miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling

Zhan-qiang, H.; Hai-hua, Q.; Chi, Zai-Long; Miao, Wanying; Cui, Z.; Zi-yin, L.; Jing, Hongyuan; Yi-wei, W.

doi:10.1016/j.nrl.2020.12.006

Cited by 19 publications

(10 citation statements)

References 18 publications

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“…MAPKs, including c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK), regulate various cellular activities and maintain normal physiological functions ( Kim and Choi, 2015 ; Liao et al, 2021 ). The compromised MAPK signaling pathways have been reported to contribute to the pathological process in various diseasesincluding cancer ( Wei et al, 2021 ), autoimmune diseases ( Banerjee et al, 2021 ), coronary heart diseases ( Yang et al, 2018 ) and neurodegenerative disorders ( Zhan-qiang et al, 2021 ). Inhibitors of MAPK have the potential to prevent osteoporosis and subchondral bone destruction during OA ( Jie et al, 2018 ; Wang et al, 2019 ; Zhao et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Selumetinib - a potential small molecule inhibitor for osteoarthritis treatment

Zheng¹,

Qiu²,

Pan

et al. 2022

Front. Pharmacol.

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Objectives: Osteoarthritis (OA) is a common disease that mainly manifests as inflammation and destruction of cartilage and subchondral bone. Recently, necroptosis has been reported to play an important role in the development of OA. Selumetinib displays a contrasting expression pattern to necroptosis-related proteins. The present study aimed to investigate the potential therapeutic effects of selumetinib in OA process.Methods:In vitro experiments, interleukin-1β (IL-1β) was used to induce necroptosis of chondrocytes. We used high-density cell culture, Western Blot and PT-PCR to observe the effect of different concentrations of selumetinib on the extracellular matrix of cartilage. Afterwards, we visualized the effect of selumetinib on osteoclast formation by TRAP staining and F-actin rings. In vivo experiment, we induced experimental osteoarthritis in mice by surgically destabilizing the medial meniscus (DMM) while administering different concentrations of selumetinib intraperitoneally.Results: Selumetinib promoted cartilage matrix synthesis and inhibited matrix decomposition. We found that selumetinib exerted a protective function by inhibiting the activation of RIP1/RIP3/MLKL signaling pathways in chondrocytes. Selumetinib also inhibited the activation of RANKL-induced NF-κB and MAPK signaling pathways in BMMs, thereby interfering with the expression of osteoclast marker genes. In the DMM-induced OA model, a postsurgical injection of selumetinib inhibited cartilage destruction and lessened the formation of TRAP-positive osteoclasts in subchondral bone.Conclusion: Selumetinib can protect chondrocytes by regulating necroptosis to prevent the progression of OA and reduce osteoclast formation. In summary, our findings suggest that selumetinib has potential as a therapeutic agent for OA.

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Section: Discussionmentioning

confidence: 99%

Selumetinib - a potential small molecule inhibitor for osteoarthritis treatment

Zheng¹,

Qiu²,

Pan

et al. 2022

Front. Pharmacol.

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“…miR-146a-5p has been extensively identified as a regulatory element in the immune response. However, miR-146a-5p may also be included in the development of Alzheimer’s disease (AD), since it has been proved that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling in mice models and SH-SY5Y cells treated with amyloid β (Aβ) [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating microRNAs in Hidradenitis Suppurativa

Felice

Montanino

Mallardo

et al. 2022

Genes

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Hidradenitis suppurativa (HS) is a pathology characterized by chronic inflammation and skin lesions. The molecular basis of the inflammatory network remains unclear; however, since microRNAs (miRNAs) are involved in the modulation of inflammation, the composition of a micro-transcriptome RNA library using the blood of HS patients was analysed here. The total miRNA expression profiles of miRNAs from HS patients was assayed by real-time qPCR. Here, compared to healthy controls, miR-24-1-5p, miR-146a-5p, miR26a-5p, miR-206, miR338-3p, and miR-338-5p expression was found significantly different in HS. Knowing the significance of the miRNA mechanism in inflammatory and immune progression, we suggest that miRNA profiles found in HS patients can be significant in understanding the pathogenesis modality and establishing efficient biomarkers for HS early diagnosis. In particular, miR-338-5p was closely related to HS invasiveness and production of cytokines and was atypically overexpressed. miR-338-5p may represent a good promise as a non-invasive clinical biomarker for HS.

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“…Others have reported that it targets TP53-induced glycolysis and apoptosis regulators, leading to the upregulation of NF-κB [43]. Finally, some have stated that it triggers oxidative stress by activating MAPK signals, thereby increasing Aβ deposition and aggravating the AD process [44]. In contrast to the above findings, most studies have reported that miR-146a has an anti-inflammatory effect in AD [45][46][47], autoimmune anterior uveitis [48], intracerebral hemorrhage [49][50][51], spinal cord injury [52][53][54], amyotrophic lateral sclerosis [55,56], depression [57,58], traumatic brain injury TBI [59], subarachnoid hemorrhage [60], experimental autoimmune encephalomyelitis [61] and diabetic encephalopathy [62].…”

Section: The Effective Action Of Mir-146a and Nr4a3 In Inflammationmentioning

confidence: 99%

Mesenchymal stem cell-derived extracellular vesicles protect retina in a mouse model of retinitis pigmentosa by anti-inflammation through miR-146a-Nr4a3 axis

Zhang

Zhao

et al. 2022

Stem Cell Res Ther

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Background Retinitis pigmentosa is a rod-cone degenerative disease that induces irreversible vision loss. This study probed the protective capacity of mesenchymal stem cell-derived small EVs (MSC-EVs) on the retinas of rd10 mice and the underlying mechanism. Methods MSC-EVs were injected into the vitreous of rd10 mice at postnatal day 14 and P21; morphology and function were examined at P28. The mechanism of action was explored by using co-culture of photoreceptor cell line 661 W and microglia cell line BV2. Results Treatment with MSC-EVs increased the survival of photoreceptors and preserved their structure. Visual function, as reflected by optomotor and electroretinogram responses, was significantly enhanced in MSC-EVs-treated rd10 mice. Mechanistically, staining for Iba1, GFAP, F4/80, CD68 and CD206 showed that MSC-EVs suppressed the activation of microglial, Müller glial and macrophages. Furthermore, western blotting showed that the treatment inhibited the NF-κB pathway. RNA-seq and qPCR showed that MSC-EVs upregulated anti-inflammatory cytokines while downregulating pro-inflammatory cytokines. MSC-EVs application in vitro decreased the number of TUNEL-positive 661 W cells co-cultured with LPS-stimulated BV2, with similar impact on the cytokine expression as in vivo study. Genetic screening predicted miR-146a to be the downstream target of MSC-EVs, which was detected in MSC-EVs and upregulated in co-cultured 661 W cells and BV2 cells after MSC-EVs treatment. Upregulation of miR-146a by using its mimic decreased the expression of the transcription factor Nr4a3, and its downregulation inhibition promoted Nr4a3 expression in both 661 W and BV2 cells. Nr4a3 was further identified as the target gene of miR-146a by dual-luciferase assay. Furthermore, overexpressing miR-146a significantly decreased the expression of LPS-induced pro-inflammatory cytokines in BV2 cells. Conclusions MSC-EVs delays retinal degeneration in rd10 mice mainly by its anti-inflammatory effect via the miR-146a-Nr4a3axis. Hence, MSC-EVs may be used in the treatment of neurodegenerative diseases.

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miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling

Cited by 19 publications

References 18 publications

Selumetinib - a potential small molecule inhibitor for osteoarthritis treatment

Selumetinib - a potential small molecule inhibitor for osteoarthritis treatment

Circulating microRNAs in Hidradenitis Suppurativa

Mesenchymal stem cell-derived extracellular vesicles protect retina in a mouse model of retinitis pigmentosa by anti-inflammation through miR-146a-Nr4a3 axis

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