Berberine-Based Heterogeneous Linear Supramolecules Neutralized the Acute Nephrotoxicity of Aristolochic Acid by the Self-Assembly Strategy

Abstract

Aristolochic acid (AA) has been reported to cause a series of health problems, including aristolochic acid nephropathy and liver cancer. However, AA-containing herbs are highly safe in combination with berberine (Ber)-containing herbs in traditional medicine, suggesting the possible neutralizing effect of Ber on the toxicity of AA. In the present study, in vivo systematic toxicological experiments performed in zebrafish and mice showed that the supramolecule self-assembly formed by Ber and AA significantly reduced the toxicity of AA and attenuated AA-induced acute kidney injury. Ber and AA can self-assemble into linear heterogenous supramolecules (A–B) via electrostatic attraction and π–π stacking, with the hydrophobic groups outside and the hydrophilic groups inside during the drug combination practice. This self-assembly strategy may block the toxic site of AA and hinder its metabolism. Meanwhile, A–B linear supramolecules did not disrupt the homeostasis of gut microflora as AA did. RNA-sequence analysis, immunostaining, and western blot of the mice kidney also showed that A–B supramolecules almost abolished the acute nephrotoxicity of AA in the activation of the immune system and tumorigenesis-related pathways.

Research progress on self-assembled nanodrug delivery systems

“…This provides a new solution and promotes traditional Chinese medicine formulas of maximum clinical benefit. 120…”

Study on Supramolecules in Traditional Chinese Medicine Decoction

“…This structure blocks the toxic site of aristolochic acid and hinders its metabolism. Therefore, the supramolecules significantly reduce the toxicity of aristolochic acid and alleviate the acute kidney injury caused by it [ 31 ].…”

“… Schematic representation of the self-assembly mechanism of the berberine (Ber)-aristolochic acid (AA) supramolecular structure [ 31 ]. …”

Supramolecular assemblies based on natural small molecules: Union would be effective

“…The enhanced antibacterial activity was ascribed to the stronger affinity of external hydrophilic glucuronic acid in baicalin-berberine NPs to bacteria comparing with wogonoside-berberine nanofibers [ 87 ]. Similarly, a great deal of evidence supported that variety of phytochemicals rhein from Rheum palmatum L, cinnamic acid from Cinnamomi cortex , tannic acid from Rhei radix et rhizome , 3,4,5-methoxycinnamic acid from Polygalae radix and aristolochic acid in Asarum and Aristolochia all could be bound with berberine to form new self-assembled supramolecular systems in order to attain the goal of reducing the toxicity and increasing the effect of medicine [ [88] , [89] , [90] , [91] , [92] ]. Hence one can see that, berberine is an excellent model compound suppling electronic acceptor rest on N + , in correspondence with electronic donors such as carboxyl and phenolic hydroxyl groups inevitably resulting in electrostatic attraction.…”

“…On the one hand, the multicomponent supramolecular assemblies can straightforwardly promote the internal absorption and tissue-penetrating of active constituents to produce synergistic efficacy, via improving solubility, increasing cellular membrane permeability, inhibiting intestinal metabolism, and opening paracellular tight junction between enterocytes [ 144 ]. And on the other hand, the assembly mode may block the toxic site of some toxins and hinder their metabolism, or regulating key signaling pathways to reduce the risk of tissues damage and slow down the side effects [ 37 , 76 , 88 , 99 , 145 ]. Taken together, supramolecular assembly is supposed as the underlying mechanism to endow TCMs with impressive bioactivity and biosafety.…”