Hepatotoxicity of Pyrrolizidine Alkaloids

Neuman, Manuela G.; Cohen, Lawrence E.; Opris, Mihai; Nanau, Radu M.; Jeong, Hyunjin

doi:10.18433/j3bg7j

Cited by 82 publications

(67 citation statements)

References 141 publications

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“…Pyrrolizidine alkaloids (PAs) are the ester derivatives of necine base and necic acid that are found in more than 6000 plants [1], [2]. PAs are potent hepatotoxins that can lead to liver injury, which over 8000 liver injury cases were reported worldwide to be associated with the use of PA-containing products such as herbal medicines [3], [4].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Drp1 protects against senecionine-induced mitochondria-mediated apoptosis in primary hepatocytes and in mice

Yang

Wang

et al. 2017

Redox Biology

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Pyrrolizidine alkaloids (PAs) are a group of compounds found in various plants and some of them are widely consumed in the world as herbal medicines and food supplements. PAs are potent hepatotoxins that cause irreversible liver injury in animals and humans. However, the mechanisms by which PAs induce liver injury are not clear. In the present study, we determined the hepatotoxicity and molecular mechanisms of senecionine, one of the most common toxic PAs, in primary cultured mouse and human hepatocytes as well as in mice. We found that senecionine administration increased serum alanine aminotransferase levels in mice. H&E and TUNEL staining of liver tissues revealed increased hemorrhage and hepatocyte apoptosis in liver zone 2 areas. Mechanistically, senecionine induced loss of mitochondrial membrane potential, release of mitochondrial cytochrome c as well as mitochondrial JNK translocation and activation prior to the increased DNA fragmentation and caspase-3 activation in primary cultured mouse and human hepatocytes. SP600125, a specific JNK inhibitor, and ZVAD-fmk, a general caspase inhibitor, alleviated senecionine-induced apoptosis in primary hepatocytes. Interestingly, senecionine also caused marked mitochondria fragmentation in hepatocytes. Pharmacological inhibition of dynamin-related protein1 (Drp1), a protein that is critical to regulate mitochondrial fission, blocked senecionine-induced mitochondrial fragmentation and mitochondrial release of cytochrome c and apoptosis. More importantly, hepatocyte-specific Drp1 knockout mice were resistant to senecionine-induced liver injury due to decreased mitochondrial damage and apoptosis. In conclusion, our results uncovered a novel mechanism of Drp1-mediated mitochondrial fragmentation in senecionine-induced liver injury. Targeting Drp1-mediated mitochondrial fragmentation and apoptosis may be a potential avenue to prevent and treat hepatotoxicity induced by PAs.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Drp1 protects against senecionine-induced mitochondria-mediated apoptosis in primary hepatocytes and in mice

Yang

Wang

et al. 2017

Redox Biology

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“…require liver transplantation. 64 Products manufactured properly are pyrrolizidine alkaloid free and currently allowed to be sold in the US and Canada, although the United Kingdom and Germany have withdrawn these products from their markets. 65 A 2012 evidence based guideline from the American Academy of Neurology was completely retired and considered invalid because of the group's desire to withdraw its endorsement of butterbur in the management of migraine.…”

Section: Mind-bodymentioning

confidence: 99%

Complementary and integrative medicine in the management of headache

Millstine

Chen

Bauer

2017

BMJ

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Headaches, including primary headaches such as migraine and tension-type headache, are a common clinical problem. Complementary and integrative medicine (CIM), formerly known as complementary and alternative medicine (CAM), uses evidence informed modalities to assist in the health and healing of patients. CIM commonly includes the use of nutrition, movement practices, manual therapy, traditional Chinese medicine, and mind-body strategies. This review summarizes the literature on the use of CIM for primary headache and is based on five meta-analyses, seven systematic reviews, and 34 randomized controlled trials (RCTs). The overall quality of the evidence for CIM in headache management is generally low and occasionally moderate. Available evidence suggests that traditional Chinese medicine including acupuncture, massage, yoga, biofeedback, and meditation have a positive effect on migraine and tension headaches. Spinal manipulation, chiropractic care, some supplements and botanicals, diet alteration, and hydrotherapy may also be beneficial in migraine headache. CIM has not been studied or it is not effective for cluster headache. Further research is needed to determine the most effective role for CIM in patients with headache.

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“…Few studies reported the presence of alkaloids, including pyrrolizidine alkaloids, in this herb and they can have hepatotoxic effects (Bosi et al, 2013;Neuman et al, 2015;Roeder and Wiedenfeld, 2013). Nevertheless, no toxic effect of A. conyzoides L. in vivo studies was observed suggesting that is safe when administered orally Diallo et al, 2010;Moura et al, 2005).…”

Section: Introductionmentioning

confidence: 96%