Background Combination therapy with multiple tyrosine kinase inhibitors (multi-TKIs) and immune checkpoint inhibitors (ICIs) has been increasingly tested in clinical studies. This study aimed to investigate the effect of the addition of ICI to multi-TKIs on the profile of treatment-related adverse events. Methods An electronic database search was performed using PubMed and Web of Science to identify published clinical studies on multi-TKI monotherapy and multi-TKI plus ICI combination therapy from July 20, 2005 to July 1, 2023. The incidence rate of common adverse events caused by multi-TKI monotherapy and multi-TKI plus ICI combination therapy was obtained and compared from the viewpoints of (1) relative risk for the combination therapy vs sunitinib, (2) adverse event incidence rate by clinical trial, and (3) pooled incidence rate. The quality of the evidence was assessed with the Cochrane risk of bias tool. Meta-analysis used random effects models. Results This systematic review identified 83 clinical studies involving 7951 patients. The combination therapy of multi-TKI and ICI was associated with an increased risk of diarrhea (relative risk [RR]: 1.24, 95% confidence interval [CI]: 1.15-1.33, P < .001), hypothyroidism (RR: 1.44, 95% CI: 1.11-1.87, P = .0064) and rash (RR: 1.71, 95% CI: 1.18-2.47, P = .0045) compared with multi-TKI monotherapy. The addition of ICI was suggested to decrease the risk of adverse events related to performance status. Conclusion Our study identified an increased risk of treatment-related adverse events associated with multi-TKI plus ICI combination therapy. This would help optimize the management of toxicities caused by multi-TKI plus ICI combination therapy.

01 Dec 2020·Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology

[Aldo-keto reductase 1 member B1 (AKR1B1) inhibits retinal ganglion cell activity via activating NF-κB pathway and inducing mouse BV-2 microglia activation].

Article

Author: Wang, Xin ; Bai, Qian ; Mao, Xu ; Hu, Dan

Objective To investigate the role and mechanism of aldo-keto reductase 1 member B1 (AKR1B1) in regulating microglial cell polarization and thereby regulating the activity of retinal ganglion cells (RGCs). Methods Lipopolysaccharide (LPS) was used to induce BV-2 polarization in microglia cells. AKR1B1 siRNA and inhibitor ponalrestat/Statil were used to treat BV-2 cells, and the effect of AKR1B1 on cell polarization was identified through morphology and inflammatory cytokine expression detection, including tumor necrosis factor α(TNF-α), interleukin 1β(IL-1β), cyclooxygenase 2(COX2), and inducible nitric oxide synthase(iNOS). Primary RGCs were cultured with the indicated BV-2 conditional medium. The activity of RGCs was detected by brain-specific homeobox protein 3a (Brn-3a) immunofluorescence staining, and apoptosis was observed by TUNEL staining. The expression of phosphorylated IKK and p65 in the nucleus were detected by Western blotting. Results LPS induced M1-type polarization of BV-2 cells, while its conditioned medium induced decreased RGC activity and increased apoptosis. Inhibition of AKR1B1 blocked M1 type polarization of BV-2 cells and restored RGC activity. Inhibition of AKR1B1 can block LPS-induced IKK phosphorylation and NF-κBp65 nuclear localization. Conclusion AKR1B1 can induce microglial activation by activating NF-κB pathway, which in turn inhibit the activity and promote apoptosis of RGCs.

01 Dec 2019·Journal of Biological Chemistry

A phenotype-directed chemical screen identifies ponalrestat as an inhibitor of the plant flavin monooxygenase YUCCA in auxin biosynthesis

Article

Author: He, Wenrong ; Guo, Hongwei ; Su, Qi ; Jiang, Kai ; Zhu, Ying ; Li, Hong-Jiang ; Wang, Yuefan ; Xie, Yinpeng ; Song, Wen ; Wen, Jing ; Yang, Zhen

Plant development is regulated by both synergistic and antagonistic interactions of different phytohormones, including a complex crosstalk between ethylene and auxin. For instance, auxin and ethylene synergistically control primary root elongation and root hair formation. However, a lack of chemical agents that specifically modulate ethylene or auxin production has precluded precise delineation of the contribution of each hormone to root development. Here, we performed a chemical genetic screen based on the recovery of root growth in ethylene-related Arabidopsis mutants with constitutive "short root" phenotypes (eto1-2 and ctr1-1). We found that ponalrestat exposure recovers root elongation in these mutants in an ethylene signal-independent manner. Genetic and pharmacological investigations revealed that ponalrestat inhibits the enzymatic activity of the flavin-containing monooxygenase YUCCA, which catalyzes the rate-limiting step of the indole-3-pyruvic acid branch of the auxin biosynthesis pathway. In summary, our findings have identified a YUCCA inhibitor that may be useful as a chemical tool to dissect the distinct steps in auxin biosynthesis and in the regulation of root development.

100 Deals associated with Ponalrestat

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KEGG	Wiki	ATC	Drug Bank
D03806	-	-	-

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