Diosmin Alleviates Doxorubicin-Induced Liver Injury via Modulation of Oxidative Stress-Mediated Hepatic Inflammation and Apoptosis via NfkB and MAPK Pathway: A Preclinical Study.
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ABSTRACT:
SUBMITTER: AlAsmari AF
PROVIDER: S-EPMC8698866 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Several interleukin (IL) family members have been demonstrated to be involved in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate the role of IL-22 in DOX-induced cardiac injury and explore its possible mechanisms. In this study, mice were given DOX, and the cardiac expression and sources of IL-22 were determined. Then, IL-22 was knocked out to observe the effects on DOX-induced cardiac injury in mice. In addition, the p38 mitogen-activated protein kinase (MAPK) pathway was inhibited, macrophages were depleted and adoptively transferred, and Fizz3 was up-regulated in mice to explore the mechanisms. The results showed that cardiac IL-22 expression was significantly increased by DOX treatment and was mostly derived from cardiac macrophages. IL-22 knockout significantly reduced cardiac vacuolization and the expression of cardiomyocyte injury markers in both serum and left ventricular tissue and improved cardiac function in DOX-treated mice. In addition, IL-22 knockout reversed DOX-induced cardiac M1 macrophage/M2 macrophage imbalance, reduced oxidative stress and protected against cardiomyocyte apoptosis. p38 MAPK pathway inhibition with SB203580 and macrophage depletion further alleviated the above effects in DOX-treated IL-22-knockout mice. The effects were stronger IL-22-knockout mice with adoptive transfer of WT macrophages than in those with adoptive transfer of IL-22-knockout macrophages. Furthermore, increasing the expression of Fizz3 reduced cardiomyocyte apoptosis and alleviated cardiac dysfunction. Our results may suggest that IL-22 knockout alleviate DOX-induced oxidative stress and cardiac injury by inhibiting macrophage differentiation and thereby increasing the expression of Fizz3. Reductions in IL-22 expression may be beneficial for clinical chemotherapy in tumor patients.
| S-EPMC7371904 | biostudies-literature
Project description:BackgroundDoxorubicin, an anthracycline chemotherapeutic known to incur heart damage, decreases heart function in up to 11% of patients. Recent investigations have implicated the Wnt signaling cascade as a key modulator of cardiac tissue repair after myocardial infarction. Wnt upregulation in murine models resulted in stimulation of angiogenesis and suppression of fibrosis after ischemic insult. However, the molecular mechanisms of Wnt in mitigating doxorubicin-induced cardiac insult require further investigation. Identifying cardioprotective mechanisms of Wnt is imperative to reducing debilitating cardiovascular adverse events in oncologic patients undergoing treatment.MethodsExposing human cardiomyocyte AC16 cells to varying concentrations of Wnt10b and DOX, we observed key metrics of cell viability. To assess the viability and apoptotic rates, we utilized MTT and TUNEL assays. We quantified cell and mitochondrial membrane stability via LDH release and JC-1 staining. To investigate how Wnt10b mitigates doxorubicin-induced apoptosis, we introduced pharmacologic inhibitors of key enzymes involved in apoptosis: FR180204 and SB203580, ERK1/2 and p38 inhibitors. Further, we quantified apoptotic executor enzymes, caspase 3/7, via immunofluorescence.ResultsAC16 cells exposed solely to doxorubicin were shrunken with distorted morphology. Cardioprotective effects of Wnt10b were demonstrated via a reduction in apoptosis, from 70.1% to 50.1%. LDH release was also reduced between doxorubicin and combination groups from 2.27-fold to 1.56-fold relative to the healthy AC16 control group. Mitochondrial membrane stability was increased from 0.67-fold in the doxorubicin group to 5.73 in co-treated groups relative to control. Apoptotic protein expression was stifled by Wnt10b, with caspase3/7 expression reduced from 2.4- to 1.3-fold, and both a 20% decrease in p38 and 40% increase in ERK1/2 activity.ConclusionOur data with the AC16 cell model demonstrates that Wnt10b provides defense mechanisms against doxorubicin-induced cardiotoxicity and apoptosis. Further, we explain a mechanism of this beneficial effect involving the mitochondria through simultaneous suppression of pro-apoptotic p38 and anti-apoptotic ERK1/2 activities.
| S-EPMC10586692 | biostudies-literature
Project description:Aflatoxin biosynthesis has established a connection with oxidative stress, suggesting a prevention strategy for aflatoxin contamination via reactive oxygen species (ROS) removal. Epigallocatechin gallate (EGCG) is one of the most active and the richest molecules in green tea with well-known antioxidant effects. Here, we found EGCG could inhibit aflatoxin B1 (AFB1) biosynthesis without affecting mycelial growth in Aspergillus flavus, and the arrest occurred before the synthesis of toxin intermediate metabolites. Further RNA-seq analysis indicated that multiple genes involved in AFB1 biosynthesis were down-regulated. In addition, EGCG exposure facilitated the significantly decreased expression of AtfA which is a bZIP (basic leucine zipper) transcription factor mediating oxidative stress. Notably, KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis indicated that the MAPK signaling pathway target transcription factor was down-regulated by 1 mg/mL EGCG. Further Western blot analysis showed 1 mg/mL EGCG could decrease the levels of phosphorylated SakA in both the cytoplasm and nucleus. Taken together, these data evidently supported that EGCG inhibited AFB1 biosynthesis and alleviated oxidative stress via MAPK signaling pathway. Finally, we evaluated AFB1 contamination in soy sauce fermentation and found that EGCG could completely control AFB1 contamination at 8 mg/mL. Conclusively, our results supported the potential use of EGCG as a natural agent to prevent AFB1 contamination in fermentation industry.
| S-EPMC8539566 | biostudies-literature
Project description:Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15?mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3?/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5?mg/kg, i.p., once a week for three times, the total cumulative dose is 15?mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.
| S-EPMC7206111 | biostudies-literature
Project description:Doxorubicin as a commonly used anthracycline has become the cornerstone of chemotherapy in a wide range of cancers owing to its high efficacy. However, clinical applications of doxorubicin are limited mainly due to its toxic effects on myocardium but the pathogenic mechanism of doxorubicin-induced cardiomyopathy are poorly understood. ADAM17 is known as tumor necrosis factor α converting enzyme (TACE), and the cleavage of TNF-α by ADAM17 is a prerequisite for pro-inflammatory TNF-α activity, which raises a possibility that inhibition of ADAM17 may exert a beneficial effect on disease processes where TNF-α plays an essential role. Our previous research has shown that cardiomyocyte specific knockout of ADAM17 improves diabetic cardiomyopathy by modulating cardiomyocyte apoptosis. However, the relationship between ADAM17 and doxorubicin-induced cardiomyopathy is unclear.Through RNA sequencing analysis, we observed significant changes in the TNF signaling pathway genes in the heart tissue of mice with or without cardiomyocyte ADAM17 knockout.
2024-09-10 | GSE276325 | GEO
Project description:Despite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.
| S-EPMC8758770 | biostudies-literature
Project description:Inflammatory signals arising from the microenvironment have emerged as critical regulators of hematopoietic stem cell (HSC) function during diverse processes including embryonic development, infectious diseases, and myelosuppressive injuries caused by irradiation and chemotherapy. However, the contributions of cellular subsets within the microenvironment that elicit niche-driven inflammation remain poorly understood. Here, we identify endothelial cells as a crucial component in driving bone marrow (BM) inflammation and HSC dysfunction observed following myelosuppression. We demonstrate that sustained activation of endothelial MAPK causes NF-κB-dependent inflammatory stress response within the BM, leading to significant HSC dysfunction including loss of engraftment ability and a myeloid-biased output. These phenotypes are resolved upon inhibition of endothelial NF-κB signaling. We identify SCGF as a niche-derived factor that suppresses BM inflammation and enhances hematopoietic recovery following myelosuppression. Our findings demonstrate that chronic endothelial inflammation adversely impacts niche activity and HSC function which is reversible upon suppression of inflammation.
| S-EPMC6997369 | biostudies-literature
Project description:Muscle weakness affects physical activity and quality of life of patients. Serine, a nutritionally non-essential amino acid has been reported to enhance protein synthesis and implicate in biosynthesis of multiple bioactive molecules. It remains unknown whether it can protect mice against oxidative stress-induced muscles weakness. This study was conducted to test the hypothesis that serine administration alleviates doxorubicin-induced oxidative damage in skeletal muscle of mice. Mice pre-treated with or without serine were intraperitoneally injected with either doxorubicin or equal volume of saline. Reactive oxygen species (ROS) accumulation, activity of antioxidant enzymes, oxidation product of protein, DNA, and lipid, activity of mitochondrial complex, and protein level of nuclear-factor-erythroid-2-related factor 2 (NRF2)/constitutive-androstane-receptor (CAR) signaling in skeletal muscle of mice were determined. Compared with the control, doxorubicin exposure led to oxidative damage as shown by increased ROS accumulation, decreased activity of antioxidant enzymes, and enhanced oxidative product of protein, DNA, and lipid in the skeletal muscle of mice. These effects of doxorubicin were associated with increased activity of complex I and reduced glutathione. Interestingly, doxorubicin-induced oxidative damage was alleviated by serine administration. Further study showed that the beneficial effect of serine was associated with enhanced NRF2/CAR signaling. Our result showed that serine attenuated doxorubicin-induced muscle weakness in mice. Serine supplementation might be a nutritional strategy to improve the function of skeletal muscle in patients exposed to doxorubicin.
| S-EPMC8458867 | biostudies-literature
Project description:Although doxorubicin (DOX) is an efficient chemotherapeutic drug for human tumors, severe cardiotoxicity restricts its clinical use. Cinnamaldehyde (CA), a bioactive component isolated from Cinnamonum cassia, possesses potent anti-oxidative and anti-apoptotic potentials. The major aim of this study was to evaluate the protective role of CA against DOX-induced cardiotoxicity. To this end, cardiomyocyte injury models were developed using DOX-treated H9c2 cells and DOX-treated rats, respectively. Herein, we found that CA treatment increased cardiomyocyte viability and attenuated DOX-induced cardiomyocyte death in vitro. CA further protected rats against DOX-induced cardiotoxicity, as indicated by elevated creatine kinase (CK) and lactate dehydrogenase (LDH) levels, myocardium injury, and myocardial fibrosis. CA alleviated DOX-induced myocardial oxidative stress by regulating reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels. Mechanistically, CA markedly accelerated nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2) and increased heme oxygenase-1 (HO-1) expression. Consequently, CA decreased DOX-induced cardiomyocyte ferroptosis, while Erastin (a ferroptosis agonist) treatment destroyed the effect of CA on increasing cardiomyocyte viability. Taken together, the current results demonstrate that CA alleviates DOX-induced cardiotoxicity, providing a promising opportunity to increase the clinical application of DOX.
| S-EPMC10569550 | biostudies-literature
Project description:Exposure to particulate matter (PM) is related to various respiratory diseases, and this affects the respiratory immune system. Alveolar macrophages (AMs), which are defenders against pathogens, play a key role in respiratory inflammation through cytokine production and cellular interactions. Coconut oil demonstrates antioxidant and anti-inflammatory properties, and it is consumed worldwide for improved health. However, reports on the protective effects of coconut oil on the PM-induced respiratory immune system, especially in AMs, are limited. In this study, we generated artificial PM (APM) with a diameter approximately of 30 nm by controlling the temperature, and compared its cytotoxicity with diesel exhaust particles (DEP). We also investigated the antioxidant and anti-inflammatory effects of coconut oil in APM- and DEP-stimulated AMs, and the underlying molecular mechanisms. Our results showed that APM and DEP had high cytotoxicity in a dose-dependent manner in AMs. In particular, APM or DEP at 100 μg/mL significantly decreased cell viability (p < 0.05) and significantly increased oxidative stress markers such as reactive oxygen species (p < 0.01); the GSSH/GSH ratio (p < 0.01); and cytokine production, such as tumor necrosis factor-α (p < 0.001), interleukin (IL)-1β (p < 0.001), and IL-6 (p < 0.001). The expression of the genes for chemokine (C-X-C motif) ligand-1 (p < 0.05) and monocyte chemoattractant protein-1 (p < 0.001); and the proteins toll-like receptor (TLR) 4 (p < 0.01), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (p < 0.001), p38 (p < 0.001); and extracellular receptor-activated kinase (p < 0.001), were also upregulated by PM. These parameters were reversed upon treatment with coconut oil in APM- or DEP-stimulated AMs. In conclusion, coconut oil can reduce APM- or DEP-induced inflammation by regulating the TLR4/MAPK pathway in AMs, and it may protect against adverse respiratory effects caused by PM exposure.
| S-EPMC9105152 | biostudies-literature