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• Discovery of increased Trim27 expression in asthma. • The deletion of Trim27 effectively relieved ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and lung tissue histopathological changes. • Verification of Trim27's impact on asthma symptoms and Revealing Trim27's role in promoting NLRP3 inflammasome activation. Asthma is a prevalent chronic respiratory disease, yet understanding its ecology and pathogenesis remains a challenge. Trim27, a ubiquitination ligase belonging to the TRIM (tripartite motif-containing) family, has been implicated in regulating multiple pathophysiological processes such as inflammation, oxidative stress, apoptosis, and cell proliferation. However, the role of Trim27 in asthma has not been investigated. Our study found that Trim27 expression significantly increases in the airway epithelium of asthmatic mice. Knockdown of Trim27 expression effectively relieved ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and lung tissue histopathological changes. Moreover, Trim27 knockdown exhibited a significant reduction in airway inflammation and oxidative stress in asthmatic mice, and in vitro analysis confirmed the favorable effect of Trim27 deletion on inflammation and oxidative stress in mouse airway epithelial cells. Furthermore, our study revealed that deletion of Trim27 in MLE12 cells significantly decreased NLRP3 inflammasome activation, as evidenced by reduced expression of NLRP3, ASC, and pro-IL-1β mRNA. This downregulation was reversed when Trim27, but not its mutant lacking ubiquitination ligase activity, was replenished in these cells. Consistent with these findings, protein levels of NLRP3, pro-caspase-1, pro-IL-1β, cleaved-caspase-1, and cleaved-IL-1β were higher in Trim27-replenished cells compared to cells expressing Trim27C/A. Functionally, the downregulation of IL-1β and IL-18 levels induced by Trim27 deletion was rescued by replenishing Trim27. Overall, our findings provide evidence that Trim27 contributes to airway inflammation and oxidative stress in asthmatic mice via NLRP3 inflammasome activation, providing crucial insights into potential therapeutic interventions targeting Trim27 as a way to treat asthma. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested that exogenous hydrogen sulfide can alleviate the development of diabetic cardiomyopathy (DCM) by inhibiting oxidative stress, inflammation, and apoptosis. However, the underlying mechanism is not fully understood. Nuclear expression and function of the transcription factor Forkhead box protein O (FoxO1) have been associated with cardiovascular diseases, and thus, the importance of FoxO1 in DCM has gained increasing attention. This study was designed to investigate the interactions between hydrogen sulfide (H2S) and nuclear FoxO1 in DCM. Methods: Diabetes was induced in adult male C57BL/6J mice by intraperitoneal injection of streptozotocin and was treated with H2S donor sodium hydrosulfide for 12 weeks. The H9C2 cardiomyoblast cell line and neonatal rat cardiomyocytes (NRCMs) were treated with the slow‐releasing H2S donor GYY4137 before high‐glucose (HG) exposure with or without pretreatment with the Akt inhibitor MK‐2206 2HCl. Changes in FoxO1 protein phosphorylation and subcellular localization were determined in H9C2 cells, NRCMs, and cardiac tissues from normal and diabetic mice. Cardiac structure and function in the diabetic mice were evaluated by echocardiography and histological analysis and compared with those in control animals. Results: The echocardiographic and histopathological data indicated that exogenous H2S improved cardiac function and attenuated cardiac hypertrophy and myocardial fibrosis in diabetic mice. H2S also improved HG‐induced oxidative stress and apoptosis in cardiac tissue and NRCMs. In addition, H2S induced FoxO1 phosphorylation and nuclear exclusion in vitro and in vivo, and this function was not inhibited by MK‐2206 2HCl. Alanine substitution mutation of three sites in FoxO1‐enhanced FoxO1 transcriptional activity, and subsequent treatment with exogenous H2S could not prevent HG‐induced nuclear retention. Conclusions: Our data indicate that H2S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H2S in inhibiting the progression of DCM. Our data indicate that hydrogen sulfide (H2S) is a novel regulator of Forkhead box protein O in cardiac cells and provide evidence supporting the potential of H2S in inhibiting the progression of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Abstract Daphnetin, one of the major bioactive components isolated from Daphne odora , has been reported to have anti-inflammatory and anti-oxidative effects. Inflammation and oxidative stress have been known to play critical roles in cisplatin-induced nephrotoxicity. The purpose of this study was to investigate the protective effects of daphnetin on cisplatin-induced nephrotoxicity. The levels of blood urea nitrogen (BUN) and creatinine, as well as the kidney reactive oxygen species (ROS), and malondialdehyde (MDA) activity were measured in this study. The expression of inflammatory cytokines TNF-α and IL-1β were measured by ELISA. The results showed that daphnetin protected against cisplatin-induced nephrotoxicity by attenuating kidney histological changes, serum BUN and creatinine. Furthermore, the expression of TNF-α and IL-1β, as well as ROS and MDA in kidney tissues were decreased by daphnetin. In addition, daphnetin dose-dependently inhibited cisplatin-induced NF-κB activation and up-regulated the expression of Nrf2 and HO-1. In conclusion, the results of this study suggested that daphnetin inhibited cisplatin-induced nephrotoxicity by inhibiting NF-κB and activating Nrf2 signaling pathways. Daphnetin might be a promising agent in the treatment of kidney injury. Highlights • Daphnetin protected against cisplatin-induced nephrotoxicity by attenuating kidney histological changes, serum BUN and creatinine. • The production of TNF-α, IL-1ß, ROS, and MDA were inhibited by daphnetin. • Daphnetin inhibited cisplatin-induced NF-κB activation and up-regulated Nrf2 and HO-1. [ABSTRACT FROM AUTHOR]

Di(2-ethylhexyl) phthalate (DEHP) has been well acknowledged for its endocrine disruption and associated metabolic diseases, leading to the search for safer industrial alternatives including di-isononyl phthalate (DINP). However, safety data for the latter chemical has been relatively scarce particularly regarding potential damage to the kidney at low doses. Five-week-old ICR male mice were exposed to vehicle, DEHP or DINP (0.05 and 4.8 mg/kg bw) daily via gavage for 5 weeks. We observed increased levels of reactive oxygen species and malondialdehyde, decreased levels of reduced glutathione, in the kidney at higher dose for both chemicals suggestive of oxidative damage. Elevated levels of inflammatory cytokines tumor necrosis factor-α and interleukin-6 of the kidney further suggested inflammatory status as a result of phthalate exposure in both high dose groups. Targeted lipidomics demonstrated greatest changes in the kidney induced by high dose of DEHP, although DINP also induced significant changes in phospholipids diacylglycerides that are associated with lipid accumulation in glomerular podocytes and inflammatory responses. Our data suggest that oxidative stress may be involved in both DEHP- and DINP-induced renal lipidomic disruption and continue to question the suitability of DINP as proper DEHP substitute. • Both DEHP and DINP induced renal oxidative stress at higher exposure levels. • Low levels of DEHP and DINP induced obesogenic effect. • DEHP and DINP caused significant disruptions in renal lipidome. • Oxidative stress may be involved in phthalate-induced renal lipidomic disruption. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox) is a potent antineoplastic agent, but its use is curtailed by severe cardiotoxicity, known as Dox-induced cardiomyopathy (DIC). The molecular mechanism underlying this cardiotoxicity remains unclear. Our current study investigates the role of Ubiquitin-Specific Protease 36 (USP36), a nucleolar deubiquitinating enzyme (DUB), in the progression of DIC and its mechanism. We found increased USP36 expression in neonatal rat cardiomyocytes and H9C2 cells exposed to Dox. Silencing USP36 significantly mitigated Dox-induced oxidative stress injury and apoptosis in vitro. Mechanistically, USP36 upregulation positively correlated with Poly (ADP-ribose) polymerase 1 (PARP1) expression, and its knockdown led to a reduction in PARP1 levels. Further investigation revealed that USP36 could bind to and mediate the deubiquitination of PARP1, thereby increasing its protein stability in cardiomyocytes upon Dox exposure. Moreover, overexpression of wild-type (WT) USP36 plasmid, but not its catalytically inactive mutant (C131A), stabilized PARP1 in HEK293T cells. We also established a DIC model in mice and observed significant upregulation of USP36 in the heart. Cardiac knockdown of USP36 in mice using a type 9 recombinant adeno-associated virus (rAAV9)-shUSP36 significantly preserved cardiac function after Dox treatment and protected against Dox-induced structural changes within the myocardium. In conclusion, these findings suggest that Dox promotes DIC progression by activating USP36-mediated PARP1 deubiquitination. This novel USP36/PARP1 axis may play a significant regulatory role in the pathogenesis of DIC. • Deficiency in USP36 provides a protective effect against cardiac oxidative stress injury and apoptosis induced by Dox. • USP36 interacts with PARP1, and it is through this interaction that USP36 influences the regulation of cardiac injury. • This research broadens our understanding of the USP family's role in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background. Oscillatory shear stress (OSS) disrupts endothelial homeostasis and promotes oxidative stress, which can lead to atherosclerosis. In atherosclerotic lesions, Toll-like receptor 4 (TLR4) is highly expressed. However, the molecular mechanism by which TLR4 modulates oxidative changes and the cell signaling transudation upon OSS is yet to be determined. Methods and Results. Carotid artery constriction (CAC) surgery and a parallel-plate flow chamber were used to modulate shear stress. The results showed that OSS significantly increased the oxidative burden, and this was partly due to TLR4 activation. OSS activated NOX2 and had no significant influence to NOX1 or NOX4 in endothelial cells (ECs). OSS phosphorylated caveolin-1, promoted its binding with endothelial nitric oxide synthase (eNOS), and resulted in deactivation of eNOS. TLR4 inhibition restored levels of nitric oxide (NO) and superoxide dismutase (SOD) in OSS-exposed cells. Conclusion. TLR4 modulates OSS-induced oxidative stress by activating NOX2 and suppressing eNOS. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer's disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment. [ABSTRACT FROM AUTHOR]

Celastrol is a triterpenoid compound extracted from the Chinese herb Tripterygium wilfordii Hook F. Previous research has revealed its anti-oxidant, anti-inflammatory, anti-cancer and immunosuppressive properties. Here, we investigated whether celastrol inhibits oxidized low-density lipoprotein (oxLDL) induced oxidative stress in RAW 264.7 cells. In addition, the effect of celastrol on atherosclerosis in vivo was assessed in apolipoprotein E knockout (apoE−/−) mouse fed a high-fat/high-cholesterol diet (HFC). We found that celastrol significantly attenuated oxLDL-induced excessive expression of lectin-like oxidized low density lipoprotein receptor-1(LOX-1) and generation of reactive oxygen species (ROS) in cultured RAW264.7 macrophages. Celastrol also decreased IκB phosphorylation and degradation and reduced production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and IL-6. Celastrol reduced atherosclerotic plaque size in apoE−/− mice. The expression of LOX-1 within the atherosclerotic lesions and generation of superoxide in mouse aorta were also significantly reduced by celastrol while the lipid profile was not improved. In conclusion, our results show that celastrol inhibits atherosclerotic plaque developing in apoE−/− mice via inhibiting LOX-1 and oxidative stress. [ABSTRACT FROM AUTHOR]