Search

Doxorubicin (DOX) is a potent chemotherapeutic agent with well-documented dose-dependent cardiotoxicity. Regular exercise is recognized for its cardioprotective effects against DOX-induced cardiac inflammation, although the precise mechanisms remain incompletely understood. The activation of inflammasomes has been implicated in the pathogenesis and treatment of DOX-induced cardiotoxicity, with the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome emerging as a key mediator in cardiovascular inflammation. This study aimed to investigate the role of exercise in modulating the NLRP3 inflammasome to protect against DOX-induced cardiac inflammation. Male Sprague–Dawley rats were randomly assigned to receive a 10-day course of DOX or saline injections, with or without a preceding 10-week treadmill running regimen. Cardiovascular function and histological changes were subsequently evaluated. DOX-induced cardiotoxicity was characterized by cardiac atrophy, systolic dysfunction, and hypotension, alongside activation of the NLRP3 inflammasome. Our findings revealed that regular exercise preserved cardiac mass and hypertrophic indices and prevented DOX-induced cardiac dysfunction, although it did not fully preserve blood pressure. These results underscore the significant cardioprotective effects of exercise against DOX-induced cardiotoxicity. While regular exercise did not entirely prevent DOX-induced hypotension, our findings demonstrate that it confers protection against DOX-induced cardiotoxicity by suppressing NLRP3 inflammasome activation in the heart, underscoring its anti-inflammatory role. Further research should explore the temporal dynamics and interactions among exercise, pyroptosis, and other pathways in DOX-induced cardiotoxicity to enhance translational applications in cardiovascular medicine. [ABSTRACT FROM AUTHOR]

An excessive inflammatory response of the gastrointestinal tract is recognized as one of the major contributors to ulcerative colitis (UC). Despite this, effective preventive approaches for UC remain limited. Rosmarinic acid (RA), an enriched fraction from Perilla frutescens, has been shown to exert beneficial effects on disease-related inflammatory disorders. However, RA-enriched perilla seed meal (RAPSM) and perilla seed (RAPS) extracts have not been investigated in dextran sulfate sodium (DSS)-induced UC in mice. RAPSM and RAPS were extracted using the solvent-partitioning method and analyzed with high-pressure liquid chromatography (HPLC). Mice with UC induced using 2.5% DSS for 7 days were pretreated with RAPSM and RAPS (50, 250, 500 mg/kg). Then, the clinical manifestation, colonic histopathology, and serum proinflammatory cytokines were determined. Indeed, DSS-induced UC mice exhibited colonic pathological defects including an impaired colon structure, colon length shortening, and increased serum proinflammatory cytokines. However, RAPSM and RAPS had a protective effect at all doses by attenuating colonic pathology in DSS-induced UC mice, potentially through the suppression of proinflammatory cytokines. Concentrations of 50 mg/kg of RAPSM and RAPS were sufficient to achieve a beneficial effect in UC mice. This suggests that RAPSM and RAPS have a preventive effect against DSS-induced UC, potentially through alleviating inflammatory responses and relieving severe inflammation in the colon. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic high-fat diet (HFD) intake instigates prediabetes and brain pathologies, which include cognitive decline and neuroinflammation. The myeloid differentiation factor 2 (MD-2)/toll-like receptor 4 (TLR4) complex plays a pivotal role in neuroinflammation. The MD-2 inhibitor (L6H21) reduces systemic inflammation and metabolic disturbances in HFD-induced prediabetes. However, the potential role of L6H21, and its comparison with metformin, on brain pathologies in HFD-induced prediabetes has never been investigated.Experimental Approach: Male Wistar rats were given either a normal diet (ND) (n = 8) or a HFD (n = 104) for 16 weeks. At the 13th week, ND-fed rats were given a vehicle, whereas HFD-fed rats were randomly divided into 13 subgroups. Each subgroup was given vehicle, L6H21 (three doses) or metformin (300-mg·kg-1 ·day-1 ) for 1, 2 or 4 weeks. Metabolic parameters, cognitive function, brain mitochondrial function, brain TLR4-MD-2 signalling, microglial morphology, brain oxidative stress, brain cell death and dendritic spine density were investigated.Key Results: HFD-fed rats developed prediabetes, neuroinflammation, brain pathologies and cognitive impairment. All doses of L6H21 and metformin given to HFD-fed rats at 2 and 4 weeks attenuated metabolic disturbance.Conclusion and Implications: In rats, L6H21 and metformin restored cognition and attenuated brain pathologies dose and time-dependently. These results indicate a neuroprotective role of MD-2 inhibitor in a model of prediabetes. [ABSTRACT FROM AUTHOR]

Background: Long‐term high‐fat diet (HFD) consumption induces not only peripheral insulin resistance with low‐grade systemic inflammation, but also neuroinflammation and subsequent brain pathologies including neurodegeneration, which can lead to cognitive impairment (1). MAC28, a novel mono‐carbonyl analogue of curcumin, was recently identified as a novel MD‐2 inhibitor, and has been shown to attenuate systemic inflammation (2). However, the effects of MAC 28 on the neuroinflammation, neurodegeneration and cognitive function in the HFD‐induced obese rats have never been studied. Method: Male Wistar rats were fed either a normal diet (ND; n = 8) or HFD (n = 40) for 16 weeks. At week 13, ND‐fed rats were orally administered a vehicle for 4 weeks, while HFD‐fed rats were randomly divided into 5 groups (n = 8/group). Each subgroup was orally administrated either vehicle, 10mg/kg/day of MAC 28, 20mg/kg/day of MAC 28, 40mg/kg/day of MAC 28 or 300 mg/kg/day of metformin for 4 weeks. At the end of experimental protocol, the novel object location (NOL) test was examined in each rat. Brains were rapidly removed to determine brain TLR4‐MD‐2 signaling pathway, inflammatory cytokines, brain oxidative stress, dendritic spine density, amyloid and tau pathology. Result: HFD‐fed rats developed obesity with peripheral insulin resistance. Neuroinflammation was observed in HFD‐fed rats, as evidenced by increased expressions of hippocampal MD‐2, TLR4 and TNF‐α levels. In addition, HFD‐fed rats not only increased the levels of brain MDA, hippocampal amyloid‐β/APP ratio, but also reduced hippocampal dendritic spine density, resulting in cognitive decline. Although all doses of MAC 28 and metformin attenuated peripheral insulin resistance, brain pathologies and cognitive impairment, MAC 28 (20mg/kg/day and 40mg/kg/day) and metformin had the highest efficacy in attenuating peripheral insulin resistance, brain inflammation, brain oxidative stress, amyloid‐β deposition and improving dendritic spines, resulting in restoring cognitive function (P < 0.05, Figure 1). Conclusion: These findings suggest that an obvious neuroprotective effect of MD‐2 inhibitor may be the potential strategy for attenuating neurodegenerative disorders in the obese‐insulin resistant condition. [ABSTRACT FROM AUTHOR]