Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NF<i>κ</i>B Pathway Suppression

Zhou, Zhong’e; Tang, Yong; Jin, Xian; Chen, Chengjun; Lü, Yi; Liu, Liang; Shen, Chengxing

doi:10.1155/2016/4847812

Cited by 95 publications

(78 citation statements)

References 31 publications

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“…Using these in vitro models, metformin‐mediated increases in (1) cell proliferation; (2) cell differentiation; (3) insulin‐stimulated glucose uptake; (4) type 1 collagen production; (5) alkaline phosphatase activity; (6) extracellular matrix deposition and mineralization; along with (7) transcriptional up‐regulation of pro‐osteogenic genes (including Runx2 , osteocalcin [ Ocn ], bone morphogenic protein‐2 [ Bmp‐2 ], osteoprotegerin [ Opg ], Igf‐1 ) have been demonstrated in cultured osteoblasts . In vitro, metformin also appears to protect against AGE‐induced cellular injury and cell death in osteoblastic cells, similar to described effects in other human and rodent complication‐affiliated cell types such as neurons, macrophages, cardiomyocytes, and renal tubular cells . In many cases, these effects are thought to be mediated by metformin activation of AMPK signaling pathways .…”

Section: Drugs and Bonementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Section: Drugs and Bonementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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“…Activating the AMPK and inhibiting the NF-ⱪB, metformin suppresses the pathway of RAGE/ NF-kB, leading to inhibited effects of AGE and change of phenotype of macrophages from M1 (classical or inflammatory) to M2 (alternatives) by changing the expression of their surface markers (CD86 and CD206, respectively). Finally, the production of inflammatory cytokines and inhibitory cytokines (IL-10) would increase (39). By producing the high mobility group box 1 (HMGB1), which has pseudo-cytokine activity, necrotic cells are able to stimulate many receptors, including TLR4 and RAGE and induce inflammatory responses.…”

Section: Metformin and Inflammatory Markersmentioning

confidence: 99%

Metformin and its anti-inflammatory and anti-oxidative effects; new concepts

et al. 2018

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Metformin is one of the oldest and commonly used blood sugar lowering drugs, having limited side effects and used as the first line treatment in patients suffering from diabetes mellitus. Moreover, various studies have emphasized on the anti-inflammatory and antioxidant role of metformin, with multiple mechanisms, which activation of AMPK by metformin has had a key role in many of them. During the searches on the internet websites of PubMed, Elsevier, Google Scholar, and Science Direct, 76 papers related to the anti-inflammatory and antioxidant role of metformin were selected and reviewed since 2003 to 2017. At the cellular level, metformin suppresses the inflammation in many cases and reduces or eliminates inflammatory factors mainly through dependent mechanisms and sometimes independent of AMPK at the cellular level and through other ways at the systematic levels. It is also effective in reducing the level of oxidative stress factors by regulating the antioxidant system of the cell. All evidence suggests the antioxidant and anti-inflammatory role of metformin in various conditions. Metformin can be an appropriate treatment option for many diseases, which inflammatory processes and oxidative stress play a role in their pathogenesis.

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“…Mechanisms of antitumor activity of metformin have primarily been attributed to gluconeogenesis inhibition, reduction in insulin concentrations, or suppression of mTORC1 via activation of the AMP-activated protein kinase (AMPK) pathway (15)(16)(17)(18). Recently, it was reported that metformin inhibits inflammatory responses in murine macrophages, in part through AMPK activation and RAGE/NFkB pathway suppression (19). These data suggested that metformin may act on cancer cells, as well as on several host inflammatory and immune cells.…”

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confidence: 99%

Metformin Mediates Protection against Legionella Pneumonia through Activation of AMPK and Mitochondrial Reactive Oxygen Species

Kajiwara

Kusaka

Kimura

et al. 2018

The Journal of Immunology

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In infection, macrophages play a critical role in the host defense response. Metformin, an oral drug for type 2 diabetes, is attracting attention as a new supportive therapy against a variety of diseases, such as cancer and infectious diseases. The novel mechanisms for metformin actions include modulation of the effector functions of macrophages and other host immune cells. In this study, we have examined the effects of metformin on infection in vitro and in vivo. Metformin treatment suppressed growth of in a time- and concentration-dependent fashion in bone marrow-derived macrophages, RAW cells (mouse), and U937 cells (human). Metformin induced phosphorylation of AMP-activated protein kinase (AMPK) in-infected bone marrow-derived macrophages, and the AMPK inhibitor Compound C negated metformin-mediated growth suppression. Also, metformin induced mitochondrial reactive oxygen species but not phagosomal NADPH oxidase-derived reactive oxygen species. Metformin-mediated growth suppression was mitigated in the presence of the reactive oxygen species scavenger glutathione. In a murine pneumonia model, metformin treatment improved survival of mice, which was associated with a significant reduction in bacterial number in the lung. Similar to in vitro observations, induction of AMPK phosphorylation and mitochondrial ROS was demonstrated in the infected lungs of mice treated with metformin. Finally, glutathione treatment abolished metformin effects on lung bacterial clearance. Collectively, these data suggest that metformin promotes mitochondrial ROS production and AMPK signaling and enhances the bactericidal activity of macrophages, which may contribute to improved survival in pneumonia.

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Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFκB Pathway Suppression

Cited by 95 publications

References 31 publications

Diabetes pharmacotherapy and effects on the musculoskeletal system

Diabetes pharmacotherapy and effects on the musculoskeletal system

Metformin and its anti-inflammatory and anti-oxidative effects; new concepts

Metformin Mediates Protection against Legionella Pneumonia through Activation of AMPK and Mitochondrial Reactive Oxygen Species

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