Acute maduramicin toxicosis in pregnant gilts

Shimshoni, Jakob A.; Britzi, Malka; Pozzi, Paolo; Edery, Nir; Berkowitz, Asaf; Bouznach, Arieli; Cuneah, Olga; Soback, S.; Bellaïche, M.; Younis, Ahmad; Blech, E.; Oren, Pnina; Galon, N.; Shlosberg, A.; Perl, S.

doi:10.1016/j.fct.2014.03.034

Cited by 26 publications

(35 citation statements)

References 10 publications

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“…Only ionophore and tetracyclines, approved by the Ministry of Agriculture for use in farm animals, were included in the analysis. 19 The antibiotics and ionophores analyzed by LC−MS/MS were below the detection limit of 60 μg/kg. The feed ingredients analyzed for aflatoxins by HPLC-FLD were below the limit of quantitation (1 μg/kg).…”

Section: ■ Resultsmentioning

confidence: 99%

Heliotropium europaeumPoisoning in Cattle and Analysis of Its Pyrrolizidine Alkaloid Profile

Shimshoni¹,

Mulder

Bouznach³

et al. 2015

J. Agric. Food Chem.

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Pyrrolizidine alkaloids (PAs) are carcinogenic and genotoxic phytochemicals found exclusively in angiosperms. The ingestion of PA-containing plants often results in acute and chronic toxicities in man and livestock, targeting mainly the liver. During February 2014, a herd of 15-18-month-old mixed-breed beef cattle (n = 73) from the Galilee region in Israel was accidently fed hay contaminated with 12% Heliotropium europaeum (average total PA intake was 33 mg PA/kg body weight/d). After 42 d of feed ingestion, sudden death occurred over a time period of 63 d with a mortality rate of 33%. Necropsy and histopathological examination revealed fibrotic livers and moderate ascites, as well as various degrees of hyperplasia and fibrosis of bile duct epithelial cells. Elevated γ-glutamyl-transferase and alkaline phosphatase levels were indicative of severe liver damage. Comprehensive PA profile determination of the contaminated hay and of native H. europaeum by LC-MS/MS revealed the presence of 30 PAs and PA-N-oxides, including several newly reported PAs and PA-N-oxides of the rinderine and heliosupine class. Heliotrine- and lasiocarpine-type PAs constituted 80% and 18% of the total PAs, respectively, with the N-oxides being the most abundant form (92%). The PA profile of the contaminated hay showed very strong resemblance to that of H. europaeum.

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Section: ■ Resultsmentioning

confidence: 99%

Heliotropium europaeumPoisoning in Cattle and Analysis of Its Pyrrolizidine Alkaloid Profile

Shimshoni¹,

Mulder

Bouznach³

et al. 2015

J. Agric. Food Chem.

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“…Importantly, there was accidental intoxication by maduramicin in humans (Sharma et al, 2005). Pathologically, maduramicin can induce focal degenerative cardiomyopathy leading to congestive heart failure and severe skeletal muscle lesion associated with rhabdomyolysis (Bastianello et al, 1995;Fourie et al, 1991;Sanford & McNaughton, 1991;Sharma et al, 2005;Shimshoni et al, 2014;Shlosberg et al, 1992Shlosberg et al, , 1997. However, to date, the molecular mechanism by which maduramicin induces degeneration of myocardial cells is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…However, it has been observed that maduramicin can be toxic in both chickens and turkeys at high doses (>10 ppm) (Dorne, Fernandez-Cruz, Bertelsen, Renshaw, Peltonen, Anadon, Feil, Sanders, Wester and Fink-Gremmels 2013, Singh and Gupta 2003). Besides, clinically maduramicin-induced toxicity has been more frequently reported in cattle, sheep and pigs (non-target animals) fed with the broiler litter as a source of protein and minerals (Bastianello, Fourie, Prozesky, Nel and Kellermann 1995, Fourie, Bastianello, Prozesky, Nel and Kellerman 1991, Sanford and McNaughton 1991, Shimshoni, Britzi, Pozzi, Edery, Berkowitz, Bouznach, Cuneah, Soback, Bellaiche, Younis, Blech, Oren, Galon, Shlosberg and Perl 2014, Shlosberg, Harmelin, Perl, Pano, Davidson, Orgad, Kali, Bor, Van Ham, Hoida, Yakobson, Avidar, Israeli and Bogin 1992, Shlosberg, Perl, Harmelin, Hanji, Bellaiche, Bogin, Cohen, Markusfeld-Nir, Shpigel, Eisenberg, Furman, Brosh, Holzer and Aharoni 1997). In addition, there are also some cases of accidental poisoning with maduramicin in humans (Jayashree and Singhi 2011, Sharma, Bhalla, Varma, Jain and Singh 2005).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, there are also some cases of accidental poisoning with maduramicin in humans (Jayashree and Singhi 2011, Sharma, Bhalla, Varma, Jain and Singh 2005). Histopathologically, maduramicin can induce severe myocardial and skeletal muscle lesions (Bastianello, Fourie, Prozesky, Nel and Kellermann 1995, Fourie, Bastianello, Prozesky, Nel and Kellerman 1991, Sanford and McNaughton 1991, Sharma, Bhalla, Varma, Jain and Singh 2005, Shimshoni, Britzi, Pozzi, Edery, Berkowitz, Bouznach, Cuneah, Soback, Bellaiche, Younis, Blech, Oren, Galon, Shlosberg and Perl 2014, Shlosberg, Harmelin, Perl, Pano, Davidson, Orgad, Kali, Bor, Van Ham, Hoida, Yakobson, Avidar, Israeli and Bogin 1992, Shlosberg, Perl, Harmelin, Hanji, Bellaiche, Bogin, Cohen, Markusfeld-Nir, Shpigel, Eisenberg, Furman, Brosh, Holzer and Aharoni 1997). However, the molecular mechanism underlying the toxicity of maduramicin in myocardial cells, including mechanisms of cell death, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, there are also some cases of accidental poisoning with maduramicin in humans (Jayashree & Singhi, 2011;Sharma, Bhalla, Varma, Jain, & Singh, 2005). Histopathologically, maduramicin can induce severe myocardial and skeletal muscle lesions (Bastianello et al, 1995;Fourie et al, 1991;Sanford & McNaughton, 1991;Sharma et al, 2005;Shimshoni et al, 2014;Shlosberg et al, 1992;Shlosberg et al, 1997). However, the molecular mechanism underlying the toxicity of maduramicin in myocardial cells, including mechanisms of cell death, remains unknown.…”

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confidence: 99%

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Maduramicin induces apoptosis and necrosis, and blocks autophagic flux in myocardial H9c2 cells

Chen

Jiang

et al. 2017

J of Applied Toxicology

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Maduramicin, a polyether ionophore antibiotic, is widely used as an anticoccidial agent in the poultry industry. It has been reported that maduramicin may cause heart and skeletal muscle cell damage, resulting in heart failure, skeletal muscle degeneration and even death in animals and humans, if improperly used. However, the molecular mechanism behind its capability to cause death of cardiac cells is not known. Here, we show that maduramicin induced apoptosis and necrosis in rat myocardial cells (H9c2). Maduramicin did not apparently upregulate the expression of pro-apoptotic proteins (e.g., BAD, BAK and BAX) or downregulate the expression of anti-apoptotic proteins (e.g. Bcl-2, Bcl-xL, Mcl-1 and survivin). Interestingly, maduramicin increased the expression of DR4 and TRAIL, activating caspases 8/3 and triggering cleavage of poly ADP ribose polymerase (PARP). In addition, maduramicin induced nuclear translocation of apoptosis inducing factor. Furthermore, maduramicin blocked autophagic flux, as evidenced by inducing accumulation of both LC3-II and p62/SQSTM1. Taken together, the above results suggest that maduramicin executes its toxicity in the myocardial cells at least by inducing caspase-dependent cell death through TRAIL/DR4-mediated extrinsic pathway and caspase-independent cell death by inducing apoptosis inducing factor nuclear translocation and blocking autophagic flux. Our findings provide a new insight into the molecular mechanism of maduramicin's toxicity in myocardial cells.

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Maduramicin induces cardiotoxicity via Rac1 signaling‐independent methuosis in H9c2 cells

Gao

Wang

et al. 2021

J of Applied Toxicology

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Maduramicin frequently induces severe cardiotoxicity in target and nontarget animals in clinic. Apoptotic and non‐apoptotic cell death mediate its cardiotoxicity; however, the underlying non‐apoptotic cell death induced by maduramicin remains unclear. In current study, a recently described non‐apoptotic cell death “methuosis” caused by maduramicin was defined in mammalian cells. Rat myocardial cell H9c2 was used as an in vitro model, showing excessively cytoplasmic vacuolization upon maduramicin (0.0625–5 μg/mL) exposure for 24 h. Maduramicin‐induced reversible cytoplasmic vacuolization of H9c2 cells in a time‐ and concentration‐dependent manner. The vacuoles induced by maduramicin were phase lucent with single membrane and were not derived from the swelling of organelles such as mitochondria, endoplasmic reticulum, lysosome, and Golgi apparatus. Furthermore, maduramicin‐induced cytoplasmic vacuoles are generated from micropinocytosis, which was demonstrated by internalization of extracellular fluid‐phase marker Dextran‐Alexa Fluor 488 into H9c2 cells. Intriguingly, these cytoplasmic vacuoles acquired some characteristics of late endosomes and lysosomes rather than early endosomes and autophagosomes. Vacuolar H+‐ATPase inhibitor bafilomycin A1 efficiently prevented the generation of cytoplasmic vacuoles and decreased the cytotoxicity of H9c2 cells triggered by maduramicin. Mechanism studying indicated that maduramicin activated H‐Ras‐Rac1 signaling pathway at both mRNA and protein levels. However, the pharmacological inhibition and siRNA knockdown of Rac1 rescued maduramicin‐induced cytotoxicity of H9c2 cells but did not alleviate cytoplasmic vacuolization. Based on these findings, maduramicin induces methuosis in H9c2 cells via Rac‐1 signaling‐independent seriously cytoplasmic vacuolization.

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Acute maduramicin toxicosis in pregnant gilts

Cited by 26 publications

References 10 publications

Heliotropium europaeumPoisoning in Cattle and Analysis of Its Pyrrolizidine Alkaloid Profile

Heliotropium europaeumPoisoning in Cattle and Analysis of Its Pyrrolizidine Alkaloid Profile

Maduramicin induces apoptosis and necrosis, and blocks autophagic flux in myocardial H9c2 cells

Maduramicin induces cardiotoxicity via Rac1 signaling‐independent methuosis in H9c2 cells

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