作者: Goda, Mitsuhiro ; Moriyama, Daishi ; Zamami, Yoshito ; Niimura, Takahiro ; Takahashi, Shimon ; Ishizawa, Keisuke ; Sonoda, Yuhei ; Aizawa, Fuka ; Yagi, Kenta ; Hamano, Hirofumi ; Kajimoto, Haruna ; Shibata, Takahiro ; Okabayashi, Ami ; Kawada, Kei ; Izawa-Ishizawa, Yuki

Some therapeutic agents have been found to have effects beyond their primary indications. Peripheral neuropathy, a common side effect of chemotherapy, remains inadequately treated. Identifying additional properties of existing medications could thus uncover novel therapeutic avenues. Previous studies have identified an additional effect of simvastatin in reducing neuropathy; however, the mechanism underlying this effect remains unclear. We investigated the novel effects of statins on chemotherapy-induced peripheral neuropathy in mice. Mice treated with oxaliplatin or paclitaxel did not show exacerbation or improvement in cold sensations upon acetone testing with statin administration. However, concurrent oral statin treatment mitigated the nociceptive response to mechanical stimuli induced by each anti-tumor agent. Co-administration of a glutathione S-transferase inhibitor, which modulates redox reactions, abolished the ameliorative effect of statins on mechanical nociceptive behavior. Additionally, the glutathione S-transferase inhibitor did not affect normal sensory perception or impair the anti-tumor effect of chemotherapy agents. A search for GST-associated molecules and pathways using artificial intelligence revealed that GST regulates inflammatory cytokines as a regulatory or causative gene. Our findings suggest that statins have class effects that ameliorate cytotoxic anti-cancer drug-induced mechanical allodynia via GST pathway activation.

2024-03-01·Pesticide Biochemistry and Physiology

The Cys-2088-Arg mutation in the ACCase gene and enhanced metabolism confer cyhalofop-butyl resistance in Chinese sprangletop (Leptochloa chinensis)

Article

作者: Liao, Min ; Jiang, Minghao ; Hu, Wei ; Zhao, Ning ; Cao, Haiqun ; Wang, Xumiao

Acetyl-CoA carboxylase (ACCase)-inhibiting herbicides are among the most commonly used herbicides to control grassy weeds, especially Leptochloa chinensis, in rice fields across China. Herein, we collected a suspected resistant (R) population of L. chinensis (HFLJ16) from Lujiang county in Anhui Province. Whole plant dose response tests showed that, compared with the susceptible (S) population, the R population showed high resistance to cyhalofop-butyl (22-fold) and displayed cross-resistance to metamifop (9.7-fold), fenoxaprop-P-ethyl (18.7-fold), quizalofop-P-ethyl (7.6-fold), clodinafop-propargyl (12-fold) and clethodim (8.4-fold). We detected an amino acid substitution (Cys-2088-Arg) in the ACCase of resistant L. chinensis. However, ACCase gene expression levels were not significantly different (P > 0.05) between R plants and S plants, without or with cyhalofop-butyl treatment. Furthermore, pretreatment with piperonyl butoxide (PBO, a cytochrome P450 monooxygenase (CYP450) inhibitor) or 4-chloro-7-nitrobenzoxadiazole (NBD-Cl, a glutathione-S-transferase (GST) inhibitor), inhibited the resistance of the R population to cyhalofop-butyl significantly (by approximately 60% and 26%, respectively). Liquid chromatography tandem mass spectrometry analysis showed that R plants metabolized cyhalofop-butyl and cyhalofop acid (its metabolite) significantly faster than S plants. Three CYP450 genes, one GST gene, and two ABC transporter genes were induced by cyhalofop-butyl and were overexpressed in the R population. Overall, GST-associated detoxification, CYP450 enhancement, and target-site gene mutation are responsible for the resistance of L. chinensis to cyhalofop-butyl.

2023-08-01·Pest management science

Metamifop resistance in Echinochloa glabrescens via glutathione S-transferases-involved enhanced metabolism.

Article

作者: Jiang, Minghao ; Li, Qi ; Liao, Min ; Cao, Haiqun ; Wang, Mali ; Zhao, Ning ; Zhang, Jingxu

BACKGROUNDEchinochloa glabrescens Munro ex Hook. f. is one of the main Echinochloa spp. seriously invading Chinese rice fields and has evolved resistance to commonly used herbicides. Previously, an E. glabrescens population (LJ-02) with suspected resistance to the acetyl-CoA carboxylase (ACCase)-inhibiting herbicide metamifop was collected. This study aimed to determine its resistance status to metamifop and investigate the internal molecular mechanisms of resistance.RESULTSSingle-dose testing confirmed that the LJ-02 population had evolved resistance to metamifop. Gene sequencing and a relative expression assay of ACCase ruled out target-site based resistance to metamifop in LJ-02. Whole-plant bioassays revealed that, compared with the susceptible population XZ-01, LJ-02 was highly resistant to metamifop and exhibited cross-resistance to fenoxaprop-P-ethyl. Pretreatment with the known glutathione S-transferase (GST) inhibitor, 4-chloro-7-nitrobenzoxadiazole (NBD-Cl), largely reversed the resistance to metamifop by approximately 81%. Liquid chromatography-tandem mass spectrometry analysis indicated that the metabolic rates of one of the major metabolites of metamifop, N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide (HPFMA), were up to 383-fold faster in LJ-02 plants than in XZ-01 plants. There were higher basal and metamifop-inducible GST activities toward 1-chloro-2,4-dinitrobenzene (CDNB) in LJ-02 than in XZ-01. Six GST genes were metamifop-induced and overexpressed in the resistant LJ-02 population.CONCLUSIONThis study reports, for the first time, the occurrence of metabolic metamifop resistance in E. glabrescens worldwide. The high-level metamifop resistance in the LJ-02 population may mainly involve specific isoforms of GSTs that endow high catalytic activity and strong substrate specificity. © 2023 Society of Chemical Industry.

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