Metformin protects against neuroinflammation through integrated mechanisms of miR-141 and the NF-ĸB-mediated inflammasome pathway in a diabetic mouse model

Docrat, Taskeen; Nagiah, Savania; Chuturgoon, Anil A.

doi:10.1016/j.ejphar.2021.174146

Cited by 14 publications

(9 citation statements)

References 57 publications

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“…Prior studies have shown that T2DM subjects treated with metformin obsessed fewer hypothalamic microglia than T2DM subjects without metformin treatment [21]. Meanwhile, animal studies have noted that metformin inhibited neuroinflammation and showed a protective effect [22,23]. However, the effects of metformin on the microglial necroptosis in the hypothalamus in obesity remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice

Cai

Luo

et al. 2021

Cell Death Discov.

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Necroptosis, a form of programmed cell death, accounts for many inflammations in a wide range of diseases. Diet-induced obesity is manifested by low-grade inflammation in the mediobasal hypothalamus (MBH), and microglia are implicated as critical responsive components for this process. Here, we demonstrate that microglial necroptosis plays a pivotal role in obesity-related hypothalamic inflammation, facilitating proinflammatory cytokine production, such as TNF-α and IL-1β. Treatment with the anti-diabetic drug metformin effectively reduces the obese phenotypes in the high-fat diet (HFD)-fed mice, attributing to remission of hypothalamic inflammation partly through repressing microglial necroptosis. Importantly, using the receptor-interacting protein kinase 1 inhibitor, necrostatin-1s, could not suppress the microglial inflammation nor prevent body weight gain in the obese mice, indicating that the microglial necroptosis is RIPK1-independent. Altogether, these findings offer new insights into hypothalamic inflammation in diet-induced obesity and provide a novel mechanism of action for metformin in obesity treatment.

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Section: Discussionmentioning

confidence: 99%

Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice

Cai

Luo

et al. 2021

Cell Death Discov.

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“…It is generally accepted that metformin inhibits pro-inflammatory cytokine release, such as IL-1β, IL-6, and TNF-α, to have anti-inflammatory effects [ 37 , 38 , 39 , 40 , 41 ]. Destabilization of the atherosclerotic plaque is associated with increased inflammatory cytokine production [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin Directly Binds to MMP-9 to Improve Plaque Stability

Chen

Wang

et al. 2023

JCDD

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Vulnerable atherosclerotic plaque rupture is the principal mechanism that accounts for myocardial infarction and stroke. High matrix metalloproteinase-9 (MMP-9) expression and activity have been proven to lead to plaque instability. Metformin, a first-line treatment for type 2 diabetes, is beneficial to plaque vulnerability. However, the mechanism underlying its anti-atherogenic effect remains unclear. Molecular docking and surface plasmon resonance experiments showed that metformin directly interacts with MMP-9, and incubated MMP-9 overexpressing HEK293A cells with metformin (1 μmol·L−1) significantly attenuates MMP-9’s activity using zymography and MMP activity assays. Moreover, metformin treatment drives MMP-9 degradation. Next, we constructed a carotid artery atherosclerotic plaque model and administered consecutive 14-day metformin (200 mg·kg−1·d−1) treatment by intragastric gavage. Immunofluorescence staining of the right carotid common artery and serum MMP activity assay results showed that metformin treatment decreased local plaque MMP-9 protein level and circulating MMP-9 activity, respectively. Histochemical staining revealed that after metformin treatment, the collagen content in plaque was significantly preserved, and the plaque vulnerability index decreased. These findings suggested that metformin improved atherosclerotic plaque stability by directly binding to MMP-9 and driving its degradation.

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“…The data highlighted the oncogenic role of miR-141-3p in ESCC. Interestingly, Docrat et al published that Met usage alleviated neuroinflammation via decreasing miR-141-3p expression in diabetic mice [14], which illustrated the implication of miR-141-3p in Met-mediated biological processes. Consistent with the previous findings, we observed that miR-141-3p level of expression was greatly diminished by Met treatment in ESCC cells.…”

Section: Met Administration Suppressed Breast Cancer Cell Invasion Mi...mentioning

confidence: 99%

“…Interestingly, miR-141-3p was found to be downregulated in ESCC tissues and cells, and miR-141-3p knockdown in ESCC cells increased cell invasion, proliferation, and migration by activating the JAK2/STAT3 pathway [13]. Previous research has also demonstrated that miR-141-3p plays a role in Met-mediated inflammation and cancer progression [14,15]. However, there is no evidence for the regulation of Met on miR-141-3p in ESCC progression.…”

Section: Introductionmentioning

confidence: 96%

Metformin attenuates the progression of esophageal squamous cell carcinoma by downregulating miR-141-3p to enhance SCEL

2023

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IntroductionMetformin (Met), a first-line oral anti-type 2 diabetes medication used globally, has been shown to hinder cancer progression via regulation of microRNAs (miRNAs). The previous reports on the relationship between Met use and the risk of esophageal squamous cell carcinoma (ESCC) have been controversial. Hence, this study aimed to explore how Met affected ESCC progression and the underlying molecular mechanism.Material and methodsCell migration, viability and invasiveness were respectively investigated using wound healing, CCK-8 and transwell assay. The expressions of miR-141-3p and Sciellin (SCEL) mRNA were examined by mean of quantitative real-time PCR (qRT-PCR) assay, and SCEL protein level was quantified by western blotting. In vivo tests of Met were performed on animals. The predicted binding of miR-141-3p to SCEL was more evidenced by dual-luciferase assay.ResultsMet treatment in ESCC cell largely impaired cell viability, migration and invasiveness. MiR-141-3p showed high expression in ESCC and was downregulated in ESCC cells after Met treatment. MiR-141-3p upregulation in Met-administered ESCC cells largely restored cell proliferative ability, migration and invasiveness. MiR-141-3p also attenuated the anti-tumor effect of Met in vivo. MiR-141-3p targeted SCEL whose expression was declined in ESCC, and SCEL expression was reinforced in ESCC cells after Met treatment. MiR-141-3p upregulation depleted SCEL expression and thus partially abolished the anti-cancer impacts of SCEL in Met-treated ESCC cells.ConclusionsMet restrains the progression of ESCC by regulating the miR-141-3p/SCEL axis. Our findings clearly show that Met is associated with a lower risk of ESCC, and its anticancer effect could potentially be used to treat ESCC.

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Metformin protects against neuroinflammation through integrated mechanisms of miR-141 and the NF-ĸB-mediated inflammasome pathway in a diabetic mouse model

Cited by 14 publications

References 57 publications

Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice

Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice

Metformin Directly Binds to MMP-9 to Improve Plaque Stability

Metformin attenuates the progression of esophageal squamous cell carcinoma by downregulating miR-141-3p to enhance SCEL

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