Discovery of novel AdipoRon analogues as potent anti-inflammatory agents against nonalcoholic steatohepatitis

Dai, Liang; Wang, Qian; Wang, Pengfei; Zhang, Shangran; Tai, Luyang; Xu, Xiangrui; Duan, Mengyu; Yuan, Haoliang; Feng, Zhiqi

doi:10.1016/j.ejmech.2022.114800

Cited by 6 publications

(4 citation statements)

References 24 publications

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“…RNA-seq was conducted on the Illumina sequencing platform by Gene Denovo Biotechnology Co., Ltd (China). Western blot analysis was performed as previously reported. , Briefly, about 20 mg liver samples were lysed using RIPA buffer. These samples were separated using SDS-PAGEs and transferred to PVDF membranes for immunoblotting to analyze the levels of NF-κB p65 (ABclonal Technology, #10609), p-NF-κB p65(Cell Signaling Technology, #3033), and GAPDH (Arigo Biolaboratories, #ARG10112).…”

Section: Methodsmentioning

confidence: 99%

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

et al. 2023

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Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are considered as potential drug targets for cholestatic liver diseases (CLD) via ameliorating hepatic cholestasis, inflammation, and fibrosis. In this work, we developed a series of hydantoin derivatives as potent PPARα/δ dual agonists. Representative compound V1 exhibited PPARα/δ dual agonistic activity at the subnanomolar level (PPARα EC50 = 0.7 nM; PPARδ EC50 = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARδ at 2.1 Å resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, V1 showed potent anti-CLD and antifibrotic effects in preclinical models at very low doses (0.03 and 0.1 mg/kg). Collectively, this work provides a promising drug candidate for treating CLD and other hepatic fibrosis diseases.

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Section: Methodsmentioning

confidence: 99%

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

et al. 2023

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“…Furthermore, the optimized AdipoRon derivative, Q7 has exhibited higher potency compared with AdipoRon in reducing fibrosis, inflammation, steatosis and liver injury in murine NASH model (high-fat, high-cholesterol, and high-fructose diet) ( Fig. 6 B) [ 145 ].…”

Section: The Secreted Proteins-receptor Signaling Regulates Nash Prog...mentioning

confidence: 99%

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis

Wang,

Yu,

Cen

et al. 2024

Metabolism Open

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Section: Therapeutic Perspectives For Mafld: the Role Of Adiporonmentioning

confidence: 99%

“…It is the pioneer with such active oral pharmacodynamics [196,197]. Furthermore, scientific evidence elucidates its anti-inflammatory effect in several models, including acute hepatitis, liver fibrosis, nephropathy, and cardiac inflammation [198,199]. In this sense, Adiponectin Receptor Agonist (ADP355) is a short active synthetic adiponectin-mimetic peptide, altered through the insertion of unnatural amino acids and labeled by the potential to reestablish regular adiponectin activity.…”

Section: Therapeutic Perspectives For Mafld: the Role Of Adiporonmentioning

confidence: 99%

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

De Cól,

de Lima,

Pompeu

et al. 2024

IJMS

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Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain–gut–liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to liver lipogenesis and systemic inflammation. This study aimed to review the connection between the brain–gut–liver axis and MAFLD. The inflammatory process, cellular alterations in hepatocytes and stellate cells, hypercaloric diet, and sedentarism aggravate the prognosis of patients with MAFLD. Thus, to understand the modulation of the physiopathology of MAFLD, it is necessary to include the organokines involved in this process (adipokines, myokines, osteokines, and hepatokines) and their clinical relevance to project future perspectives of this condition and bring to light new possibilities in therapeutic approaches. Adipokines are responsible for the activation of distinct cellular signaling in different tissues, such as insulin and pro-inflammatory cytokines, which is important for balancing substances to avoid MAFLD and its progression. Myokines improve the quantity and quality of adipose tissues, contributing to avoiding the development of MAFLD. Finally, hepatokines are decisive in improving or not improving the progression of this disease through the regulation of pro-inflammatory and anti-inflammatory organokines.

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Discovery of novel AdipoRon analogues as potent anti-inflammatory agents against nonalcoholic steatohepatitis

Cited by 6 publications

References 24 publications

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

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