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Amanita phalloides is one of the deadliest mushrooms worldwide, causing most fatal cases of mushroom poisoning. Among the poisonous substances of Amanita phalloides , amanitins are the most lethal toxins to humans. Currently, there are no specific antidotes available for managing amanitin poisoning and treatments are lack of efficacy. Amanitin mainly causes severe injuries to specific organs, such as the liver, stomach, and kidney, whereas the lung, heart, and brain are hardly affected. However, the molecular mechanism of this phenomenon remains not understood. To explore the possible mechanism of organ specificity of amanitin-induced toxicity, eight human cell lines derived from different organs were exposed to α, β, and γ-amanitin at concentrations ranging from 0.3 to 100 μM. We found that the cytotoxicity of amanitin differs greatly in various cell lines, among which liver-derived HepG2, stomach-derived BGC-823, and kidney-derived HEK-293 cells are most sensitive. Further mechanistic study revealed that the variable cytotoxicity is mainly dependent on the different expression levels of the organic anion transporting polypeptide 1B3 (OATP1B3), which facilitates the internalization of amanitin into cells. Besides, knockdown of OATP1B3 in HepG2 cells prevented α-amanitin-induced cytotoxicity. These results indicated that OATP1B3 may be a crucial therapeutic target against amanitin-induced organ failure. [Display omitted] • The cytotoxicity of amanitins differs greatly in various human cell lines. • The variable cytotoxicity is mainly due to different expression levels of OATP1B3. • Knockdown of OATP1B3 in HepG2 cells prevented α-amanitin induced cytotoxicity. • OATP1B3 may be a crucial therapeutic target against amanitin-induced organ failure. [ABSTRACT FROM AUTHOR]

Phenazine-1-carboxylic acid (PCA) as a natural product widely exists in microbial metabolites of Pseudomonads and Streptomycetes and has been registered for the fungicide against rice sheath blight in China. To find higher fungicidal activities compounds and study the effects on fungicidal activities after changing the carboxyl group of PCA, we synthesized a series of PCA derivatives by modifying the carboxyl group of PCA and their structures were confirmed by 1 H NMR and HRMS. Most compounds exhibited significant fungicidal activities in vitro . In particular, compound 6 exhibited inhibition effect against Rhizoctonia solani with EC 50 values of 4.35 mg/L and compound 3b exhibited effect against Fusarium graminearum with EC 50 values of 8.30 mg/L, compared to the positive control PCA with its EC 50 values of 7.88 mg/L ( Rhizoctonia solani ) and 127.28 mg/L ( Fusarium graminearum ), respectively. The results indicated that the carboxyl group of PCA could be modified to be amide group, acylhydrazine group, ester group, methyl, hydroxymethyl, chloromethyl and ether group etc . And appropriate modifications on carboxyl group of PCA were useful to extend the fungicidal scope. [ABSTRACT FROM AUTHOR]

Phenazine-1-carboxylic acid (PCA) is a natural product that has been characterized by special chemical structures, interesting bioactivities and has been registered for fungicide against rice sheath blight in China. Phloem mobility is of great significance to long-distance transport of systemic pesticides in plants. In order to improve the phloem mobility and bioactivities of PCA, seventeen PCA-amino acid ester conjugates were designed and synthesized by conjugating PCA with different amino-acid esters. The conjugates were evaluated for their fungicidal activities against Rhizoctonia solani Kuhn and their phloem mobility was determined by HPLC. Results showed that conjugates a , b , c , d , e , l , m and p (EC 50 values between 5.35 and 18.85 μg/mL) were more active than PCA (25.66 μg/mL). In particular, conjugates l and m exhibited the best fungicidal activities against Rhizoctonia solani Kuhn (EC 50 values of them were 6.47 μg/mL and 5.35 μg/mL respectively). All these conjugates didn’t have phloem mobility. [ABSTRACT FROM AUTHOR]