Organic anion transporting polypeptide 1B1 (OATP1B1), the hepatic-specific uptake transporter, plays key roles in the absorption, distribution, and excretion of a broad range of endogenous and exogenous compounds. Altered expression and function of OATP1B1 affect the bioavailability and pharmacokinetics of various clinically important drugs. In this study, OATP1B1 uptake function was found to be significantly suppressed by SRC proto-oncogene, non-receptor tyrosine kinase family kinase inhibitors, with SU6656 demonstrating the most potent inhibitory effect. Knockdown and overexpression experiments revealed that YES1 is the specific SRC proto-oncogene, non-receptor tyrosine kinase family kinase responsible for regulating OATP1B1. Further, YES1 was found to interact with OATP1B1, and the tyrosine phosphorylation status of the transporter was suppressed by both the SU6656 treatment and the knockdown of the tyrosine kinase. Moreover, Caveolin 1 (CAV-1), the oligomeric scaffolding protein, was found to interact with OATP1B1. CAV-1 knockdown significantly suppressed the uptake function of OATP1B1. Although the reduction of CAV-1 did not affect the interaction between YES-1 and the transporter, it affected the phosphorylation level of OATP1B1. Immunofluorescence analysis indicated that CAV-1 colocalized with OATP1B1, and the disruption of lipid rafts significantly reduced the association of CAV-1 with OATP1B1, suggesting that the integrity of lipid rafts is essential for the effect of CAV-1 on OATP1B1. In conclusion, YES1 was identified as a regulator for OATP1B1. The tyrosine kinase physically interacts with OATP1B1, and the conformation that facilitates the phosphorylation of OATP1B1 by YES1 is likely maintained by CAV-1. SIGNIFICANCE STATEMENT: The present study found that YES-1 regulates the function of organic anion transporting polypeptide 1B1 (OATP1B1) by interacting with the transporter and influencing its tyrosine phosphorylation status. Caveolin-1 was shown to interact with OATP1B1 as well. Abrogation of Caveolin-1 exhibited no effect on the interaction between YES-1 and OATP1B1 but reduced the phosphorylation level of the transporter. Taken together, inhibitors of YES-1 may alter the uptake function of OATP1B1, potentially leading to drug-drug interactions related to post-translational modification.

2025-07-01·Lupus Science & Medicine

Mesenchymal stem cells improve ovarian function by suppressing fibrosis through CTGF/FAK signalling in systemic lupus erythematosus

Article

作者: Wu, Yingyi ; Chen, Hongwei ; Sun, Lingyun ; Shi, Yirui ; Zhang, Haiwei ; Zhang, Yueyang ; Xu, Min ; Yang, Hui

Objective:

SLE is a multisystem autoimmune disease characterised by chronic inflammation and progressive organ damage, including ovarian dysfunction. This study investigated the therapeutic efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) in ameliorating ovarian impairment and restoring ovarian function through the inhibition of fibrosis in a lupus mouse model.

Methods:

Serum levels of sex hormones were quantified via ELISA. Ovarian tissue samples were histologically evaluated for follicle count and fibrosis via H&E and Masson’s trichrome staining. Quantitative reverse-transcriptase-PCR, western blot, immunofluorescence and immunohistochemistry were employed to evaluate inflammatory cytokines, fibrotic factors, hormone receptors and signalling proteins. Primary granulosa cells (GCs) isolated from lupus mice (MRL/lpr) were cocultured with MSCs and the expression of fibrotic factors was analysed by western blot. Additionally, a human GC line (KGN) was used to further explore the relationships among connective tissue growth factor (CTGF), focal adhesion kinase (FAK)/FAK-Tyr576/577 phosphorylation and fibrosis. This was achieved through stimulation with recombinant CTGF, the CTGF antagonist FG-3019 or the FAK inhibitor SU6656.

Results:

UC-MSC transplantation significantly downregulated the expression of proinflammatory cytokines ( Tnf-α , Il-1β ) and fibrotic markers ( Ctgf , α-Sma ) while upregulating the expression of key hormone receptors ( Amh , Esr1 , Esr2 ). Additionally, a reduction in CD3 + /CD4 + T-cell infiltration, C3 complement deposition and IgG levels was observed, accompanied by an increase in regulatory T cells. Further analysis revealed that fibrotic markers and FAK-Tyr576/577 phosphorylation were markedly suppressed in primary ovarian GCs following MSC transplantation. In vitro experiments demonstrated that recombinant CTGF promoted fibrogenesis in the human GC line KGN. Conversely, MSC treatment inhibited phosphorylated FAK-Tyr576/577 and downregulated the expression of Collagen 1 and α-SMA, suggesting that UC-MSCs alleviate ovarian fibrosis by suppressing FAK-Tyr576/577 phosphorylation.

Conclusion:

This study demonstrated that UC-MSC treatment ameliorated ovarian dysfunction and attenuated ovarian fibrosis in lupus mice by modulating the CTGF/FAK-Tyr576/577 phosphorylation pathway.

2025-02-13·JOURNAL OF MEDICINAL CHEMISTRY

Small Molecule Modulators of AMP-Activated Protein Kinase (AMPK) Activity and Their Potential in Cancer Therapy

Review

作者: Reigan, Philip ; Nguyen, Vu T. ; Astridge, Daniel D. ; Strang, Juliet E.

AMP-activated protein kinase (AMPK) is a central mediator of cellular metabolism and is activated in direct response to low ATP levels. Activated AMPK inhibits anabolic pathways and promotes catabolic activities that generate ATP through the phosphorylation of multiple target substrates. AMPK is a therapeutic target for activation in several chronic metabolic diseases, and there is increasing interest in targeting AMPK activity in cancer where it can act as a tumor suppressor or conversely it can support cancer cell survival. Small molecule AMPK activators and inhibitors have demonstrated some success in suppressing cancer growth, survival, and drug resistance in preclinical cancer models. In this perspective, we summarize the role of AMPK in cancer and drug resistance, the influence of the tumor microenvironment on AMPK activity, and AMPK activator and inhibitor development. In addition, we discuss the potential importance of isoform-selective targeting of AMPK and approaches for selective AMPK targeting in cancer.

100 项与 SU6656 相关的药物交易

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