Agalsidase Beta(Nipro ES Pharma)

Background  Peroxisome proliferator‐activated receptors (PPAR) mediate inflammatory processes and alter cardiac function. However, it is not clear whether inflammatory cytokines or PPAR ligands regulate PPARs in the cardiomyocytes to modulate cardiac functions. We investigated the effects of tumour necrosis factor‐alpha (TNF‐α) and PPAR ligands on the expression of PPARs in HL‐1 cardiomyocytes.Materials and methods  HL‐1 cardiomyocytes were incubated with and without TNF‐α (1, 10, 25 and 50 ng mL−1) or PPAR ligands (rosiglitazone, pioglitazone and fenofibrate) at concentrations of 0·1, 1 and 10 µm for 24 h. The cells also received SN‐50 (NF‐κB inhibitor, 50 µg mL−1), ascorbic acid (100 µm) and coenzyme Q10 (10 µm) alone or combined with TNF‐α.Results  Using reverse transcriptase–polymerase chain reaction and Western blot, we found that incubation of TNF‐α (50 ng mL−1) for 24 h decreased PPAR‐α, but increased PPAR‐γ without altering PPAR‐δ. These effects were not changed by co‐administration of SN‐50. However, co‐administration of ascorbic acid prevented the effect of TNF‐α both on PPAR‐α and PPAR‐γ. Coenzyme Q10 partially attenuated the effect of TNF‐α on PPAR‐γ but did not alter its effect on PPAR‐α. The administration of rosiglitazone (10 µm) and pioglitazone (10 µm) for 24 h increased PPAR‐γ mRNA, but did not alter PPAR‐α or PPAR‐δ. Moreover, fenofibrate (0·1, 1 and 10 µm) increased PPAR‐γ without any effects on PPAR‐α or PPAR‐δ.Conclusions  Oxidative stress causes the regulations of PPAR‐α and PPAR‐γ in the TNF‐α‐treated cardiomyocytes. The up‐regulation of PPAR‐γ by PPAR ligands may contribute to their anti‐inflammation effects.

Astrocyte swelling and brain edema are major neuropathological findings in the acute form of hepatic encephalopathy (fulminant hepatic failure), and substantial evidence supports the view that elevated brain ammonia level is an important etiological factor in this condition. Although the mechanism by which ammonia brings about astrocyte swelling remains to be determined, oxidative/nitrosative stress and mitogen‐activated protein kinases (MAPKs) have been considered as important elements in this process. One factor known to be activated by both oxidative stress and MAPKs is nuclear factor κB (NFκB), a transcription factor that activates many genes, including inducible nitric oxide synthase (iNOS). As the product of iNOS, nitric oxide (NO), is known to cause astrocyte swelling, we examined the potential involvement of NFκB in ammonia‐induced astrocyte swelling. Western blot analysis of cultured astrocytes showed a significant increase in NFκB nuclear translocation (a measure of NFκB activation) from 12 h to 2 days after treatment with NH4Cl (5 mM). Cultures treated with anti‐oxidants, including superoxide dismutase, catalase, and vitamin E as well as the MAPKs inhibitors, SB239063 (an inhibitor of p38‐MAPK) and SP600125 (an inhibitor of c‐Jun N‐terminal kinase), significantly diminished NFκB activation by ammonia, supporting a role of oxidative stress and MAPKs in NFκB activation. The activation of NFκB was associated with increased iNOS protein expression and NO generation, and these changes were blocked by BAY 11–7082, an inhibitor of NFκB. Additionally, ammonia‐induced astrocyte swelling was inhibited by the NFκB inhibitors, BAY 11–7082 and SN‐50, thereby implicating NFκB in the mechanism of astrocyte swelling. Our studies indicate that cultured astrocytes exposed to ammonia display NFκB activation, which is likely to be a consequence of oxidative stress and activation of MAPKs. NFκB activation appears to contribute to the mechanism of ammonia‐induced astrocyte swelling, apparently through its up‐regulation of iNOS protein expression and the subsequent generation of NO.