Oxidative Stress Injury Research Articles

Mercury-Mediated Cardiovascular Toxicity: Mechanisms and Remedies.

Mercury is a significant environmental pollutant and public health threat, primarily recognized for its neurotoxic effects. Increasing evidence also highlights its harmful impact on the cardiovascular system, particularly in adults. Exposure to mercury through contaminated soil, air, or water initiates a cascade of pathological events that lead to organ damage, including platelet activation, oxidative stress, enhanced inflammation, and direct injury to critical cells such as cardiomyocytes and endothelial cells. Endothelial activation triggers the upregulation of adhesion molecules, promoting the recruitment of leukocytes and platelets to vascular sites. These interactions activate both platelets and immune cells, creating a pro-inflammatory, prothrombotic environment. A key outcome is the formation of platelet-leukocyte aggregates (PLAs), which exacerbate thromboinflammation and endothelial dysfunction. These processes significantly elevate cardiovascular risks, including thrombosis and vascular inflammation. This study offers a comprehensive analysis of the mechanisms underlying mercury-induced cardiotoxicity, focusing on oxidative stress, inflammation, and cellular dysfunction.

HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice

BackgroundHECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1 (HACE1) has been found to be associated with mitochondrial protection. Mitochondrial damage is a critical contributor to myocardial ischemia–reperfusion injury (I/RI). However, little is known about the role of HACE1 in the pathogenesis of myocardial I/RI.MethodsMale C57BL6 mice with HACE1 knockout (KO) were subjected to 30 min of ischemia via ligation of the left anterior descending artery, followed by 0, 2, 6, or 24 h of reperfusion. The mice were evaluated for myocardial histopathological injury, serum troponin I (cTnI) levels, oxidative stress injury, apoptosis and cardiac function. Prior to ischemia, Mdivi-1(1.2 mg/kg) or vehicle was administered.ResultsThe study revealed that increased expression of HACE1 was associated with myocardial ischemia/reperfusion injury (I/RI), and that knockout of HACE1 resulted in more severe myocardial damage and cardiac dysfunction during I/R(P < 0.05). The HACE1 knockout group exhibited higher levels of malondialdehyde (MDA), greater mitochondrial fission, and dissipation of mitochondrial membrane potential (MMP), leading to more apoptosis and severe cardiac dysfunction compared to the wild-type I/R group(P < 0.05). On the other hand, HACE1 knockout further reduced superoxide dismutase (SOD) activity in the myocardium(P < 0.05), further supporting the findings. However, the adverse effects were almost completely eliminated by pharmacological blockade of the dynamin-related protein 1 (Drp1) inhibitor, Mdivi-1, which inhibits mitochondrial fission during cardiac I/R(P < 0.05).ConclusionCollectively, our data show that myocardial I/RI is associated with HACE1 downregulation and Drp1 activation, causing cardiomyocytes to undergo cell death. Therefore, HACE1 could be a promising therapeutic target for the treatment of myocardial I/RI.

LDHA-mediated glycolysis in stria vascularis endothelial cells regulates macrophages function through CX3CL1-CX3CR1 pathway in noise-induced oxidative stress

According to the World Health Organization, more than 12% of the world’s population suffers from noise-induced hearing loss (NIHL). Oxidative stress-mediated damage to the stria vascularis (SV) is one of the pathogenic mechanisms of NIHL. Recent studies indicate that glycolysis plays a critical role in endothelial cells (ECs)-related diseases. However, the specific role of glycolysis in dysfunction of SV-ECs remain largely unknown. In this study, we investigated the effects of glycolysis on SV-ECs in vitro and on the SV in vivo. Our previous research identified the glycolysis pathway as a potential mechanism underlying the SV-ECs injuries induced by oxidative stress. We further examined the expression levels of glycolytic genes in SV-ECs under H2O2 stimulation and in noise-exposed mice. We found that the gene and protein expression levels of glycolytic-related enzyme LDHA significantly decreased at early phase after oxidative stress injury both in vitro and in vivo, and exhibited anti-inflammatory effects on macrophages (Mφ). Moreover, we analyzed the differential secretomes of SV-ECs with and without inhibition of LDHA using LC-MS/MS technology, identifying CX3CL1 as a candidate mediator for cellular communication between SV-ECs and Mφ. We found that CX3CL1 secretion from SV-ECs was decreased following LDHA inhibition and exhibited anti-inflammatory effects on Mφ via the CX3CR1 pathway. Similarly, the pro-inflammatory effect of LDHA-overexpressing SV-ECs was attenuated following inhibition of CX3CL1. In conclusion, our study revealed that glycolysis-related LDHA was reduced in oxidative stress-induced SV-ECs, and that LDHA inhibition in SV-ECs elicited anti-inflammatory effects on Mφ, at least partially through the CX3CL1-CX3CR1 pathway. These findings suggest that LDHA represent a novel therapeutic strategy for the treatment of NIHL.

Extracellular vesicles released by ALL patients contain HNE-adducted proteins: implications of collateral damage

Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off-target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage by isolating EVs from pediatric ALL patients throughout their first 2 months of treatment. EVs were measured throughout the collection points for: 1) number of EV particles generated using nanoparticle tracking analysis (NTA); 2) markers of neurons (NeuN), astrocyte activation (GFAP), neuronal stability (BDNF), 3) markers of pre-B cell ALL (CD19 and CD22); and) 4-hydroxy-2-nonenal (HNE) adducted proteins. HNE protein adductions were measured in the patient sera and CSF. Pro-inflammatory cytokine levels were also measured in patient sera because of their contribution to oxidative stress and neuronal injury. Our results: 1) demonstrate EVs are a sensitive indicator of oxidative damage; 2) suggest EVs as a marker of a decline in neuronal stability; and 3) show the presence of leukemia has a greater contribution to pro-inflammatory cytokine production in the patient's serum than the cancer treatment. Specifically, we observed a significant decrease in cytokine levels (e.g., TNF-α, IL-1β, IL-6, and IL-8) following the initiation of treatment, highlighting the influence of leukemia burden on systemic inflammation. The results support the utilization of EVs as a sensitive marker of oxidative stress and off-target tissue damage.

Baicalein disrupts the KEAP1-NRF2 interaction to alleviate oxidative stress injury by inhibiting M1 macrophage polarization.

Macrophages are key players in maintaining the balance of tissues and dealing with inflammation, carrying out vital functions specific to different tissues while safeguarding the body against infections. The intricate interplay between oxidative stress and macrophage polarization and how this contributes to pneumonia is not fully understood. Herein, a predominant accumulation of baicalein in lung macrophages of pathogen-infected mice was observed by an alkynyl-modified probe. Baicalein effectively reduces oxidative stress in vivo and in vitro by modulating the KEAP1-NRF2/ARE signaling pathway. Further investigation indicated that baicalein has inhibitory effects on M1 macrophage polarization and phagocytic capacity, reducing inflammatory cytokine expression. As a protein-protein interaction (PPI) inhibitor, baicalein disrupts the KEAP1-NRF2 interaction by competitively binding to the DGR/Kelch domain of KEAP1. This process helps NRF2 move to the nucleus, which activates the antioxidant transcriptional program, suppresses the production of reactive oxygen species (ROS), and mitigates oxidative stress damage. These findings suggest a different approach to developing treatments for oxidative stress that focuses on inhibiting the interaction between KEAP1-NRF2.

Delivery of FBXO6 with highly branched poly(β-amino ester)s to modulate the inflammatory environment for the treatment of osteoarthritis.

Osteoarthritis (OA) is a chronic joint disease characterized by the progressive degradation of articular cartilage. Delivering functional genes to chondrocytes to modulate the inflammatory environment offers a promising approach to treating OA. However, the dense extracellular matrix (ECM) in the OA microenvironment and the rapid clearance of naked nucleic acids from synovial fluid present significant challenges. Here we report the development of highly branched poly(β-amino ester)s (HPAEs) for effective delivery of F-box protein 6 (FBXO6) gene to treat OA. Four HPAEs were synthesized using an "A2+B4+C2" Michael addition strategy. By optimizing the chemical compositions and topological structures, the optimal HMDA-2 was identified to exhibit superior transfection efficiency, outperforming the commercial reagents Lipofectamine 3000 and branched polyethyleneimine (PEI). HMDA-2 was further employed to deliver FBXO6 plasmid to effectively regulate H2O2 expression, improve oxidative stress injury, and reduce the expression of MMP-13 and COX-2 in chondrocytes, leading to significant reductions in synovial inflammatory cell infiltration, cartilage loss, and bone erosion. After intra-articular injection in an anterior cruciate ligament transection (ACLT) rat model, HMDA-2/FBXO6 polyplexes substantially reduced synovitis and cartilage damage, improved cartilage surface integrity, and restored proteoglycan levels. The delivery of FBXO6 with HMDA-2 to chondrocytes offers a potential treatment for OA.

Xuefu Zhuyu Decoction improves hyperlipidemia through the MAPK/NF-κB and MAPK/PPARα/CPT-1A signaling pathway.

Xuefu Zhuyu Decoction (XZD) is widely used in the treatment of cardiovascular diseases. The purpose of this study was to explore the pharmacological effects and molecular mechanisms of XZD in improving hyperlipidemia and to provide a theoretical framework for clinical application. In this study, the signaling pathways regulated by XZD in improving hyperlipidemia were predicted by network pharmacology. Molecular docking was used to verify the affinity between the components in XZD and the target. Furthermore, a hyperlipidemic model in rats was constructed through feeding a high-fat diet. The effect of XZD on hyperlipidemia was verified by histopathological staining, Elisa, and western blot. The results found that the XZD improved dyslipidemia and inflammatory factor disorders, and inhibited liver function damage, pathological damage, and oxidative stress damage in hyperlipidemic rats. The findings from molecular docking and network pharmacology suggested that the mechanism of XZD improving hyperlipidemia may be closely related to the MAPK, NF-κB, and PPAR pathways. This study demonstrated that the XZD inhibited liver lipid metabolism disorder and inflammatory response by regulating the MAPK/NF-κB and MAPK/PPARα/CPT-1A pathway, significantly improved liver histopathological damage and oxidative stress injury, and played a protective role in hyperlipidemic rats.

Protective effect of soluble protein hydrolysate against H2O2‑induced intestinal injury: An interventional study.

The present study aimed to investigate whether soluble protein hydrolysate (SPH) protects against intestinal oxidative stress injury. An in vitro lactate dehydrogenase assay was used to assess the cytotoxicity and protective effect of SPH. For in vivo assessment, friend virus B NIH Jackson mouse pups aged 21 days were administered with 5% w/v soluble protein hydrolysate (SPH) through drinking water for 14 days and then luminally injected with 0.3% or 0.6% H2O2. Thereafter, the fecal samples of mice were collected, and the mice were sacrificed. Intestinal epithelial injury was assessed, and the expressions of 84 oxidative stress‑related genes in intestinal tissues was determined. SPH prophylactically protected against H2O2‑induced oxidative stress injury in human intestinal epithelial cells. An animal model of oxidative stress‑induced intestinal injury was established using 0.3 and 0.6% H2O2. SPH treatment reduced oxidative stress (0.3% H2O2)‑induced gut injury in mice. As no accelerated body growth was observed in SPH‑treated mice, it was hypothesized that the underlying protective mechanism of SPH is not related to nutrient oversupply. Treatment with SPH upregulated five oxidative protective genes that were not consistent between the sexes. Some antioxidative genes, including ferritin heavy polypeptide‑1 (Fth1), heme oxygenase‑1 (Hmox1), NAD(P)H dehydrogenase quinone 1 (Nqo1) and superoxide dismutase 1 (Sod1), were commonly upregulated in both male and female mice. Overall, an antioxidative protective effect was observed following SPH treatment, which may be attributed to the upregulation of genes that protect against oxidative damage. The findings of the present study highlight the promising potential of SPH as a functional food for alleviating intestinal oxidative stress injury.

Therapeutic Effects of Natural Products in the Treatment of Chronic Diseases: The Role in Regulating KEAP1-NRF2 Pathway.

Oxidative stress represents a pivotal mechanism in the pathogenesis of numerous chronic diseases. The Kelch-like ECH-associated protein 1-transcription factor NF-E2 p45-related factor 2 (KEAP1-NRF2) pathway plays a crucial role in maintaining redox homeostasis and regulating a multitude of biological processes such as inflammation, protein homeostasis, and metabolic homeostasis. In this paper, we present the findings of recent studies on the KEAP1-NRF2 pathway, which have revealed that it is aberrantly regulated and induces oxidative stress injury in a variety of diseases such as neurodegenerative diseases, cardiovascular diseases, metabolic diseases, respiratory diseases, digestive diseases, and cancer. Given this evidence, targeting KEAP1-NRF2 represents a highly promising avenue for developing therapeutic strategies for chronic diseases, and thus the development of appropriate therapeutic strategies based on the targeting of the NRF2 pathway has emerged as a significant area of research interest. This paper highlights an overview of current strategies to modulate KEAP1-NRF2, as well as recent advances in the use of natural compounds and traditional Chinese medicine, with a view to providing meaningful guidelines for drug discovery and development targeting KEAP1-NRF2. Additionally, it discusses the challenges associated with harnessing NRF2 as a therapeutic target.

Application of Composite Soaking Solution in Fillet Storage and Caco-2 Cell Antioxidant Repair

The inhibitory effect of compound soaking solution on the quality deterioration of fish fillets during storage and its repair effect on a cell oxidative damage model were investigated. Water holding capacity, cooking loss, thawing loss, thiobarbituric acid and sensory evaluation were used to verify that the composite soaking solution could improve the water loss and quality deterioration of fillets during frozen storage. At 180 d, water holding capacity was increased by 4.59% in the compound soaking solution group compared with the control. Cooking loss decreased by 6.47%, and thawing loss decreased by 13.06% (p &lt; 0.05). The TBA value was reduced by 50%, and the degree of lipid oxidation was lower (p &lt; 0.05). The results of the microstructure analysis showed that the tissue structure of fillets treated by the compound soaking solution was more orderly. The oxidative damage model of cells was achieved by soaking in treated fish fillet digestive juice, which inhibited the increase in reactive oxygen species content, maintained the integrity of the cell structure, and increased cell viability by 32.24% (p &lt; 0.05). Compound soaking solution treatment could inhibit the quality deterioration of fish fillets during storage, and the digestive solution of fish fillets could improve the oxidative stress injury of Caco-2 cells induced by H2O2.

The mechanism of endoplasmic reticulum (ER) stress in cell apoptosis and ROS (reactive oxygen species) of CNE2 cell line induced by single wall carbon nanohorn (SWCNH)

IntroductionThe interaction between the materials themselves and cancer cells are rarely explored. Therefore, the biological roles of raw single wall carbon nanohorn (SWCNH) on endoplasmic reticulum (ER) stress in the apoptosis of CNE2 were explored.MethodsTherefore, ERS of CNE2 cells was induced by SWCNH, and 4-phenylbutyrate (4-PBA) was selected as a inhibitor of ERS. CNE2 cells were co-cultured with SWCNH, 4-PBA and SWCNH+4-PBA, respectively. Furthermore, the apoptotic status of CNE2 cells and its ROS (Reactive oxygen species) levels were determined. Moreover, the apoptotic protein expression of caspase 3 (cysteinyl aspartate specific proteinase 3), the expression levels of ER pathway protein eIF2α, ATF4 and CHOP, or the OS (Oxidative stress)-related proteins NQO1, GCLC, HO-1, and Nrf2 was detected, respectively.ResultsCNE2 apoptotic rate, ROS levels, the caspase 3 or ER pathway proteins ATF4 and CHOP expression, even the NQO1, GCLC, HO-1, and Nrf2 levels of oxidative stress-related proteins in the groups of SWCNH and SWCNH+4-PBA were higher compared to the control group. Moreover, these indicators were higher compared to the group of SWCNH+4-PBA (p &amp;lt; 0.05).DiscussionER stress is the key possible mechanism of CNE2 apoptosis induced by SWCNH. After injury of ERS, SWCNH causes oxidative stress injury, which may eventually lead to apoptosis of CNE2 cells.

Probiotic Limosilactobacillus reuteri DSM 17938 Alleviates Acute Liver Injury by Activating the AMPK Signaling via Gut Microbiota-Derived Propionate.

Limosilactobacillus reuteri DSM 17938 (L. reuteri DSM 17938) was one of the most widely used probiotics in humans for gastrointestinal disorders, but few studies have investigated its role in drug-induced liver injury (DILI). Here, we evaluated the efficacy of L. reuteri DSM 17938 using a mouse model of DILI induced by triptolide. Pregavage of L. reuteri DSM 17938 for 1 week remarkably lowered hepatic inflammatory cytokines level and oxidative stress, with diminished serum alanine transaminase and aspartate aminotransferase levels. Metabolomics and RT-qPCR analysis confirmed its ability in ameliorating TP-disrupted hepatic fatty acid β oxidation. Genome annotation of L. reuteri showed its ability to modulate energy metabolism. Targeted metabolomics demonstrated that L. reuteri DSM 17938 modified the short fatty acid profiles in cecum, especially enhancing propionate levels. Further experiments found that L. reuteri DSM 17938 can activate AMPK signaling by upregulating gut microbiota-derived propionate level, thus restoring impaired mitochondrial biogenesis and energy supply processes to recover energy homeostasis, which leads to diminished ROS production and oxidative stress injury in hepatocytes. Besides, AMPK inhibitor dorsomorphin abolished all the effects on propionate protecting mitochondria and energy metabolism. This study established probiotic therapy of L. reuteri DSM 17938 as a preventive intervention for DILI in clinical. We also revealed that L. reuteri DSM 17938 can activate AMPK signaling by propionate, facilitating a deeper understanding of the action mechanism of L. reuteri DSM 17938 against acute liver injury and contributing to the development of its postbiotics and wider applications.

VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L

Oxidative stress-associated proximal tubular cells (PTCs) damage is an important pathogenesis of hypertensive renal injury. We previously reported the protective effect of VEGFR3 in salt-sensitive hypertension. However, the specific mechanism underlying the role of VEGFR3 in kidney during the overactivation of the renin-angiotensin-aldosterone system remains unclear. In the present study, hypertensive nephropathy was established by angiotensin II (Ang II). We found that VEGFR3 was highly increased in PTCs of Ang II-infused mice. Activation of VEGFR3 mitigated renal dysfunction, pathological damage, and oxidative stress in Ang II-induced hypertensive mice. Moreover, we found that VEGFR3 restored mitophagy deficiency induced by Ang II both in vivo and in vitro to alleviate oxidative stress injury in PTCs. Furthermore, in vitro experiment demonstrated that VEGFR3 improved abnormal mitophagy by enhancing PARKIN mitochondrial translocation. LC-MS/MS and Co-IP assays identified HSPA1L as the interacted protein of VEGFR3, which promoted the mitochondrial translocation of PARKIN. Mechanistically, VEGFR3 disorder domain bound to HSPA1L, and crotonylation modification of HSPA1L at K130 by VEGFR3 was required for mitophagy regulation in the context of Ang II-induced PTCs. Finally, the protective effect of VEGFR3 on mitophagy and oxidative stress were attenuated by transfection K130 (HSPA1L-K130R) mutant plasmid in vivo and in vitro. These findings indicated that VEGFR3 alleviated oxidative stress by promoting PARKIN-dependent mitophagy pathway via regulating HSPA1L crotonylation at K130 site in Ang II-induced PTCs, which provided a mechanistic basis for the therapeutic target in hypertensive renal injury.

TFEB-dependent autophagy-lysosomal pathway is required for NRF2-driven antioxidative action in obstructive sleep apnea-induced neuronal injury.

Nearly one billion individuals worldwide suffer from obstructive sleep apnea (OSA) and are potentially impacted by related neurodegeneration. TFEB is considered a master regulator of autophagy and lysosomal biogenesis, but little is known about its role in neuronal oxidative stress and resultant injury induced by OSA. This study aimed to investigate these issues. Here, we demonstrated that neuronal TFEB induction is repressed in OSA mouse models. Activation of a TFEB-dependent autophagy-lysosomal pathway (ALP) reduces hippocampal neuronal cell death and mitigates OSA-related cognitive impairment. Neuronal NRF2 induction was also found to be defective in OSA mouse models. A series of staining assays for HO1, SOD3, ROS, GSH, 8-OHdG, MDA and PI revealed that enhancement of NRF2 expression restores neuronal redox balance and protects hippocampal neurons. We then identified a novel interplay between TFEB-dependent ALP and NRF2-mediated relief of oxidative stress. Inhibition of NRF2 hinders TFEB expression and lysosomal biogenesis. Conversely, knockdown of TFEB or blocking autophagy dampens the antioxidative effect of NRF2. Our findings highlight the unexpected and crucial role of TFEB-dependent ALP as a downstream event of NRF2 in NRF2-promoted redox balance. This study provides novel insights into the mechanism behind NRF2-driven antioxidative action and the regulation of TFEB-dependent ALP.

Low Field Magnetic Resonance Imaging to Detect Acute Kidney Injury.

Renal oxygenation is essential for maintaining kidney function. Disruptions in oxygen delivery can lead to renal hypoxia, which can exacerbate kidney injury through multiple pathways, including inflammation, oxidative stress, and ischemia-reperfusion injury. Despite the recognized importance of oxygenation in renal pathology, non-invasive and reliable methods for assessing kidney oxygen levels are limited. Current techniques either lack sensitivity or involve invasive procedures, restricting their use in routine monitoring. Therefore, there is a pressing need for innovative approaches to assess renal oxygenation, particularly in kidney injury. This study evaluated Electron Paramagnetic Resonance (EPR)-based oxygen imaging using the paramagnetic tracer Ox071 to assess kidney oxygen levels in mice with cyclophosphamide-induced kidney injury. Urine pO2 was also assessed as a potential surrogate marker. EPR oximetry accurately measured kidney oxygen distribution, revealing a temporary increase in pO2 post-injury. Urine oximetry, however, did not reliably reflect changes in kidney oxygenation. Furthermore, EPR oximetry provided high-resolution spatial mapping of oxygen levels within the kidney, allowing for a detailed understanding of the impact of hypoxia on renal tissue. EPR oximetry is a promising, non-invasive tool for monitoring renal oxygenation, offering high-resolution mapping and longitudinal assessment. Its ability to provide detailed information about oxygen distribution within the kidney makes it a valuable tool for studying the pathophysiology of renal diseases and for developing novel therapeutic strategies. Translational Statement: Quantitative spatially resolved measurement of renal oxygenation has the potential to guide clinical decision making in renal disorders such as acute kidney injury. In this study we demonstrate the utility of electron paramagnetic resonance imaging to provide non-invasive and quantitative high-resolution mapping of kidney oxygen concentrations.

CXCL12 as a Potential Hub Gene for N-Acetylcysteine Treatment of T1DM Liver Disease

The etiology of type 1 diabetes mellitus (T1DM) is intricate, leading to its classification as an autoimmune metabolic disorder. T1DM often coexists with various visceral diseases. N-acetylcysteine (NAC) is widely acknowledged for its potent antioxidant properties. Studies have demonstrated that the combination of NAC and insulin can effectively alleviate iron-induced nephropathy in T1DM and mitigate oxidative stress injury in skeletal muscle associated with the condition. However, the potential impact of NAC alone on liver disease in individuals with T1DM remains uncertain. In this study, a beagle model was established to simulate T1DM, enabling investigation into the role of NAC in liver disease using RNA-seq biogenic analysis and subsequent validation through molecular biological methods. The findings revealed suppressed expression of CXCL12 chemokine in the livers of individuals with T1DM, while treatment with NAC induced specific activation of CXCL12 within the liver affected by T1DM. These results suggest that CXCL12 may serve as a regulatory factor involved in the therapeutic effects of NAC on liver disease associated with TIDM. This discovery holds significant implications for utilizing NAC as an adjunctive therapy for managing complicated liver diseases accompanying type 1 diabetes mellitus.

Nrf2/HO-1 Pathway Mediated Protective Effects of Hydrogen in a Model of Lung Transplantation Simulated by Rat Pulmonary Microvascular Endothelial Cells.

This study aimed to observe the mechanism of hydrogen (H2) in a lung transplantation model simulated by pulmonary microvascular endothelial cells (PMVECs), which were divided into 5 groups. The blank group was the normal PMVECs. During cold ischemia period, PMVECs in the control, O2, or H2 groups were aerated with no gas, O2, or 3% H2, and 3% H2 after transfected with a small interfering RNA targeting Nrf2 in the H2+si-Nrf2 group. Treatment with O2 and H2 decreased the oxidative stress injury, inflammation, cell apoptosis, and attenuated energy metabolism compared with the control group (P < 0.05). And the H2 group showed a better outcome with the increased protein expression of the Nrf2 and HO-1, which were conversed in the H2+si-Nrf2 group. In conclusion, H2 attenuated inflammation, oxidative stress injury, cell apoptosis, and maintained the balance between energy supply and demand in a rat PMVECs lung transplantation model via Nrf2/HO-1.

A novel Sai-based antioxidant agent attenuates antibody-mediated rejection in allogeneic rat kidney transplantation.

Antibody-mediated rejection (ABMR) remains a leading cause of graft loss during kidney transplantation. Ischemia reperfusion injury (IRI) has been reported to promote T-cell proliferation, leading to B-cell activation and subsequent production of donor-specific antibodies (DSA), which target antigens on the vascular endothelium. We hypothesize that a novel therapeutic strategy targeting highly toxic reactive oxygen species could mitigate oxidative stress and immune responses associated with IRI. Our previous study demonstrated that oral administration of a silicon (Si)-based agent consistently generates substantial amounts of hydrogen, effectively suppressing IRI-induced oxidative stress and acute kidney injury in a rat renal clamp model. Here, we investigated the effect of the Si-based agent on immune responses in an allogeneic kidney transplant setting. Using both short-term and long-term evaluation models, we found that the Si-based agent suppressed oxidative stress and acquired immunity activation. Furthermore, early suppression of DSA production and amelioration of chronic ABMR were observed. These findings indicate that the Si-based agent offers protective effects on graft function and survival, highlighting its potential clinical application to improve outcomes for kidney transplant recipients.

Autophagy serves as a protective effect against inflammatory injury of oxidative stress in ARPE-19 cell.

To test the effect of autophagy on inflammatory damage resulting from oxidative stress in adult retinal pigment epithelial cell line (ARPE-19). ARPE-19 cells were pretreated with 200 and 600 µmol/L hydrogen peroxide (H2O2) at various time intervals. The changes of cell morphology, cell viability, reactive oxygen species (ROS) level, autophagic activity, and the inflammatory cytokines (TNFα, IL-6, and TGFβ) were measured at baseline and after treatment with autophagy inducer rapamycin (Rapa) and suppressor wortmannin (Wort) or shATG5. The levels of ROS, cytokines (TNFα, IL-6, and TGFβ), and autophagic activity were significantly increased in ARPE-19 cells after pretreated with H2O2 (all P<0.05) and IL-10 was significantly decreased (P<0.05). By upregulating autophagy, Rapa significantly reduced oxidative stress-induced secretion of pro-inflammatory factors (TNFα and IL-6) and ROS (all P<0.05), yet elevated the production of TGFβ (P<0.05). In contrast, suppression of autophagy through Wort or ATG5 knockdown reduced cell viability, increased cell apoptotic rate, and exacerbated the generation of ROS and inflammatory cytokines (TNFα, IL-6, and TGFβ; all P<0.05). Autophagy demonstrates a protective effect on ARPE-19 cell through mitigating oxidative damage and oxidative stress-induced inflammatory response. Regulation of autophagy may be a potential way for age-related macular degeneration.

Irisin-mediated KEAP1 degradation alleviates oxidative stress and ameliorates pancreatitis.

Oxidative stress (OS) injury is pivotal in acute pancreatitis (AP) pathogenesis, contributing to inflammatory cascades. Irisin, a ubiquitous cytokine, exhibits antioxidant properties. However, the role of irisin in AP remains inconclusive. Our study aims to elucidate irisin expression in AP patients and investigate its mechanism of action to propose a novel treatment strategy for AP. Serum irisin levels in 65 AP patients were quantified using an enzyme-linked immunosorbent assay and correlated with disease severity scores. Core genes implicated in AP-related oxidative stress were identified and screened via bioinformatics analysis. The therapeutic efficacy of irisin in AP was confirmed using a murine cerulein-induced AP model. The intrinsic mechanism of irisin's antioxidative stress action was investigated and verified in pancreatic AR42J cells (Supplementary Fig.1). Common targets shared by irisin and AP were further validated using a molecular docking model which was constructed for virtual docking analysis. This study investigated alterations in redox status in AP and found a significant reduction in serum irisin levels, correlating inversely with AP severity. In a murine AP model, we showed that irisin triggers an antioxidative stress program via the KEAP1 gene; this process helps reestablish redox balance by decreasing the buildup of reactive oxygen species (ROS) and suppressing the secretion of inflammatory mediators within pancreatic tissues Notably, increased KEAP1 expression counteracted the antioxidative effects of irisin. Our findings unveil a novel therapeutic mechanism for AP, wherein irisin inhibits KEAP1 to alleviate OS. Increasing irisin levels in vivo presents a promising strategy for AP treatment.