Purpose: Methylglyoxal (MGO) is a highly reactive dicarbonyl species implicated in diabetic-associated diseases. Acute lung injury (ALI) symptoms and prognosis are worsened by diabetes and obesity. Here, we hypothesized that elevated MGO levels aggravate ALI, which can be prevented by metformin. Therefore, this study evaluated the lung inflammation in lipopolysaccharide (LPS)-exposed mice pretreated with MGO. Methods: C57Bl/6 male mice treated or not with MGO for 12 weeks were intranasally instilled with LPS (30 μg) to induce ALI, and metformin (300 mg/kg) was given as gavage in the last two weeks of treatment. After 6 h, bronchoalveolar lavage fluid (BALF) and lung tissues were collected to quantify the cell infiltration, cytokine levels, reactive-oxygen species (ROS) production, and RAGE expression. Results: LPS exposure markedly increased the neutrophil infiltration in BALF and lung tissue, which was accompanied by higher levels of IFN-γ, TNF-α and IL-1β compared with untreated group. MGO treatment significantly increased the airways neutrophil infiltration and mRNA expressions of TNF-α and IL-1β, whereas COX-2 expression remained unchanged. In lung tissues of LPS-exposed mice, MGO treatment significantly increased the immunostaining and mRNA expression of RAGE, and the ROS levels. Serum MGO concentration achieved after 12-week intake was 9.2-fold higher than control mice, which was normalized by metformin treatment. Metformin also reduced the inflammatory markers in response to MGO. Conclusion: MGO intake potentiates the LPS-induced ALI, increases RAGE expression and ROS generation, which is normalized by metformin. MGO scavengers may be a good adjuvant therapy to reduce ALI in patients with cardiometabolic diseases.

Exposure to methylglyoxal (MGO) increases the levels of receptor for advanced glycation end products (RAGE) and reactive-oxygen species (ROS) in mouse airways, exacerbating the inflammatory responses. Metformin scavenges MGO in plasma of diabetic individuals. We investigated if amelioration by metformin of eosinophilic inflammation reflects its ability to inactivate MGO. Male mice received 0.5% MGO for 12 weeks together or not with 2-week treatment with metformin. Inflammatory and remodeling markers were evaluated in bronchoalveolar lavage fluid (BALF) and/or lung tissues of ovalbumin (OVA)-challenged mice. MGO intake elevated serum MGO levels and MGO immunostaining in airways, which were reduced by metformin. The infiltration of inflammatory cells and eosinophils and levels of IL-4, IL-5 and eotaxin significantly increased in BALF and/or lung sections of MGO-exposed mice, which were reversed by metformin. The increased mucus production and collagen deposition by MGO exposure were also significantly decreased by metformin. In MGO group, the increases of RAGE and ROS levels were fully counteracted by metformin. Superoxide anion (SOD) expression was enhanced by metformin. In conclusion, metformin counteracts OVA-induced airway eosinophilic inflammation and remodeling, and suppresses the RAGE-ROS activation. Metformin may be an option of adjuvant therapy to improve asthma in individuals with high levels of MGO.

The involvement of methylglyoxal (MGO) and advanced glycation end products (AGEs) in bladder dysfunction of diabetic ob/ob mice treated with the AGE breaker ALT-711 was investigated here. Diabetic mice exhibited high levels of MGO, AGEs, receptor for AGEs (RAGE), and collagen in serum and/or bladder tissues along with increased volume per void, all of which were reduced by ALT-711. Activation of the MGO-AGEs-RAGE pathway in the bladder wall contributes to the pathogenesis of diabetes-associated bladder dysfunction.

Background/Objectives: Methylglyoxal (MGO) and subsequent activation of advanced glycation end products (AGEs)–RAGE receptor signaling has been implicated in the complications of diabetes mellitus (DM), such as bladder dysfunction. Chronic treatment with MGO leads to bladder overactivity, but the effects of acute MGO exposure have not yet been evaluated. Methods: In this study, we used female wild-type, endothelial nitric oxide (eNOS) knockout (eNOS^−/−), and triple (neuronal/endothelial/inducible) NOS^−/− mice to investigate the effects of incubation of MGO (10 to 300 µM) on bladder contractions induced by carbachol and electrical field stimulation (EFS). We also analyzed the activity of the MGO detoxification enzyme glyoxalase 1 (Glo1). Results: Incubation with MGO at 10 and 30 µM in urothelium-intact preparations produced marked detrusor hypercontractility to both carbachol and EFS that was abolished by urothelium removal. Detrusor hypercontractility was associated with the generation of reactive oxygen species (ROS), RAGE activation, Rho kinase sensitization, and activation of TRPA1 and TRPV4 channels. At higher concentrations (100 and 300 µM), MGO did not significantly affect the detrusor contractility to carbachol and EFS, but L-NAME pretreatment restored the hypercontractile state by MGO. Likewise, in bladder strips obtained from eNOS^−/− or triple NOS^−/− mice, MGO exposure (300 µM) significantly enhanced carbachol and EFS-induced contractions, indicating a major role for nitric oxide (NO) counteracting the hypercontractility. No concentration of MGO altered Glo1 activity in bladder tissues. Conclusions: In conclusion, progressive MGO accumulation may account for the transition from the initial hyperactive phase to the subsequent hypoactive decompensated phase of diabetic bladder dysfunction.