Indeglitazar

We previously characterized the volatile compounds of black pepper (Piper nigrum) essential oil (BPEO) and demonstrated its mitigating effect against dexamethasone-induced pancreatic damage.Herein, we investigated the protective effect of the oil against dexamethasone-induced hepatotoxicity in rats and pinned the possible underlying mechanisms.In the in vivo experiment, male Wistar rats were divided into five groups.The first group served as the normal control receiving a saline solution (Control).The second group was subjected to hepatic damage through dexamethasone exposure (Dexa) at 10 mg/kg.The third group received both dexamethasone and metformin (Met) at a dose of 50 mg/kg.The remaining two groups were exposed to dexamethasone along with black pepper oil administration at low and high doses (BPEO, 0.5 mL/kg and 1 mL/kg).We showed that BPEO offset toxicity manifestations, as indicated by reducing monocyte infiltration, hepatocyte degeneration and vacuolation, and reduction of ALT and AST levels.Moreover, relative to the dexamethasone-treated rats, BPEO declined the number of PGC-1α pos. hepatocytes and activated the expression of PPAR-α in the liver.BPEO showed comparable hepatoprotective potency to the standard drug, metformin, especially at the higher dose tested (1 mL/kg).This study showcases the promising potential of BPEO in thwarting dexamethasone-induced adverse effects on the liver by alleviating hepatic biomarkers hikes and preventing histopathol. changes and fibrosis.Finally, it opens a new avenue on the potential role of BPEO in modulating steroid-induced hepatic injury through the PGC-1α/ PPAR-α pathway.

Metabolic syndrome is a complex disease with diverse symptoms, but current pharmacological interventions have limited efficacy. Indeglitazar, a pan-agonist targeting the three-peroxisome proliferator activated receptors (PPAR), exhibits significant therapeutic effects on both diabetic and fatty liver animal models. However, its short half-life limits the in vivo efficacy, which might be attributed to the β-oxidation of indolepropionic acid at Indeglitazar. To overcome this metabolic instability, two deuterium atoms were introduced to the α-position of indolepropionic acid to block the β-oxidation. In this study, several deuterated derivatives were found to sustain PPARs activity and extend the half-life of liver microsomes. In oral glucose tolerance tests, I-1 exhibited the strongest glucose-lowering effect on ob/ob mice in this series. In db/db mice, I-1 reduced lipid levels, liver steatosis and promoted UCP1 expression in white adipose tissue. Mechanistic studies further revealed that I-1 exerts stronger effects than Indeglitazar on the regulation of genes related to lipid metabolism, mitochondrial function, and oxidative stress. Furthermore, I-1 significantly reduced liver steatosis, hepatocellular ballooning, inflammation, and fibrosis in NASH model induced by HFD + CCl₄, and even exerted better therapeutic effect than that of Indeglitazar. With the above attractive efficacy, deuterated derivative I-1 is considered as a promising treatment for metabolic syndrome.