BIOPHARMACEUTICS & DRUG DISPOSITION
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2020
·Vol. 41
·期 6
·231-238
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IF 1.663
Zhe Wang,Xiaoyu Wang,Yaqin Jia,Hang Yin,Yuyi Feng,Lili Jiang,Jun Cao,Yong Liu
Cancer therapy with tyrosine kinase inhibitors (TKIs) is a rapidly developing field, and several TKIs have been reported to have an impact on the activities of UDP-glucosyltransferases (UGTs), implying a potential risk for drug–drug interaction (DDI). Herein, we investigated the inhibitory effects of two commonly used TKIs, midostaurin and ruxolitinib, on human UGTs and quantitatively evaluated their DDI potential via UGT inhibition. It was found that midostaurin was a potent inhibitor of the majority of human UGTs, including UGT1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17, with IC 50 values lower than 4 μM (IC 50 0.0128–3.85 μM), while ruxolitinib exhibited weak inhibition towards the activity of almost all the tested UGT isoforms. Furthermore, based on reversible inhibition, the co-administration of midostaurin at the clinical available dose was predicted to increase the plasma exposure to sensitive UGT1A3, 1A7, and 1A8 substrates by at least 61.4%, 25.6%, and 651%, respectively. In summary, our data identify that midostaurin is a potent inhibitor of the majority of human UGTs and may bring a potential risk of DDI via inhibition against UGT1A3, 1A7, and 1A8, while ruxolitinib cannot trigger UGT-mediated DDI due to its weak inhibition towards UGTs.
研究领域:
药理学
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癌症治疗
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临床药学
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
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IF 4.2
He Li,Peipei Meng,Yuhang Meng,Yige Yang,Wensheng Zheng,Hongdong Huang,Zhigang Zhao
Renal fibrosis represents a critical pathological hallmark in progressive chronic kidney disease (CKD), yet effective therapeutic strategies remain elusive. Emerging evidence suggests that impaired mitophagy contributes to its pathogenesis. This study investigated whether ruxolitinib alleviates renal fibrosis by enhancing PINK1/Parkin-mediated mitophagy. Network pharmacology was employed to explore the potential regulatory mechanisms of ruxolitinib in renal fibrosis treatment, revealing that ruxolitinib might exert therapeutic effects through modulation of inflammation, oxidative stress and mitophagy. Subsequent in vivo and in vitro studies demonstrated that ruxolitinib treatment not only attenuated renal fibrosis progression but also reduced inflammatory responses and oxidative stress while enhancing mitophagic activity. Mechanistically, the enhancement of mitochondrial autophagy and the amelioration of renal fibrosis by ruxolitinib might be mediated via the PINK1/Parkin pathway. These results suggest that ruxolitinib may ameliorate renal fibrosis by activating PINK1/Parkin-mediated mitophagy, providing new perspectives for CKD therapeutic development.
研究领域:
药理学
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细胞生物学
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肾脏病学
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PubMed
高影响因子
Annals of Translational Medicine
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2020
·
IF 3.297
Li Li,Xingfeng He,Xingtong Wang,Yu Sun,Guosheng Wu,He Fang,Chen Wang,Pengfei Luo,Zhaofan Xia
Background Ruxolitinib is an inhibitor of Janus kinases (JAK) 1/2. It was authorised recently by the U.S. Food and Drug Administration (FDA) as a new Myelofibrosis treatment. In this study, we identified ruxolitinib as a new inhibitor of nitric oxide (NO) production in response to lipopolysaccharide (LPS)stimulation of RAW 264.7 cells. Methods In vitro direct effects of ruxolitinib were determined through NO production on RAW 264.7 cells. Also the expression level of iNOS, TNF-α and IL-6 were detected by Western Blotting and qRT-PCR. In vivo therapeutic effects of ruxolitinib on sepsis were evaluated by an endotoxemia model with C57 mice. The survival was calculated and histopathological damage of organs was observed by HE. Cytokines in serum were detected by Mouse Cytokine Array Panel. Results Ruxolitinib was found to significantly reduce NO production, inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 expression, suggesting that ruxolitinib blocks LPS signaling that leads to pro-inflammatory factor expression. Furthermore, the inhibitory effects of ruxolitinib contributed to the survival of septic mice by 70% and pro-inflammatory cytokines in serum declined apparently. The results taken together indicate that ruxolitinib can significantly suppress LPS-stimulated NO production and improve the survival of septic mice, perhaps by interfering with the NF-κB pathway. Conclusions These findings suggest ruxolitinib might be a possible therapeutic candidate for sepsis therapy.
研究领域:
药理学
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免疫学
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传染病学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Qiao Zeng,Xu Chen,Xinghao Chen,Wenying Yu,Qiao Wang,Zhan Tang
Novel in situ Ru gel improved Ru solubility, bioavailability, and retention. • Ru gel enhanced aqueous humor exposure by 5.14-fold and extended ocular retention. • Ru gel promoted corneal epithelial migration under hyperosmotic stress. • Ru gel suppressed inflammation, exhibiting dual therapeutic effects. The local delivery of JAK inhibitors for dry eye disease (DED) remains challenging due to poor drug solubility and rapid ocular clearance. This study reports an ion-sensitive in situ gelling system for ruxolitinib (Ru) using polyvinylpyrrolidone-K12 and gellan gum to enhance solubility and ocular retention. The optimized Ru gel exhibited shear-thinning behavior and rapid ion-activated gelation. In vitro permeation studies indicated that the gel matrix did not impede Ru diffusion. In scratch assays and Transwell assays performed under hypertonic stress conditions, the Ru gel demonstrated a more pronounced pro-migratory effect on cells within the scratch assay. This observation may indicate variations in the gel matrix's mechanism of action across different cellular migration patterns. Pharmacokinetic evaluation in rabbits demonstrated a 5.14-fold increase in aqueous humor exposure (AUC) compared with Ru solution, without significantly altering T max , MRT, or t 1/2 , suggesting that enhanced efficacy stems from prolonged precorneal retention rather than improved corneal penetration. In a benzalkonium chloride-induced rat DED model, the Ru gel significantly restored tear secretion, prolonged tear film break-up time, and repaired corneal integrity to levels comparable to healthy controls. While blank gel provided physical protection and reduced pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) possibly through lubrication and barrier effects, Ru-loaded gel uniquely promoted histological recovery of corneal epithelium and conjunctival goblet cells. These findings demonstrate that the engineered Ru gel is a safe and potent therapeutic platform that enhances ocular exposure and mitigates inflammation through prolonged retention and pharmacological repair, offering a promising strategy for DED management. Download: Download high-res image (256KB) Download: Download full-size image
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高影响因子
CHEMBIOCHEM
·
2021
·Vol. 23
·期 5
·e202100589
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IF 3.164
Yunfeng Cui,Liangyan Zhu,Xi Chen,Jinhui Feng,Qiaqing Wu,Dunming Zhu
Graphical Rational engineering of the carbonyl reductase PhADH resulted in a double mutant H93C/A139L, which enhanced the enantioselectivity toward the reduction of 3-cyclopentyl-3-ketopropanenitrile 1 a from 85 % to 99 %, as well as a 6-fold improvement in the specific activity. ( S )-3-Cyclopentyl-3-hydroxypropanenitrile (( S )- 1 b ) was prepared at 200 g/L (1.5 M) substrate concentration. ( S )-3-Cyclopentyl-3-hydroxypropanenitrile is the key precursor for the synthesis of ruxolitinib. The bioreduction of 3-cyclopentyl-3-ketopropanenitrile ( 1 a ) offers an attractive method to access this important compound. A carbonyl reductase (PhADH) from Paraburkholderia hospita catalyzed the reduction of 1 a giving the ( S )-alcohol ( 1 b ) with 85 % ee. Rational engineering of PhADH resulted in a double mutant H93C/A139L, which enhanced the enantioselectivity from 85 % to >98 %, as well as a 6.3-fold improvement in the specific activity. The bioreduction of 1 a was performed at 200 g/L (1.5 M) substrate concentration, leading to isolation of ( S )- 1 b in 91 % yield. Similarly, using this mutant enzyme, 3-cyclohexyl-3-ketopropanenitrile ( 2 a ) and 3-phenyl-3-ketopropanenitrile ( 3 a ) were reduced at high concentration affording the corresponding alcohols in >99 % ee, and 90 % and 92 % yield, respectively. The results showed that the variant H93C/A139L was a powerful biocatalyst for reduction of β-substituted-β-ketonitriles.
研究领域:
生物化学
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药物化学
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合成生物学
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高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Qi Chen,Yue Zhou,Xudong Zhu,Lei Xu,Ge Bai,Yaru Zhou,Nannan Zhang,Hongwen Liu,Yani Pan,Yu Liu,Lishan Wang,Xueni Fu,Jingjing Wei,Lina Zhou,Lu Xu,Yuxiang Sun,Zhangding Wang,Shanshan Shen,Yun Zhu,Lei Wang
Tumor-associated neutrophils (TANs), particularly the N2 phenotype, contribute to T cell exhaustion in cholangiocarcinoma (CCA), leading to low response rates to PD-1 inhibitor therapy. To address this issue, cancer-associated fibroblast (CAF)-derived extracellular vesicles loaded with ruxolitinib (CEVs@Ru) are developed to selectively target and reprogram N2 TANs, thereby modulating the immunosuppressive tumor microenvironment (TME). The combination of CEVs@Ru with anti-PD-1 antibody therapy significantly enhanced antitumor efficacy, reducing tumor weight by 89.86% and normalizing liver weight, without significant adverse effects. This approach improved the local concentration of ruxolitinib, increased CD8+ T cell infiltration, and reduced regulatory T cells, indicating a remodeled TME conducive to effective antitumor immunity. The findings provide a promising strategy for enhancing PD-1 inhibitor efficacy and improving patient outcomes in CCA and potentially other solid tumors.
研究领域:
肿瘤学
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免疫学
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药理学
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高影响因子
MICROCHEMICAL JOURNAL
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2026
·
IF 5.2
Wenzhan Yu,Minjin Wu,Jiamin Xie,Zihao Huang,Xiaoping Wei,Jianping Li
A MIP-ECL sensor was developed for the dual-potential resolved simultaneous detection of RUX and LEN. • The combining dummy template imprinting with probes click-labeling enables simultaneous detection of signal-free analytes. • This strategy provides a new detection platform for therapeutic drug monitoring in combination therapy. Combination therapy is widely used in clinics to improve efficacy and reduce side effects by administering two or more drugs for personalized precise dosing. For the combination therapy of ruxolitinib (RUX) and lenalidomide (LEN) in primary myelofibrosis treatment, therapeutic drug monitoring (TDM) of both drugs in blood is required. This paper presents the development of a molecularly imprinted (MIP) electrochemiluminescence (ECL) sensor for the simultaneous detection of RUX and LEN. To address the challenge that neither RUX nor LEN generates ECL signals on electrodes, a dummy template molecule with terminal allyl groups, structurally similar to RUX, was designed to copolymerize with LEN for the preparation of the MIP film. A novel strategy based on dummy template competitive adsorption and photo-initiated click reactions was developed for simultaneous determination of RUX and LEN. It relies on the competitive adsorption between RUX and its dummy template on MIP, followed by click labeling of two ECL probes onto the dummy template and LEN, with detection of RUX and LEN achieved by recording the cathodic and anodic ECL signals, respectively. The MIP-ECL sensor exhibits a detection range of 5 to 5000 ng/mL for both RUX and LEN, with detection limits of 0.11 ng/mL and 0.49 ng/mL, respectively. The sensor was successfully applied to the analysis of human serum samples. It not only provides a novel approach for the detection of multiple targets without responding signals using MIP, but also offers a more sensitive and convenient technical platform for TDM. An MIP-ECL sensor combining dummy-template imprinting with probe click-labeling was developed for the potential-resolved simultaneous detection of ruxolitinib and lenalidomide. This strategy overcomes the challenge of simultaneously detecting signal-free analytes and amplifies detection signals, improving sensitivity with LODs of 0.11 ng/mL for ruxolitinib and 0.49 ng/mL for lenalidomide. Download: Download high-res image (193KB) Download: Download full-size image
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高影响因子
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