflammation and oxidative damage, with apoptosis and autophagy supported mainly by experimental evidence. In the current research, we researched the protective effects of oleuropein (OLE) in a thioacetamide (TAA)-induced HE model, particularly through the PI3K/Akt/mTOR signalling pathway. To execute the planned experimental design, Sprague Dawley rats (n = 28) were divided into four groups: Control, OLE, TAA, and TAA + OLE. OLE was administered orally (50 mg/kg) during a 14-day period, followed by intraperitoneal TAA (50 mg/kg) for 14 days in the TAA groups. Behavioral tests (open field and Y-maze) were used to determine cognitive and anxiety-like disorders in the rats. Oxidative stress indicators (MDA, SOD, and GSH), pro-inflammatory cytokines (IL-1ß, IFN-γ, and TNF-α), autophagic and apoptotic processes (Caspase-3, Bcl-2, Beclin-1, LC3), PI3K/Akt/mTOR pathway proteins, and AQP4 levels were analyzed in the serum and tissue. Histopathological evaluation was used to evaluate tissue damage in the liver and brain. The results indicated that the TAA-activated PI3K/Akt/mTOR pathway was suppressed by OLE, oxidative damage, autophagy, apoptosis, and inflammation were reduced, and behavioral and histological improvements were achieved. These results suggest that OLE offers hepatoprotective effects and ameliorates HE-associated brain injury via the PI3K/Akt/mTOR pathway.
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Apoptosis , Autofagia , Conducta Animal , Encefalopatía Hepática , Glucósidos Iridoides , Iridoides , Estrés Oxidativo , Animales , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Ratas Sprague-Dawley , Serina-Treonina Quinasas TOR/metabolismo , Autofagia/efectos de los fármacos , Autofagia/fisiología , Ratas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucósidos Iridoides/farmacología , Glucósidos Iridoides/uso terapéutico , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Encefalopatía Hepática/inducido químicamente , Encefalopatía Hepática/metabolismo , Encefalopatía Hepática/tratamiento farmacológico , Tioacetamida/toxicidad , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Iridoides/farmacología , Iridoides/uso terapéuticoRESUMEN
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by metabolic imbalance, oxidative stress, and granulosa cell (GC) dysfunction. Given the established role of BRCA1 in maintaining genomic stability and regulating stress responses, its potential involvement in PCOS pathogenesis warrants investigation. We examined the impact of BRCA1 on PCOS using a dehydroepiandrosterone (DHEA)-induced mouse model and testosterone-stimulated KGN cells. Lentiviral vectors overexpressing BRCA1 were administered by ovarian injection in PCOS mice or used to infect KGN cells. The IL-1ß, TNF-α, and IL-6 levels were measured using enzyme-linked immunosorbent assay. Western blotting was performed to evaluate the expression levels of BRCA1 and other proteins related to inflammation, apoptosis, and endoplasmic reticulum stress (ERS). A TUNEL assay and flow cytometry were used to assess cell apoptosis. Spectrophotometry was used to measure the levels of reactive oxygen species, malondialdehyde, superoxide dismutase, and catalase. Cell survival was evaluated using a CCK-8 assay. Hematoxylin and eosin staining was used to assess the pathological alterations in the ovaries of PCOS mice. Additionally, rescue experiments were conducted on KGN cells treated with the ERS inducer thapsigargin (TG) to determine whether the protective effects of BRCA1 overexpression could be reversed through reactivating ERS. BRCA1 expression was reduced in PCOS. BRCA1 overexpression normalized sex hormone levels, improved ovarian morphology, and attenuated inflammatory signaling, oxidative stress, apoptosis, and ERS in vivo and in vitro. Notably, the ERS inducer TG reversed these protective effects, indicating ERS dependence. These findings suggest that BRCA1 mitigates PCOS phenotypes primarily by suppressing ERS and downstream inflammatory/oxidative and apoptotic pathways, thereby highlighting BRCA1 as a potential molecular target for PCOS therapy.
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This study investigates the phytochemical constituents and hepatoprotective properties of Onopordum cyrenaicum Maire & Weiller, a traditional medicinal herb. Phytochemical analysis revealed phenolic acids and flavonoids at concentrations of 3.06 GAE/g and 1.02 CE/g, respectively. LC-ESI-MS/MS identified 35 compounds known for their antioxidant and anti-inflammatory properties. In vitro antioxidant assays showed scavenging abilities against DPPH and ABTS free radicals with IC50 values of 198.68 and 151.19 µg/mL. Rats treated with diethylnitrosamine (DEN) exhibited liver injury. Still, those treated with O. cyrenaicum showed nearly normal liver anatomy and significantly lower levels of pro-inflammatory markers compared to the HCC group. Additionally, anti-oxidative stress biomarkers were higher in the treated groups. The higher dose improved DEN-induced liver damage while maintaining healthy hepatocyte structure. Molecular docking indicated potential bioactivity of Onopornoids against specific enzymes, with favourable ADMET characteristics suggesting O. cyrenaicum's potential as a natural therapeutic agent for liver protection and cancer treatment.
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Alcohol-associated liver disease (ALD) is a severe liver disease caused by excessive alcohol consumption. ALD remains a clinical challenge with limited therapeutic options. Following 5-day pretreatment with Lactobacillus acidophilus (Lac), mice were administered ethanol by gavage to induce ALD. Tissues were collected and analyzed for serum markers, hepatic pathology/inflammation/oxidative stress, ileal morphology/tight junctions, and cecal microbiota via 16 S rRNA gene sequencing. The fecal microbiota transplantation (FMT) experiment was performed, and tissues were then collected and analyzed as above. Moreover, the anti-inflammatory and antioxidant properties of Lac-derived particulate matter (pLac) were evaluated on RAW264.7 macrophages in vitro. Lac administration improved gut microbiota composition, enhanced intestinal barrier integrity and reduced lipopolysaccharide (LPS) translocation to the liver, thereby inhibiting the toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB) pro-inflammatory pathway and activating the adenosine monophosphate activated protein kinase (AMPK)- peroxisome proliferator activated receptor α (PPARα) signaling axis. This led to significant attenuation of hepatic inflammation, oxidative stress and steatosis. The FMT experiments further validated that Lac-mediated protection is dependent on gut microbiota modulation. In vitro studies revealed that pLac exhibit direct anti-inflammatory and antioxidant properties. These findings elucidate the mechanistic basis for Lac in alleviating acute ALD, positioning it as a promising treatment or dietary intervention to enhance clinical management.
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Neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS, and Huntington's disease pose a growing global health challenge due to their prevalence in aging populations and their devastating impact on cognitive and motor functions. Current treatments focus on symptom management, with no options available to reverse neuronal damage. Emerging evidence highlights the potential role of extra virgin olive oil (EVOO) polyphenols in neuroprotection, particularly in the context of the Mediterranean diet, which is associated with lower rates of neurodegenerative disorders. EVOO's rich polyphenolic compounds, including hydroxytyrosol, oleuropein, tyrosol, and oleocanthal, exhibit potent antioxidant, anti-inflammatory, and neuroprotective properties. These bioactive molecules have shown potential in modulating disease-specific pathways, such as reducing oxidative stress, inhibiting abnormal protein aggregation, and regulating neuroinflammation. This paper explores the therapeutic potential of olive oil polyphenols for neurodegenerative diseases, detailing their mechanisms of action across different conditions. Our findings suggest that incorporating EVOO into dietary and medical interventions could serve as a promising strategy for mitigating neurodegenerative disease progression and enhancing cognitive health.
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Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Aceite de Oliva , Polifenoles , Aceite de Oliva/química , Aceite de Oliva/uso terapéutico , Humanos , Polifenoles/uso terapéutico , Polifenoles/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Fármacos Neuroprotectores/uso terapéutico , Animales , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/uso terapéutico , Dieta Mediterránea , Antiinflamatorios/uso terapéuticoRESUMEN
BACKGROUND: Prenatal smoke exposure impairs fetal lung development, but the interplay between cotinine, oxidative stress, and early respiratory dysfunction remains unclear. This study aimed to quantify the effects of prenatal smoke exposure on neonatal respiratory function and develop a validated predictive model to identify this dysfunction. METHODS: This prospective cohort study included term newborns with prenatal tobacco smoke exposure (n = 50) and healthy controls (n = 41). Cord blood cotinine, oxidative stress markers, and tidal breathing parameters assessed at 48 h post-delivery were compared. A decision tree model was developed and rigorously validated for performance, calibration, and temporal stability to predict decreased expiratory flow. RESULTS: Smoke-exposed newborns exhibited significantly impaired expiratory flow (p < .001), elevated cord cotinine (p < .001), and increased systemic oxidative stress (p < .05). The decision tree model selected a cord blood cotinine level >26.1 ng/mL as the primary predictor, conferring a 94% probability of dysfunction. For those with lower cotinine, a total oxidant status >9.75 µmol/L was a secondary predictor (87.5% probability). The final model achieved 72.5% accuracy and demonstrated good calibration. CONCLUSION: Prenatal smoke exposure induces quantifiable neonatal respiratory dysfunction mediated by oxidative stress. Cord blood cotinine and total oxidant status are robust biomarkers for risk stratification. Our validated decision tree offers a practical framework for identifying respiratory dysfunction in newborns.
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Biomarcadores , Cotinina , Sangre Fetal , Efectos Tardíos de la Exposición Prenatal , Contaminación por Humo de Tabaco , Humanos , Femenino , Recién Nacido , Biomarcadores/sangre , Embarazo , Sangre Fetal/metabolismo , Árboles de Decisión , Estudios Prospectivos , Cotinina/sangre , Masculino , Estrés Oxidativo , Contaminación por Humo de Tabaco/efectos adversos , Efectos Tardíos de la Exposición Prenatal/diagnóstico , Efectos Tardíos de la Exposición Prenatal/sangre , Exposición Materna/efectos adversos , AdultoRESUMEN
Contamination of agricultural soils with cadmium (Cd) and lead (Pb) poses significant risks to forage production and food chain safety in arid and semi-arid regions. Kochia (Kochia scoparia L.) is a fast-growing, stress-tolerant forage species with potential for phytoremediation. This study evaluated the biochemical, uptake, and translocation responses of kochia roots to soil contaminated with Cd or Pb at concentrations of 25-800 mg kg-1. Key parameters assessed included non-enzymatic antioxidants (e.g., phenols, flavonoids, proline, glycine betaine), enzymatic activities (catalase, peroxidase, superoxide dismutase, ascorbate peroxidase), hydrogen peroxide content, osmolyte accumulation (water-soluble carbohydrates and proteins), and metal bioconcentration factor (BCF), biological accumulation coefficient (BAC), translocation factor (TF), and translocation efficiency (TE %). Results demonstrated that kochia accumulated substantial Cd and Pb in roots, with maximum root concentrations correlating positively with soil levels (polynomial relationships; R2 > 0.95). Cd exhibited high root-to-shoot translocation (TF up to 1.5 at 800 mg kg-1; TE % up to 60%), while Pb was predominantly sequestered in roots (TF < 0.5; TE % < 30%). Cd induced stronger oxidative stress, evidenced by greater elevations in hydrogen peroxide (up to 115.2% increase at 800 mg kg-1), antioxidant enzymes (e.g., ascorbate peroxidase increased 79.3% at 800 mg kg-1), and osmoprotectants (e.g., proline 33.9%, glycine betaine 66.9%) compared to Pb (proline 27%, glycine betaine 50.1%). Biomass declined more severely under Cd (shoot dry weight reduced 83.4% at 800 mg kg-1) than Pb (67.6%). BCF and BAC were highest at 25 mg kg-1 (BCF > 4 for both metals) and decreased with concentration. These findings position kochia as an effective Cd phytoremediator due to high translocation, but highlight food chain risks from shoot Cd accumulation when used as forage, necessitating strict biomass management in contaminated sites.
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Carbapenem-resistant Klebsiella pneumoniae (CRKP), as a critical nosocomial pathogen, has emerged as a major global public health challenge due to its multidrug resistance and enhanced pathogenicity. This study systematically elucidated the virulence characteristics of CRKP and its host interaction mechanisms by comparing CRKP (ST258, blaKPC-positive) with carbapenem-susceptible K. pneumoniae (CSKP, ST86) in zebrafish infection models. We established dual infection models (adult intraperitoneal injection and larval immersion), revealing that ST258 CRKP strain exhibited significantly enhanced virulence: its median lethal dose (LD50) was 7.3-fold lower than ST86 CSKP strain, with persistent proliferation in liver and intestinal tissues causing more severe histopathological damage. Mechanistic studies demonstrated that CRKP infection induced stronger oxidative stress and more pronounced apoptosis. 16S rRNA sequencing revealed CRKP-specific gut microbiota dysbiosis: a 147 % increase in Klebsiella abundance with significant depletion of protective Faecalibacterium and Cetobacterium, whereas CSKP infection primarily promoted Aeromonas and Citrobacter proliferation. Functional prediction analysis further identified CRKP-specific activation of drug metabolism pathways (e.g., cytochrome P450) and disruption of amino acid metabolism (e.g., suppressed cysteine/methionine pathways), which were closely associated with impaired host antioxidant defenses. This study provides zebrafish model evidence that the ST258 CRKP strain enhances pathogenicity through multiple mechanisms compared to the ST86 CSKP strain: enhanced tissue invasiveness, induction of oxidative stress and apoptosis, and disruption of gut microbial homeostasis. These findings offer novel insights into the pathogenesis of this high-risk CRKP clone and inform the development of microbiota-targeted therapeutic strategies against drug-resistant infections.
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Cryptorchidism is recognized as a significant risk factor for male germ cell tumors and infertility, with a complex and multifaceted mechanism contributing to male infertility. When the testes fail to descend into the scrotum, increased local temperature and pressure lead to increased apoptosis of spermatogenic and Sertoli cells. Additionally, disruptions in the hypothalamic-pituitary-gonadal axis result in decreased testosterone levels within the testes, and abnormal secretion of follicle-stimulating hormone and luteinizing hormone, negatively impacting spermatogenesis. Cryptorchidism also induces increased oxidative stress within the testes, leading to sperm DNA damage and impairment of the sperm plasma membrane, hindering sperm-oocyte fusion. Unilateral cryptorchidism may cause injury to the ipsilateral genitofemoral nerve, further affecting the contralateral testis by increasing oxidative stress and apoptosis. Moreover, the production of antisperm antibodies can trigger autoimmune responses, potentially damaging germ cells and contributing to infertility. Damage to type A dark spermatogonia (type Ad spermatogonia) is also considered a high-risk factor for male infertility. Understanding the mechanisms by which cryptorchidism leads to male infertility may provide new avenues for enhancing fertility in affected patients.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to disability and death. Genetic animal models, like transgenic mice, are critical for studying disease mechanisms and developing therapies. Model validity, experimental standardization, and predictability are key to successful research. This retrospective study analyzed physiological parameters of the S-FUS (1-359) transgenic mouse model over 10 years, focusing on lifespan, body weight dynamics, symptomatic stages, and molecular changes. Hemizygous mice had a mean lifespan of 137.8 days (males) and 125.1 days (females), longer than homozygous counterparts. The symptomatic stage, marked by motor deficits, began at ~ 123 days and lasted 10-15 days. Body weight loss correlated with disease progression, reaching 28.93% of baseline at death. Molecular analysis revealed regional FUS expression differences (midbrain > spinal cord), alongside proinflammatory cytokine activation (Il6, Tnf alpha) and oxidative stress. Dopaminergic dysregulation was evident, with striatal dopamine/metabolite levels rising 40-60%, linked to Maob downregulation and impaired GABAergic inhibition. Midbrain-selective caspase-3 suppression suggested a shift from apoptosis to necroptosis, while spinal cord astrogliosis indicated compensatory mechanisms. Heterogeneity in lifespan, symptom onset timing, and disease duration was observed, underscoring the need for rigorous experimental design, particularly for therapies aiming to delay symptoms or extend survival. Dopamine oxidation emerged as a novel neurotoxicity contributor, highlighting potential therapeutic targets: modulating dopaminergic signaling and reducing oxidative stress.
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Esclerosis Amiotrófica Lateral , Dopamina , Proteína FUS de Unión a ARN , Animales , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/patología , Ratones , Ratones Transgénicos , Masculino , Dopamina/metabolismo , Femenino , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Peso Corporal , Médula Espinal/metabolismo , Modelos Animales de Enfermedad , Longevidad , Trastornos del Movimiento/genéticaRESUMEN
In this study, the antioxidant mechanisms of yak casein-derived antioxidant peptides (YCAPs: AFK, IEQI, FPFF, LPVPQ, RELEEL) were systematically investigated using an H2O2-induced HEK-293 cell model. Treatment with YCAPs at a concentration of 200 µg/mL significantly improved cell viability and enhanced cellular antioxidant capacity, as indicated by increased activities of CAT and SOD to 0.60 ± 0.094 and 1.17 ± 0.016 U/104 cells, respectively. Concurrently, MDA and GSSG levels were reduced to 0.062 ± 0.0004 nmol/104 cells and 0.74 ± 0.26 µg/106 cells, respectively (P < 0.05). Furthermore, YCAPs upregulated the expression of Nrf2, HO-1, and NQO1, while downregulating Keap1 expression under oxidative stress conditions in vitro (P < 0.05). Molecular docking analysis revealed strong binding affinities between YCAPs and Keap1, with binding energies ranging from -7.8 to -10.1 kcal/mol, suggesting that YCAPs interfere with the protein-protein interaction between Keap1 and Nrf2. These findings indicate that YCAPs exert their antioxidant effects primarily through activation of the Keap1-Nrf2/ARE signaling pathway.
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Cancer cells face a hostile microenvironment characterized by hypoxia, nutrient deprivation, endoplasmic reticulum (ER) stress, and oxidative imbalance. To cope with these challenges, they activate an interconnected network of adaptive pathways including autophagy, the unfolded protein response, metabolic reprogramming, and the integrated stress response., which promote cell survival, therapy resistance, immune evasion, and metastasis. CRISPR-based functional genomics has emerged as a powerful strategy to systematically dissect these stress-adaptive networks, enabling the identification of key regulators and vulnerabilities across diverse contexts. In this review, we first summarize tumor progression in major stress conditions and then highlight how CRISPR screening strategies ranging from genome-wide loss-of-function studies to single-cell and combinatorial platforms, are unraveling critical stress regulators. We further discuss emerging tools, model systems, and translational perspectives, underscoring how the integration of CRISPR technologies with multi-omics, artificial intelligence, and advanced preclinical models is reshaping our understanding of cancer stress biology and guiding the development of novel therapeutic strategies. Finally, we addressed how these novel dissection technologies influence translational opportunities, specifically in the context of combining stress-pathway modulators with immunotherapy and targeted therapy drugs.
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Sepsis frequently gives rise to acute hepatic injury, representing a prevalent and critical pathological manifestation associated with high morbidity and mortality, yet effective therapeutic strategies remain limited. In this study, sepsis-induced acute liver injury was modeled in mice using cecum ligation and puncture (CLP) surgery. The therapeutic potential and underlying mechanisms of Nicotinamide nitrogen oxide (NAMO) were evaluated via intraperitoneal injection at doses of 40, 80, and 160â¯mg/kg. Histological analysis revealed that increasing doses of NAMO led to more orderly hepatocyte arrangement and significantly reduced vacuolar degeneration and inflammatory cell infiltration. NAMO treatment significantly downregulated the mRNA expression of pro-inflammatory cytokines (iNOS, IL-1ß, TNF-α, and IL-6) and upregulated the anti-inflammatory cytokine IL-10. Additionally, NAMO enhanced the activity of antioxidant enzymes (CAT, GSH, and T-AOC), while reducing levels of lipid peroxidation markers (MDA) and reactive oxygen species (ROS) in both liver tissues and hepatocytes. Furthermore, NAMO restored the protein expression of mitochondrial regulatory factors NRF1 and PGC-1α and preserved intracellular ATP levels, indicating improved mitochondrial function. Mechanistic investigations showed that NAMO exerted its protective effects by modulating mitochondrial homeostasis and oxidative stress through the SIRT3/AKT signaling pathway being blocked. In conclusion, by minimizing oxidative stress and inflammation, keeping mitochondrial integrity, and managing the SIRT3/AKT pathway, NAMO shields with sepsis-induced acute liver injury. The results indicate that NAMO holds significant potential as a therapeutic agent for managing hepatic impairment associated with sepsis.
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Mitochondrial cysteinyl-transfer RNA synthetase 2 (CARS2) is involved not only in the ligation of cysteine to transfer RNA but also in the synthesis of intracellular supersulfides. In this study, we investigated the role of CARS2 in the survival of retinal ganglion cells (RGCs) under excitotoxic conditions. Immunohistochemical analysis showed strong expression of CARS2 in RBPMS-positive RGCs in the mouse retina. Overexpression of exogenous human CARS2 (hCARS2) in mouse retinas and in the rat-derived retinal cell line R28 did not affect endogenous CARS2 mRNA levels. Adeno-associated virus 2-mediated overexpression of hCARS2 in RGCs significantly reduced cell death induced by excitotoxicity following intravitreal injection of N-methyl-D-aspartate. Similarly, hCARS2 overexpression decreased glutamate-induced excitotoxic cell death in R28 cells. Quantitative reverse transcription polymerase chain reaction analysis demonstrated a significant increase in CARS2 expression in R28 cells treated with glutamate. Using specific probes, we found that hCARS2-overexpressing R28 cells treated with glutamate exhibited higher intracellular levels of sulfane sulfur species and lower levels of reactive oxygen species (ROS) than control cells with basal CARS2 expression. Moreover, the oxidative stress marker gene Hmox1 was significantly downregulated in CARS2-overexpressing R28 cells compared with control cells. Taken together, these findings suggest that CARS2 plays a critical role in protecting retinal cells from excitotoxic cell death by increasing sulfane sulfur production and decreasing ROS accumulation. Given that CARS2 is predominantly expressed in RGCs among retinal cells, it may serve as a preemptive defense mechanism that enhances antioxidative activity at basal expression levels to support RGC survival.
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BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) markedly impairs cardiac functional recovery and represents a major determinant of adverse outcomes in patients with ischemic heart disease. Ginsenosides, the principal bioactive constituents of ginseng, exert significant cardioprotection against MIRI. This review systematically summarizes and analyzes in vivo (animal) studies to clarify the efficacy and underlying mechanisms of ginsenosides in MIRI. METHODS: The PubMed, EMbase, Web of Science, Cochrane Library, CNKI, WanFang, and Cqvip databases were systematically searched from inception to 31 July 2024. In vivo studies evaluating ginsenosides pretreatment or post-treatment in models of MIRI were identified. Outcome measures comprised myocardial infarct size and indices of hemodynamic performance, myocardial injury, apoptosis, inflammation, and oxidative stress. A meta-analysis was conducted with RevMan 5.4 and Stata/MP 14.0. RESULTS: Thirty-four eligible articles encompassing 505 experimental animals were included. Funnel plots, Egger's tests, and sensitivity analyses confirmed the robustness of the findings. Compared with controls, ginsenosides treatment significantly reduced myocardial infarct size and improved hemodynamic indices (P < 0.0001). Ginsenosides also attenuated MIRI-induced elevations of lactate dehydrogenase, creatine kinase-MB, creatine kinase, malondialdehyde, tumor necrosis factor-α, interleukin-6, interleukin-1ß, and cardiomyocyte apoptosis (P < 0.0001). Subgroup analysis further revealed that pre-ischemic ginsenosides administration conferred greater protection than post-reperfusion treatment. CONCLUSION: Ginsenosides play a significant role in the prevention and treatment of MIRI. Ginsenosides can reduce the area of myocardial infarction and improve myocardial damage through anti-inflammatory, antioxidative stress, anti-apoptosis, regulation of autophagy, and energy metabolism.