Ethanol (EtOH) is a common trigger for gastric mucosal diseases, and mitigating oxidative stress is essential for attenuating gastric mucosal damage. Capsaicin (CAP) has been identified as a potential agent to counteract oxidative damage in the gastric mucosa; however, its precise mechanism remains unclear. This study demonstrates that CAP alleviates EtOH-induced gastric mucosal injuries through two primary pathways: by suppressing the chemokine receptor 4 (CCR4)/Src/p47phox axis, thereby reducing oxidative stress, and by inhibiting the phosphorylation and nuclear translocation of nuclear factor- κ B p65 (NF- κ B) p65, resulting in diminished inflammatory responses. These findings elucidate the mechanistic pathways of CAP and provide a theoretical foundation for its potential therapeutic application in the treatment of gastric mucosal injuries.
CCL22, which could induce chondrocyte apoptosis, was identified to be overexpressed in damaged cartilage. This study was conducted with the aim of investigating the effects of CCL22 interference on chondrocyte injury. The osteoarthritis model was established by stimulating chondrocytes with LPS. The expressions of CCL22, CCR4, matrix metallopeptidase (MMP) 3, MMP9, MMP13, (a disintegrin and metalloproteinase with thrombospondin-like motifs) ADAMTS-4, collagen II and inflammatory cytokines were measured using quantitative reverse transcription PCR (RT-qPCR) and western blot. Besides, immunoprecipitation (IP) was employed to verify the binding of CCL22 and CCR4. After CCR4 was overexpressed, cell viability was observed using Cell Counting Kit-8 (CCK-8). Additionally, cell apoptosis as well as its related proteins was detected by TUNEL and western blot, respectively. ng What’s more, glycosaminoglycan (GAG) level was detected using GAG kits. CCL22 and CCR4 expression increased noticeably in LPS-stimulated ATDC5 chondrocytes. CCL22 inhibition could suppress the expression of CCR4 in LPS-induced ATDC5 cells. Likewise, CCL22 inhibition could revive the activation of LPS-induced ATDC5 cells by regulating CCR4. In addition, CCL22 knockdown alleviated inflammatory response and cell apoptosis through CCR4. Furthermore, the cartilage degradation of ADTC5 cells could be relieved by CCL22 silence via regulating CCR4. CCL22/CCR4 expression was increased in osteoarthritic cartilage injury and participated in the inflammation and cartilage degradation of chondrocytes.
Tao Ye,Xinhuang Lv,Qiyao Li,Xiaolan Liao,Lu Zhan,Conghui Dai,Kun Xiang,Xiaoou Lin,Jing Sun,Jiaming Liu
Gut microbial metabolites abnormity links to Alzheimer’s disease (AD) progression, yet the mechanism remains unknown. Here, we observed a markedly decreased level of indole-3-acetic acid (IAA) in AD patients, and the IAA level was negatively correlated with cognitive impairment. IAA supplementation improved cognitive dysfunction and synaptic damage, and suppressed microglial activation and synaptic phagocytosis in AD mouse and cell models. RNA sequencing revealed an increase in phagocytosis-associated pathway activity and gene expression, and C-C chemokine receptor 4 (CCR4) was identified as a key regulator of this process. IAA could inhibit the expression level of CCR4, and siRNAs CCR4 markedly inhibited microglia-mediated phagocytosis of synapse. We further demonstrated that microglial CCR4 interacts with aryl hydrocarbon receptor (AHR), a key receptor of IAA, and proposed the hypothesis that AHR binds to the CCR4 promoter, thereby inhibiting its transcriptional activity. Moreover, we further revealed that bacteria producing IAA supplementation inhibited microglia-mediated synaptic loss by down-regulating CCR4, thus delaying Alzheimer’s progression. These findings elucidate the mechanisms underlying microbial metabolite IAA’s impact on AD, highlighting that targeting CCR4 inhibition in microglia-mediated synaptic phagocytosis represents a promising therapeutic strategy for AD.
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