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Inhibition of inflammation and oxidative stress by an imidazopyridine derivative X22 prevents heart injury from obesity.

ABSTRACT: Inflammation and oxidative stress plays an important role in the development of obesity-related complications and cardiovascular disease. Benzimidazole and imidazopyridine compounds are a class of compounds with a variety of activities, including anti-inflammatory, antioxidant and anti-cancer. X22 is an imidazopyridine derivative we synthesized and evaluated previously for anti-inflammatory activity in lipopolysaccharide-stimulated macrophages. However, its ability to alleviate obesity-induced heart injury via its anti-inflammatory actions was unclear. This study was designed to evaluate the cardioprotective effects of X22 using cell culture studies and a high-fat diet rat model. We observed that palmitic acid treatment in cardiac-derived H9c2 cells induced a significant increase in reactive oxygen species, inflammation, apoptosis, fibrosis and hypertrophy. All of these changes were inhibited by treatment with X22. Furthermore, oral administration of X22 suppressed high-fat diet-induced oxidative stress, inflammation, apoptosis, hypertrophy and fibrosis in rat heart tissues and decreased serum lipid concentration. We also found that the anti-inflammatory and anti-oxidative actions of X22 were associated with Nrf2 activation and nuclear factor-kappaB (NF-κB) inhibition, respectively, both in vitro and in vivo. The results of this study indicate that X22 may be a promising cardioprotective agent and that Nrf2 and NF-κB may be important therapeutic targets for obesity-related complications.

SUBMITTER: Qian Y

PROVIDER: S-EPMC4956940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAcute lung injury (ALI), characterized by disruption of the lung alveolar-capillary membrane barrier and resultant pulmonary edema, and associated with a proteinaceous alveolar exudate, is a leading cause of morbidity and mortality. Currently, inflammation-oxidative stress interaction between TNF-α and NF-κB was identified as a key pathway of ALI. We hypothesized that a TNFR-Fc fusion protein would have beneficial effects in experimental ALI, and sought to test this idea in mice by blocking TNF-α.Methods and resultsIntratracheal instillation of lipopolysaccharide (LPS) into the lungs of ALI mice led to histiocyte apoptosis, and detection of serum and bronchoalveolar lavage fluid (BALF) cytokines, feedback between NF-κB and TNF-α, lung albumin leakage, lung damage, IκB kinase (IKK) and NF-κB activation, I-κB degradation, and oxidative injury. LPS administration raised pulmonary inflammation as reflected by increased inflammatory cytokines, alveoli protein concentration, and ALI scores. IKK is phosphorylated following LPS challenge, leading to I-κB degradation and NF-κB p65 phosphorylation. Furthermore, NF-κB is translocated into the nucleus and up-regulates TNF-α gene transcription. Infusion of TNFR-Fc 24h before LPS challenge significantly abrogated the increase of inflammatory cytokines, especially serum TNF-α concentration, as well as pulmonary alveoli protein levels, and diminished IKK and NF-κB activation and I-κB degradation. The nuclear translocation of NF-κB was inhibited, following by down-regulation of TNF-α gene transcription. In addition, LPS intratracheal instillation induced marked oxidative damage, such as a decrease in total anti-oxidation products and an increase in malondialdehyde (MDA), as well as up-regulation of oxidation enzymes. Histologic analysis and apoptosis scores revealed that the extent of tissue lesions was significantly reduced, but not abrogated, by TNF-α blockade.ConclusionTreatment with LPS alone increased inflammation and oxidative stress in ALI mice, while administration of TNFR-Fc 24h before LPS challenge broke the feedback between NF-κB and TNF-α, resulting in decreased pulmonary inflammation/oxidative damage and tissue destruction. These results suggest a potential role for TNF-α therapy to treat clinical ALI.

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Inhibition of inflammation and oxidative stress by an imidazopyridine derivative X22 prevents heart injury from obesity.

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