Metformin inhibits IgE‐ and aryl hydrocarbon receptor‐mediated mast cell activation in vitro and in vivo

Wang, Hsueh Chun; Huang, Shau Ku

doi:10.1002/eji.201847706

Cited by 25 publications

(21 citation statements)

References 25 publications

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“…20 Possible reasons for sex-specific effects of metformin include the influence of sex hormones and epigenetic changes on the Y chromosome. 46 There are 2 other potential ways in which metformin might cause sex-specific responses in Covid-19: Metformin inhibits IgE-and aryl hydrocarbon-mediated mast cell activation, 47 and mast cell activation has been implicated as an early indicator of inflammatory response to SARS-CoV2 and possibly cytokine storm. 48 Mast cells from female rats cause a greater increase in TNFα than mast cells in male rats, which could be one reason for greater benefit from metformin in women than men.…”

Section: Discussionmentioning

confidence: 99%

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19

Bramante

Ingraham

Murray

et al. 2020

Preprint

110

147

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Background Type 2 diabetes (T2DM) and obesity are significant risks for mortality in Covid19. Metformin has been hypothesized as a treatment for COVID19. Metformin has sex specific immunomodulatory effects which may elucidate treatment mechanisms in COVID-19. In this study we sought to identify whether metformin reduced mortality from Covid19 and if sex specific interactions exist. Methods De-identified claims data from UnitedHealth were used to identify persons with at least 6 months continuous coverage who were hospitalized with Covid-19. Persons in the metformin group had at least 90 days of metformin claims in the 12 months before hospitalization. Unadjusted and multivariate models were conducted to assess risk of mortality based on metformin as a home medication in individuals with T2DM and obesity, controlling for pre-morbid conditions, medications, demographics, and state. Heterogeneity of effect was assessed by sex. Results 6,256 persons were included; 52.8% female; mean age 75 years. Metformin was associated with decreased mortality in women by logistic regression, OR 0.792 (0.640, 0.979); mixed effects OR 0.780 (0.631, 0.965); Cox proportional-hazards: HR 0.785 (0.650, 0.951); and propensity matching, OR of 0.759 (0.601, 0.960). TNF-alpha inhibitors were associated with decreased mortality in the 38 persons taking them, by propensity matching, OR 0.19 (0.0378, 0.983). Conclusions Metformin was significantly associated with reduced mortality in women with obesity or T2DM in observational analyses of claims data from individuals hospitalized with Covid-19. This sex-specific finding is consistent with metformin reducing TNF-alpha in females over males, and suggests that metformin conveys protection in Covid-19 through TNF-alpha effects. Prospective studies are needed to understand mechanism and causality.

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Section: Discussionmentioning

confidence: 99%

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19

Bramante

Ingraham

Murray

et al. 2020

Preprint

110

147

View full text Add to dashboard Cite

show abstract

“…The major advantages of drug repurposing are previously established low cytotoxicity and pharmacokinetic activity [33]. For example, metformin, a widely used anti-diabetic drug [34] that also has anti-cancer effects [35–37], has been shown to inhibit IgE and aryl hydrocarbon receptor-mediated mast cell activation in vitro and in vivo [38]. Additionally, the antidiarrheal medicine berberine, which is widely used for gastrointestinal ailments such as bacterial gastroenteritis and dysentery [39], has been found to suppress mast cell-mediated allergic responses via down-regulation of FcɛRI activation and MAPK signaling [40].…”

Section: Discussionmentioning

confidence: 99%

CDK4/6 inhibitor palbociclib suppresses IgE-mediated mast cell activation

Hou

Sun

et al. 2019

J Transl Med

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Background Mast cell activation causes degranulation and release of cytokines, thereby promoting inflammation. The aim of this study was to investigate the inhibitory effect of CDK4/6 inhibition on mast cell activation in vitro and in vivo. Methods RBL-2H3 rat basophilic leukemia cells (BLCs) and mouse bone marrow-derived mast cells (BMMCs) were sensitized with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated with DNP-human serum albumin (HSA) antigens, and treated with the CDK4/6 inhibitor palbociclib. Histological stains were applied to reveal cytomorphological changes. Murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models were used to examine palbociclib effects on allergic reactions in vivo. Western blots were performed to detect the expression of cell signaling molecules associated with mast cell activation. Results Activated BLCs and BMMCs released copious granule-related mediators (histamine and β-hexosaminidase), which was reduced by palbociclib in a concentration-dependent manner. Palbociclib inhibited expression of the mast cell activation marker CD63 in activated BLCs and inhibited granule release (visualized with toluidine blue staining) while preventing morphological changes, (elongated shape maintained) and filamentous actin (F-actin) reorganization. Palbociclib suppressed molecular Lyn and/or mitogen-activated protein kinase (MAPK) signaling associated with mast cell activation in stimulated BLCs and attenuated allergic reactions in PCA mice dose dependently. Palbociclib attenuated body temperature reduction and diminished serum histamine levels in ovalbumin OVA-challenged ASA mice. Conclusion Palbociclib suppresses IgE-mediated mast cell activation in vitro and in vivo, suggesting that it may be developed into a therapy for mast cell-mediated allergic diseases via inhibition of mast cell degranulation.

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“…Metformin is also associated with changes in many asthma-related cells and cytokines. Ig-E and aryl hydrocarbon receptor-mediated mast cell activation could be inhibited by metformin in vitro and in vivo [ 22 ]. Metformin downregulated the expression levels of inflammatory cytokines (IL-1 β , IL-4, and IL-6 and TNF- α ) in intracerebral hemorrhage model rats [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Association of Metformin Use with Asthma Exacerbation in Patients with Concurrent Asthma and Diabetes: A Systematic Review and Meta-Analysis of Observational Studies

Wen

Wang

Chai

et al. 2020

Canadian Respiratory Journal

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Background. Asthma and diabetes are both diseases that affect a wide range of people worldwide. As a common treatment for diabetes, metformin has also been reported to be effective in improving asthma outcomes. We conducted a combined analysis to examine the efficacy of metformin in reducing asthma exacerbation in patients with concurrent asthma and diabetes. Methods. We searched the PubMed, Embase, and CENTRAL databases for articles published prior to April 2020 to find observational studies of individuals with concurrent asthma and diabetes that compared the risk of asthma exacerbation between metformin users and nonusers. Two researchers separately screened the studies, extracted data, and evaluated the risk of bias. The primary outcome was the adjusted risk of asthma exacerbation. The secondary outcomes were the adjusted risk of asthma-related hospitalization and emergency room visits. Review Manager was used for data analysis and plotting. I2 and χ2 tests were used to estimate heterogeneity. A random effects or fixed effects model was used depending on the heterogeneity. Odds ratios were calculated for dichotomous variables. Results. We included two studies with a total of 25252 patients. The pooled effect size showed that metformin was inversely associated with a risk of asthma exacerbation (OR = 0.65, 95% CI 0.28–1.48; χ2 = 5.42, P=0.02; I2 = 82%), asthma-related emergency department visits (OR = 0.81, 95% CI 0.74–0.89; χ2 = 0.36, P=0.55; I2 = 0%), and hospitalizations (OR = 0.43, 95% CI 0.14–1.29; χ2 = 4.01, P=0.05; I2 = 75%). Conclusion. This meta-analysis suggested that metformin decreased the risk of asthma-related emergency room visits for patients with concurrent asthma and diabetes. Metformin reduced the risk of asthma-related hospitalization and exacerbation but was not statistically significant. More randomized trials involving larger samples should be considered, and the mechanisms of these effects need to be fully elucidated.

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Metformin inhibits IgE‐ and aryl hydrocarbon receptor‐mediated mast cell activation in vitro and in vivo

Cited by 25 publications

References 25 publications

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19

CDK4/6 inhibitor palbociclib suppresses IgE-mediated mast cell activation

Association of Metformin Use with Asthma Exacerbation in Patients with Concurrent Asthma and Diabetes: A Systematic Review and Meta-Analysis of Observational Studies

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