ABSTRACT
Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics; however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction. In this study, the expression of TfR1, a ferroptosis biomarker, was upregulated in the outer hair cells of cisplatin-treated mice. Moreover, several key ferroptosis regulator genes were altered in cisplatin-damaged cochlear explants based on RNA sequencing, implying the induction of ferroptosis. Ferroptosis-related Gpx4 and Fsp1 knockout mice were established to investigate the specific mechanisms associated with ferroptosis in cochleae. Severe outer hair cell loss and progressive damage of synapses in inner hair cells were observed in Atoh1-Gpx4-/- mice. However, Fsp1-/- mice showed no significant hearing phenotype, demonstrating that Gpx4, but not Fsp1, may play an important role in the functional maintenance of HCs. Moreover, findings showed that FDA-approved luteolin could specifically inhibit ferroptosis and alleviate cisplatin-induced ototoxicity through decreased expression of transferrin and intracellular concentration of ferrous ions. This study indicated that ferroptosis inhibition through the reduction of intracellular ferrous ions might be a potential strategy to prevent cisplatin-induced hearing loss.
Subject(s)
Cisplatin , Ferroptosis , Hearing Loss , Mice, Inbred C57BL , Mice, Knockout , Phospholipid Hydroperoxide Glutathione Peroxidase , Animals , Cisplatin/adverse effects , Ferroptosis/drug effects , Ferroptosis/genetics , Mice , Hearing Loss/chemically induced , Hearing Loss/genetics , Hearing Loss/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Disease Models, Animal , Receptors, Transferrin/metabolism , Receptors, Transferrin/genetics , Reactive Oxygen Species/metabolism , Lipid Peroxidation/drug effects , Hair Cells, Auditory, Outer/metabolism , Hair Cells, Auditory, Outer/drug effects , Hair Cells, Auditory, Outer/pathology , Ototoxicity/etiology , Ototoxicity/metabolism , Antineoplastic Agents/adverse effects , Apoptosis/drug effectsABSTRACT
Boric acid, a well-established chemical insecticide, has a good control effect on various types of cockroaches. In this study, we investigated the oral virulence effect of boric acid on German cockroach (Blattella germanica) of various instars and characterized its effect on the gut microbiota by high-throughput sequencing technology. The results of an oral toxicity test showed that the toxicity of boric acid was positively correlated with its concentration and negatively correlated with the instar of cockroach nymphs. The 1-3 instar nymphs showed the strongest sensitivity to boric acid, which exhibited a median lethal time of only 3.16 d, while the 6-7 instar nymphs showed the weakest sensitivity, and exhibited a median lethal time of 10.15 d. There was no significant difference between male and female insects regarding their sensitivity to boric acid. Oral treatment of boric acid resulted in severe dysbiosis in cockroaches, the relative abundances of Bacteroides, which can degrade a variety of complex macromolecules, and Enterococcus, which can inhibit pathogenic microorganisms, were significantly reduced, while the relative abundance of the opportunistic pathogenic bacterium Weissella was significantly increased. It was speculated that dysbiosis of gut microbiota might accelerate the toxicity of boric acid on German cockroaches.
Subject(s)
Blattellidae , Gastrointestinal Microbiome , Insecticides , Animals , Boric Acids/toxicity , Cockroaches , Dysbiosis , Female , Insecticides/toxicity , MaleABSTRACT
(1) Background: The widespread use of insecticides has cause extensive resistance in German cockroach (Blattella germanica) populations globally. Biological control has the potential to mitigate insecticide resistance, and Metarhizium anisopliae (Meschn.) Sorokin, an entomopathogenic fungus, alone and in combination with various insecticides, has shown good effects against cockroaches. (2) Methods: This experiment compared the cumulative mortality after infecting B. germanica with M. anisopliae conidia by two routes, per os and topical application. To probe the mechanisms that underlie the synergism between M. anisopliae and hydramethylnon, we conducted dose-response assays with cockroaches fed combinations of M. anisopliae and hydramethylnon and characterized the gut microbiomes of the treated cockroaches. (3) Results: The study showed that the mortality with per os infection was lower than that with topical application. In addition, the combination of M. anisopliae and hydramethylnon had a synergistic effect in 16 treatments. The gut microbiome was also altered by hydramethylnon treatment. The abundance of Parabacteroides and Enterococcus declined with the hydramethylnon and combination treatments, which are known to have anti-inflammatory and antifungal activities. The abundance of Alistipes, which is a fungal cell wall component, significantly increased in these treatments. (4) Conclusions: Therefore, we speculate that the major mechanism underlying this synergism is hydramethylnon promoting the survival of M. anisopliae in the harsh gut environment and enhancing its virulence for German cockroaches by altering the gut microbiome. This may provide a method for the fight against B. germanica and lay the foundation for the development of new baits.
