AMP-activated protein kinase activators in diabetic ulcers: from animal studies to Phase II drugs under investigation

Lin, Jiun‐Tsai; Chen, Han-Min; Chiu, Chien Chao; Liang, Yao-Jen

doi:10.1517/13543784.2014.922951

Cited by 22 publications

(17 citation statements)

References 71 publications

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“…It should be noted that the improvement that resulted from MET might also be linked to non-glucose-lowering mechanisms, most of which are known to be associated with AMPK activation (48,49). AMPK, as a major cellular energy sensor, plays a positive role in diabetes-associated complications (50,51). Recently, AMPK activation has been shown to reduce HG-induced ␣-SMA expression by inhibiting nuclear translocation of Smad4 (60).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Nrf2 Protein Modulator Salvianolic Acid A Alone or Combined with Metformin on Diabetes-associated Macrovascular and Renal Injury

et al. 2016

Journal of Biological Chemistry

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Nuclear factor E2-related factor 2 (Nrf2) is considered a promising target against diabetic complications such as cardiovascular diseases and diabetic nephropathy. Herein, we investigated the effects of a potential Nrf2 modulator, salvianolic acid A (SAA), which is a natural polyphenol, on diabetes-associated macrovascular and renal injuries in streptozotocin-induced diabetic mice. Given that lowering glucose is the first objective of diabetic patients, we also examined the effects of SAA combined with metformin (MET) on both complications. Our results showed that SAA significantly increased the macrovascular relaxation response to acetylcholine and sodium nitroprusside in diabetic mice. Interestingly, treatment with SAA alone only provided minor protection against renal injury, as reflected by minor improvements in impaired renal function and structure, despite significantly reduced oxidative stress observed in the diabetic kidney. We demonstrated that decreased oxidative stress and NF-κB p65 expression were associated with SAA-induced expression of Nrf2-responsive antioxidant enzymes heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase (quinone) 1 (NQO-1), and glutathione peroxidase-1 (GPx-1) in vivo or in vitro, which suggested that SAA was a potential Nrf2 modulator. More significantly, compared with treatment with either SAA or MET alone, we found that their combination provided further protection against the macrovascular and renal injury, which was at least partly due to therapeutic activation of both MET-mediated AMP-activated protein kinase and SAA-mediated Nrf2/antioxidant-response element pathways. These findings suggested that polyphenol Nrf2 modulators, especially combined with drugs activating AMP-activated protein kinase, including hypoglycemic drugs, are worthy of further investigation to combat diabetic complications.

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Section: Discussionmentioning

confidence: 99%

Effects of the Nrf2 Protein Modulator Salvianolic Acid A Alone or Combined with Metformin on Diabetes-associated Macrovascular and Renal Injury

et al. 2016

Journal of Biological Chemistry

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“…It exerts its antihyperglycemic effect at several levels including inhibition of hepatic glucose production, reduction of intestinal glucose absorption, improvement of glucose uptake, and utilization by peripheral tissues [72]. Emerging evidence indicates novel pleiotropic effects of metformin that include potential renal and cardiovascular protection, antioxidant, antifibrotic, and antiproliferative properties [73] and the ability to increase number and function of endothelial precursor cells [74,75]. Metformin's mechanism of action is linked to inhibition of the complex 1 of mitochondrial electron transport chain and subsequent reduced ATP production and increased AMP:ATP ratio with activation of 5 -AMP-activated protein kinase (AMPK).…”

Section: Metforminmentioning

confidence: 99%

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

et al. 2020

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Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing.

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“…a higher AMP/ATP ratio), AMPK balances energy consumption by inhibiting energy/ATP-consuming pathways and activating the compensatory energy/ATPproducing processes. In addition to the traditional role of AMPK in energy metabolism, several studies have indicated a pivotal role of AMPK in immune regulation (Sag et al, 2008;Viollet et al, 2010;Lin et al, 2014). Using AMPK activators (5-aminoimidazole-4-carboxamide-1-β-Dribofuranoside, AICAR) and inhibitors (Compound C) (Corton et al, 1995;Zhou et al, 2001), there is now ample evidence that AMPK1α, through its signalling network, suppress inflammation (Salt and Palmer, 2012;Palomer et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide ribonucleoside-mediated adenosine monophosphate-activated protein kinase activation induces protective innate responses in bacterial endophthalmitis

Kumar

Giri

2016

Cellular Microbiology

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The retina is considered to be the most metabolically active tissue in the body. However, the link between energy metabolism and retinal inflammation, as incited by microbial infection such as endophthalmitis remains unexplored. In this study, using a mouse model of Staphylococcus aureus (SA) endophthalmitis, we demonstrate that the activity (phosphorylation) of AMP-activated protein kinase alpha (AMPKα), a cellular energy sensor, and its endogenous substrate; acetyl-CoA carboxylase (ACC) is downregulated in the SA-infected retina. Intravitreal administration of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) restored AMPKα and ACC phosphorylation. AICAR treatment reduced both the bacterial burden and intraocular inflammation in SA-infected eyes by inhibiting NF-κB and MAP kinases (p38 and JNK) signaling. The anti-inflammatory effects of AICAR were diminished in eyes pretreated with AMPK inhibitor, Compound C. The bioenergetics (Seahorse) analysis of SA-infected microglia and bone marrow-derived macrophages (BMDM) revealed an increase in glycolysis, which was reinstated by AICAR treatment. AICAR also reduced the expression of SA-induced glycolytic genes, including hexokinase 2 (HK2), and glucose transporter 1 (Glut1) in microglia, BMDM, and the mouse retina. Interestingly, AICAR treatment enhanced the bacterial phagocytic and intracellular killing activities of cultured microglia, macrophages, and neutrophils. Furthermore, AMPKα1 global knockout mice exhibited increased susceptibility towards SA endophthalmitis, as evidenced by increased inflammatory mediators and bacterial burden and reduced retinal function. Together, these findings provide the first evidence that AMPK activation promotes retinal innate defense in endophthalmitis by modulating energy metabolism, and that it can be targeted therapeutically to treat ocular infections.

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AMP-activated protein kinase activators in diabetic ulcers: from animal studies to Phase II drugs under investigation

Cited by 22 publications

References 71 publications

Effects of the Nrf2 Protein Modulator Salvianolic Acid A Alone or Combined with Metformin on Diabetes-associated Macrovascular and Renal Injury

Effects of the Nrf2 Protein Modulator Salvianolic Acid A Alone or Combined with Metformin on Diabetes-associated Macrovascular and Renal Injury

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

5-Aminoimidazole-4-carboxamide ribonucleoside-mediated adenosine monophosphate-activated protein kinase activation induces protective innate responses in bacterial endophthalmitis

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