Unraveling the enigma: Molecular mechanisms of berberrubine-induced nephrotoxicity reversed by its parent form berberine.
Phytomedicine
; 129: 155648, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38669970
ABSTRACT
BACKGROUND:
Berberine is an isoquinoline alkaloid that is extensively applied in the clinic due to its potential therapeutic effects on dysentery and infectious diarrhoea. Its main metabolite, berberrubine, a promising candidate for ameliorating hyperlipidaemia, has garnered more attention than berberine. However, our study revealed that berberrubine induces severe kidney damage, while berberine was proven to be safe.PURPOSE:
Herein, we explored the opposite biological effects of these two compounds on the kidney and elucidated their underlying mechanisms.METHODS:
First, integrated metabolomic and proteomic analyses were conducted to identify relevant signalling pathways. Second, a click chemistry method combined with a cellular thermal shiftassay, a drug affinity responsive target stability assay, and microscale thermophoresis were used to identify the direct target proteins. Moreover, a mutation experiment was performed to study the specific binding sites.RESULTS:
Animal studies showed that berberrubine, but not berberine, induced severe chronic, subchronic, and acute nephrotoxicity. More importantly, berberine reversed the berberrubine-reduced nephrotoxicity. The results indicated that the cPLA2 signalling pathway was highly involved in the nephrotoxicity induced by berberrubine. We further confirmed that the direct target of berberrubine is the BASP1 protein (an upstream factor of cPLA2 signalling). Moreover, berberine alleviated nephrotoxicity by binding cPLA2 and inhibiting cPLA2 activation.CONCLUSION:
This study is the first to revel the opposite biological effects of berberine and its metabolite berberrubine in inducing kidney injury. Berberrubine, but not berberine, shows strong nephrotoxicity. The cPLA2 signalling pathway can be activated by berberrubine through targeting of BASP1, while berberine inhibits this pathway by directly binding with cPLA2. Our study paves the way for studies on the exact molecular targets of herbal ingredients. We also demonstrated that natural small molecules and their active metabolites can have opposite regulatory roles in vivo through the same signalling pathway.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Berberina
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Rim
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article