Olaquindox (OLA) has been widely used as an animal feed additive in China for decades; however, its toxicity and toxic mechanisms have not been well investigated. In this study, the developmental neurotoxicity and toxic mechanisms of OLA were evaluated in zebrafish. Zebrafish embryos were exposed to different concentrations of OLA (25-1,000 mg/L) from 6 to 120 hours post fertilization (hpf). OLA exposure resulted in many abnormal phenotypes in zebrafish, including shortened body length, notochord degeneration, spinal curvature, brain apoptosis, damage of axon and peripheral motor neuron, and hepatotoxicity. Interestingly, OLA increased zebrafish spontaneous tail coiling, while reduced locomotor capacity. Quantitative polymerase chain reaction (Q-PCR) showed that the expression levels of nine marker genes for nervous system functions or development, namely, α1-tubulin, glial fibrillary acidic protein (gfap), myelin basic protein (mbp), synapsinII a (syn2a), sonic hedgehog a (shha), encoding HuC (elavl3), mesencephalic astrocyte-derived neurotrophic factor (manf) growth associated protein 43 (gap43), and acetylcholinesterase (ache) were all down-regulated significantly in zebrafish after treated with OLA. Besides, the antiapoptotic and pro-apoptotic genes bcl-2/bax ratio was reduced. These results show that OLA exposure could cause severe developmental neurotoxicity in the early stages of zebrafish life and OLA might induce neurotoxicity by inhibiting the expression of neuro-developmental genes and promoting apoptosis.
Tripterygium wilfordii Hook F. (TWHF) is a Chinese traditional medicine with cardiac toxicities. However, the mechanism of acute cardiac toxicity is not very clear. By using patch clamp techniques, we found that 0.05 mg/ml and 0.1 mg/ml of the aqueous crude extract of TWHF inhibit 21.4 ± 1.6% and 86.7 ± 5.7% (n = 5) of hERG current Amplitudes (IhERG) respectively. We further found that Celastrol, one of main components of TWHF, inhibits hERG with an IC50 of 0.83 μM. Additional mutagenesis studies show that mutations of T623A, S624A and F656A significantly alter the inhibition and S624A has the strongest effect, supported by our docking model. Our data suggest that inhibition of hERG channel activity by Celastrol contributed to TWHF cardiotoxicity.
The lower respiratory tract infection, induced by influenza virus, coronaviruses, and respiratory syncytial virus, remains a serious threat to human health that can cause a global pandemic. Thus, finding effective chemicals and therapeutic measures to advance the functional restoration of the respiratory tract after infection has been the emphasis of the studies on the subjects. Mosla scabra is a natural medicinal plant used for treating various lung and gastrointestinal diseases, including viral infection, cough, chronic obstructive pulmonary disease, acute gastroenteritis, and diarrhoea. In this study, the antiviral and anti-inflammatory effects of total lignans (MSTL) extracted from the plant were investigated in influenza A virus (IAV)-infected mice and RAW 264.7 macrophages. MSTL could not only protect the macrophages against IAV-induced pyroptosis but also could lighten the lung inflammation induced by IAV in vivo and in vitro. The network pharmacology analysis revealed that differentially expressed genes, mainly involving in EGFR tyrosine kinase inhibitor resistance, endocrine resistance, HIF-1 signaling pathway, C-type lectin receptor signaling pathway, and FOXO signaling pathway, contributed to the IAV-induced alveolar macrophage dysfunction. It indicated that MSTL enhanced the function of alveolar macrophages and improved IAV-induced lung injury in mice.
2-Aminoethoxydiphenyl borate (2-APB), a boron-containing compound, is a multitarget compound with potential as a drug precursor and exerts various effects in systems of the human body. Ion channels are among the reported targets of 2-APB. The effects of 2-APB on voltage-gated potassium channels (KV) have been reported, but the types of KV channels that 2-APB inhibits and the inhibitory mechanism remain unknown. In this paper, we discovered that 2-APB acted as an inhibitor of three representative human KV1 channels. 2-APB significantly blocked A-type Kv channel KV1.4 in a concentration-dependent manner, with an IC50 of 67.3 μM, while it inhibited the delayed outward rectifier channels KV1.2 and KV1.3, with IC50s of 310.4 μM and 454.9 μM, respectively. Further studies on KV1.4 showed that V549, T551, A553, and L554 at the cavity region and N-terminal played significant roles in 2-APB’s effects on the KV1.4 channel. The results also indicated the importance of fast inactivation gating in determining the different effects of 2-APB on three channels. Interestingly, a current facilitation phenomenon by a short prepulse after 2-APB application was discovered for the first time. The docked modeling revealed that 2-APB could form hydrogen bonds with different sites in the cavity region of three channels, and the inhibition constants showed a similar trend to the experimental results. These findings revealed new molecular targets of 2-APB and demonstrated that 2-APB’s effects on KV1 channels might be part of the reason for the diverse bioactivities of 2-APB in the human body and in animal models of human disease.
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