The impact of metformin and aspirin on T-cell mediated inflammation: A systematic review of in vitro and in vivo findings

Nyambuya, Tawanda M.; Dludla, Phiwayinkosi V.; Mxinwa, Vuyolwethu; Mokgalaboni, Kabelo; Ngcobo, Siphamandla Raphael; Tiano, Luca; Nkambule, Bongani B.

doi:10.1016/j.lfs.2020.117854

Cited by 21 publications

(15 citation statements)

References 79 publications

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“…Thrombotic cardiovascular events can be propagated by unchecked inflammation in stages Concurrently, DAPT did not change a bevy of other thromboinflammatory markers in CKD patients including no changes in platelet-leukocyte interactions that are known to increase signaling-dependent transcription of inflammatory mediators (e.g., IL-1β and TNFα). 21 Although others have shown that platelet-leukocyte interactions, and the post-receptor downstream changes can be suppressed by the P2Y12 antagonists in animal models [22][23][24][25] and in healthy volunteers, 16,17,26,27 our results failed to find such changes on DAPT in CKD. Part of the reason could be masking of these changes due to concomitant statin therapy in CKD patients;…”

Section: Discussioncontrasting

confidence: 74%

Platelet-Dependent Inflammatory Dysregulation in Patients with Stages 4 or 5 Chronic Kidney Disease: A Mechanistic Clinical Study

et al. 2022

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Background. Chronic kidney disease (CKD) is characterized by dysregulated inflammation that worsens with CKD severity. The role of platelets in modulating inflammation in stages 4 or 5 CKD remains unexplored. We investigated whether there are changes in platelet-derived thromboinflammatory markers in CKD with dual antiplatelet therapy (DAPT- aspirin 81 mg/d plus P2Y12 inhibitor). Methods. In a mechanistic clinical trial, we compared platelet activation markers, circulating platelet-leukocyte aggregates, leukocyte composition, and plasma cytokine profile of non-CKD controls (n=26) and CKD outpatients (n=48) with glomerular filtration rate (GFR expressed in ml/min/1.73m2) <30 on 2 weeks of DAPT. Results. Patients with CKD demonstrated reduced mean platelet count, elevated mean platelet volume, reduced platelet-leukocyte aggregates, reduced platelet-bound monocytes, higher total non-classical monocytes in the circulation, and higher levels of IL-1RA, VEGF, and fractalkine. There were no differences in platelet activation markers between CKD and controls. Although DAPT reduced platelet aggregation, it had multifaceted effects on thromboinflammatory markers in CKD, including a reduction in TNFα levels among a CKD subgroup younger than 55 years, diabetics, had GFR ≥15 or albuminuria ≥1000 mg/g; and, no change in a number of other cytokines. Correlation analysis and minimum spanning trees plot of 45-cytokine panel showed platelet-derived CD40L showed a large reduction in weight factor after DAPT in CKD. Additionally, platelet-derived IL-1β and PDGF were tightly correlated with other cytokines with IL-1β as the hub cytokine. Conclusion. Attenuated interactions between platelets and leukocytes in the CKD state coincided with no change in platelet activation status, an altered differentiation state of monocytes, and heightened inflammatory markers. Platelet derived cytokines were one of the central cytokines in CKD. DAPT had multifaceted effects on thromboinflammation suggesting that there are platelet-dependent and platelet-independent inflammation in stages 4 or 5 CKD.

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Section: Discussioncontrasting

confidence: 74%

Platelet-Dependent Inflammatory Dysregulation in Patients with Stages 4 or 5 Chronic Kidney Disease: A Mechanistic Clinical Study

et al. 2022

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“…The role of a dysfunctional T-cell-mediated immune response in the onset and progression of CV disease is well documented and increasing evidence supports inhibition of T-cell-mediated inflammation by metformin [ 129 ]. Overall, in vitro and in vivo studies in animal models of chronic inflammation indicate that metformin exerts its anti-inflammatory effect through an AMPK-dependent modulation of the mTOR and the signal transducer and activator of transcription (STAT) 3 and 5 of T-cells [ 130 ].…”

Section: Mechanisms Of Beneficial Impact Of Metformin On Heart Failurementioning

confidence: 99%

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

et al. 2021

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Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved.

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“…As several studies revealed an association between T2DM and psoriasis [ 31 , 32 ] and suggested a severity-dependent relationship between psoriasis and T2DM [ 17 ], the management of T2DM is considered extremely important in the treatment of psoriasis. Metformin treatment has been reported to inhibit several signaling pathways including the mammalian target of rapamycin [ 33 ] and mitogen-activated protein kinase signaling [ 34 ], in addition to NF-κB signaling. As such, we cannot thus exclude the possibility that other kinases might have been affected by metformin in the experiments.…”

Section: Discussionmentioning

confidence: 99%

The Antidiabetic Agent Metformin Inhibits IL-23 Production in Murine Bone-Marrow-Derived Dendritic Cells

Matsuda-Taniguchi

Takao

Nakahara

et al. 2021

JCM

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Psoriasis is a chronic inflammatory skin disease, and its immune mechanism has been profoundly elucidated. Biologics targeting interleukin (IL)-23 have prevented the development of psoriasis. As major sources of IL-23, dendritic cells (DCs) play a pivotal role in psoriasis; however, the regulatory mechanism of IL-23 in DCs remains unclear. IL-36γ was reported to reflect the disease activity of psoriasis. Therefore, we hypothesized that IL-36γ may affect IL-23 production in DCs. To reveal the mechanism by which IL-36γ controls IL-23 production in DCs, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-36γ. IL-36γ stimulation upregulated the mRNA and protein expression of Nfkbiz in BMDCs. Nfkbiz knockdown using siRNA transfection partially inhibited the upregulation of IL-23 mRNA expression induced by IL-36γ stimulation. Since NF-κB signaling regulates Nfkbiz expression and the anti-diabetic agent metformin reportedly modulates NF-κB signaling, we examined the effect of metformin treatment on IL-36γ-induced IL-23 production. Metformin treatment impaired the phosphorylation of NF-κB induced by IL-36γ stimulation with the subsequent downregulation of Nfkbiz, resulting in the inhibition of IL-23 production in BMDCs. These data provided evidence that metformin treatment can inhibit IL-36γ-mediated IL-23 production in BMDCs, which might contribute to the prevention of psoriasis.

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The impact of metformin and aspirin on T-cell mediated inflammation: A systematic review of in vitro and in vivo findings

Cited by 21 publications

References 79 publications

Platelet-Dependent Inflammatory Dysregulation in Patients with Stages 4 or 5 Chronic Kidney Disease: A Mechanistic Clinical Study

Platelet-Dependent Inflammatory Dysregulation in Patients with Stages 4 or 5 Chronic Kidney Disease: A Mechanistic Clinical Study

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

The Antidiabetic Agent Metformin Inhibits IL-23 Production in Murine Bone-Marrow-Derived Dendritic Cells

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