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A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ.

ABSTRACT: Berberine (BBR) exerts specific therapeutic effects on various diseases such as diabetes, obesity, and other inflammation-associated diseases. However, the low oral bioavailability (below 1%) of berberine due to its poor solubility and membrane permeability limits its clinical use. In this paper, we have prepared a 1:1 co-crystal berberine-ibuprofen (BJ) using drug salt metathesis and co-crystal technology. Pharmacokinetic studies demonstrate a 3-fold increase in vivo bioavailability of BJ compared to that of BBR, and BJ is more effective in treating obesity and its related metabolism in vitro and in vivo. We also find that BJ promotes mitochondrial biogenesis by inhibiting TBK1 and inducing AMP-activated protein kinase (AMPK) phosphorylation, and BJ increases adipocyte sensitivity to catecholamine by inhibiting IKKε. Together, our findings support that co-crystal BJ is likely to be an effective agent for treating obesity and its related metabolic diseases targeting TBK1 and IKKε.

SUBMITTER: Wang M

PROVIDER: S-EPMC9374667 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ.

Wang Man M Xu Rong R Liu Xiaoli X Zhang Ling L Qiu Siyan S Lu Yuting Y Zhang Peng P Yan Ming M Zhu Jing J

Communications biology 20220812 1

Berberine (BBR) exerts specific therapeutic effects on various diseases such as diabetes, obesity, and other inflammation-associated diseases. However, the low oral bioavailability (below 1%) of berberine due to its poor solubility and membrane permeability limits its clinical use. In this paper, we have prepared a 1:1 co-crystal berberine-ibuprofen (BJ) using drug salt metathesis and co-crystal technology. Pharmacokinetic studies demonstrate a 3-fold increase in vivo bioavailability of BJ compa ...[more]

PMID: 35962183

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Project description:Tumor metastasis is the major cause of death for prostate cancer (PCa) patients. However, the treatment options for metastatic PCa are very limited. Epithelial-mesenchymal transition (EMT) has been reported to be an indispensable step for tumor metastasis and is suggested to associate with acquisition of cancer stem cell (CSC) attributes. We propose that small-molecule compounds that can reverse EMT or induce mesenchymal-epithelial transition (MET) of PCa cells may serve as drug candidates for anti-metastasis therapy. Methods: The promoters of CDH1 and VIM genes were sub-cloned to drive the expression of firefly and renilla luciferase reporter in a lentiviral vector. Mesenchymal-like PCa cells were infected with the luciferase reporter lentivirus and subjected to drug screening from a 1274 approved small-molecule drug library for the identification of agents to reverse EMT. The dosage-dependent effect of candidate compounds was confirmed by luciferase reporter assay and immunoblotting. Wound-healing assay, sphere formation, transwell migration assay, and in vivo intracardiac and orthotopic tumor xenograft experiments were used to evaluate the mobility, metastasis and tumor initiating capacity of PCa cells upon treatment. Possible downstream signaling pathways affected by the candidate compound treatment were analyzed by RNA sequencing and immunoblotting. Results: Drug screening identified Amlexanox, a drug used for recurrent aphthous ulcers, as a strong agent to reverse EMT. Amlexanox induced significant suppression of cell mobility, invasion, serial sphere formation and in vivo metastasis and tumor initiating capacity of PCa cells. Amlexanox treatment led to downregulation of the IKK-ɛ/ TBK1/ NF-κB signaling pathway. The effect of Amlexanox on EMT reversion and cell mobility inhibition can be mimicked by other IKK-ɛ/TBK1 inhibitors and rescued by reconstitution of dominant active NF-κB. Conclusions: Amlexanox can sufficiently suppress PCa metastasis by reversing EMT through downregulating the IKK-ɛ/TBK1/NF-κB signaling axis.

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A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ.

Publications

A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ.

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