(+)-Usnic Acid-induced Myocardial Toxicity in Rats

Yokouchi, Yusuke; Imaoka, Masako; Niino, Noriyo; Kiyosawa, Naoki; Sayama, Ayako; Jindo, Toshimasa

doi:10.1177/0192623313504308

Cited by 12 publications

(12 citation statements)

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“…The total RNA was treated with deoxyribonuclease I (Takara, Shiga, Japan) in the manufacturer's buffer supplemented with 10 mM dithiothreitol, 0.5 mM deoxyribonucleoside triphosphates, and 40U RNase inhibitor (Toyobo Life Science, Tokyo, Japan). Nine representative genes were selected based on the previous study (Yokouchi et al 2015). They were classified into 3 gene groups including 3 genes each: amino acid limitation-related genes (methylenetetrahydrofolate dehydrogenase 2, methenyltetrahydrofolate cyclohydrolase Supplemental Table 1.…”

Section: Rna Extraction and Real-time Quantitative Reverse Transcriptmentioning

confidence: 99%

“…UA-induced toxicity has been investigated mainly in the liver, and a few reports have provided examples of potential toxicity in other organs such as skeletal muscular necrosis in sheep (Cook et al 2007; Dailey et al 2008). In our previous study, the myocardial change indicative of mitochondrial stress (mitochondrial swelling and increased expression of prohibitin) was revealed microscopically in rats following a 2-week repeated dosing (Yokouchi et al 2015). Toxicogenomic analysis revealed upregulation of amino acid limitation and oxidative and endoplasmic reticulum (ER) stress–related gene groups (Yokouchi et al 2015).…”

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confidence: 99%

“…In our previous study, the myocardial change indicative of mitochondrial stress (mitochondrial swelling and increased expression of prohibitin) was revealed microscopically in rats following a 2-week repeated dosing (Yokouchi et al 2015). Toxicogenomic analysis revealed upregulation of amino acid limitation and oxidative and endoplasmic reticulum (ER) stress–related gene groups (Yokouchi et al 2015). Especially, the number of upregulated genes in the amino acid limitation–related gene group was larger than those in other groups.…”

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Comprehensive Evaluation of (+)-Usnic Acid–induced Cardiotoxicity in Rats by Sequential Cross-omics Analysis

et al. 2017

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Two-week administration of (+)-usnic acid (UA) induces mitochondrial swelling of cardiomyocytes, and toxicogenomic analysis of the heart revealed upregulation of oxidative stress, amino acid limitation, and endoplasmic reticulum stress-related genes in rats. To analyze the pathogenesis, UA was orally administrated to rats for 1, 4, 7, and 14 days, and sequential histopathological, genomic, and metabolomic analyses were performed on the heart, liver, and plasma. As a result, mitochondrial swelling of cardiomyocytes was observed on day 15 preceded by genomic upregulation on days 5 and 8. Of the focused gene groups, amino acid limitation-related genes represented by Mthfd2 showed numerically higher values or upregulation from day 5, which was sustained through the experimental period. On the contrary, oxidative stress-related genes were upregulated temporally on day 5. In metabolomic analysis, amino acids such as taurocholate and their metabolites fluctuated in concert with the upregulation of amino acid limitation-related genes in the heart, liver, and plasma. Moreover, accumulations of bile acids were manifested in all the tested tissues, while no histopathological change was seen in the liver. Increased bile acids might have an indirect effect on the myocardium; however, more detailed analysis is required. In conclusion, amino acid limitation was suggested as the pivotal toxic trigger of UA-induced cardiotoxicity.

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Section: Rna Extraction and Real-time Quantitative Reverse Transcriptmentioning

confidence: 99%

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Comprehensive Evaluation of (+)-Usnic Acid–induced Cardiotoxicity in Rats by Sequential Cross-omics Analysis

et al. 2017

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“…However, it has not been clarified whether UA causes toxicity in other organs such as the heart. For example, it is reported that a 14-day administration of UA (100 mg/kg/day) provoked mitochondrial swelling in cardiac myocytes in rats [22]. However, there are few studies determining whether UA has a pharmacological effect on the function of heart.…”

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confidence: 99%

(+)-Usnic Acid Isolated from the Lichen Cladonia substellata Impairs Myocardial Contractility

Mendonça

Vasconcelos

Cruz

et al. 2017

PMIO

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Supporting information Details on the chemical characterization of UA from C. substellata are available online at http:// www.thieme-connect.de/products ABStR AC tThe scientific interest in ( + )-usnic acid has grown because of its antitumor, cytotoxic, and antimicrobial activities as well as weight loss. However, overuse of usnic acid has been related with severe hepatotoxicity, making its use questionable. In this study, we decided to expand the knowledge of usnic acid biological activities by characterizing its effects on the mammalian myocardium as a potential pharmacological target. Usnic acid was isolated from samples of Cladonia substellata and submitted to chemical characterization. Molecular inclusion complexes of usnic acid with hydroxypropyl β-cyclodextrin were prepared to improve its water solubility. The effects of usnic acid on the atrial contractility and Ca 2 + influx were carried out in the left atrium of guinea pigs and the effect of usnic acid on the L-type Ca 2 + current was performed in rat ventricular cardiomyocytes enzymatically isolated. To evaluate the membrane integrity of cells subjected to usnic acid, we used histological procedures. Usnic acid reduced atrial contraction with an EC 50 of 43.0 ± 1.0 μM. This effect was related to a reduction of Ca 2 + entry in myocardial cells. In isolated cardiac myocytes, usnic acid at 100 μM inhibited the L-type Ca 2 + current by 73.0 %. In addition, usnic acid caused an irreversible myocardial contracture, reflecting a serious disturbance of the intracellular Ca 2 + homeostasis. Such an effect could not be ascribed to tissue death because cell membrane integrity was confirmed by histological observation. Taken together, our results show that usnic acid impairs cardiac function. Clearly more studies will be necessary to allow further applications of this natural product.

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The recent article by Yokouchi et al (2015) provided for highly interesting reading. Usnic acid (UNA) also exerts significant antineoplastic properties.

UNA attenuates tumor growth in lung carcinomas.

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Usnic Acid and Its Evolving Role as a Potent Antineoplastic Agent

Kapoor

2016

Toxicol Pathol

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The recent article by Yokouchi et al. (2015) provided for highly interesting reading. Usnic acid (UNA) also exerts significant antineoplastic properties.UNA attenuates tumor growth in lung carcinomas. It mediates this role in part by enhancing Poly (ADP-ribose) polymerase [PARP] cleavage. As a result, UNA administration significantly accentuates intratumoral apoptosis. Singh et al. (2013) have recently demonstrated that UNA also upregulates p21/cip1 expression significantly. This results in accentuated intratumoral G0/G1 phase arrest. In addition, it downregulates cyclin D1 expression. These changes have recently been confirmed in A549 cell lines. At the same time, it induces mitochondrial membrane depolarization. Besides the above changes, UNA also has a negative impact on CDK4 and CDK6 expression thereby further mitigating tumor growth in pulmonary malignancies. Similarly, UNA reduces tumor growth in mammary malignancies. It primarily accentuates intratumoral apoptosis. In addition, Song et al. (2012) have recently demonstrated that UNA has an inhibitory effect on VEGFR2-mediated AKT and ERK1/2 signaling pathways. These changes have recently been confirmed in Bcap-37 cell lines. As a result, UNA has a negative impact on endothelial cell proliferation as well as migration. Tube formation is also attenuated concurrently thereby further limiting tumor growth in breast carcinomas.UNA plays a similar role in mitigating tumor growth in hepatocellular carcinomas. It mediates this role in part by attenuating CYP2E1 activity. In addition, UNA has a positive impact on UGT1A4 expression. Sahu et al. (2012) have recently demonstrated that at the same time, UNA accentuates cell cycle proteins cyclin C (CCNC) activity and attenuates Granulocyte-macrophage colony-stimulating factor (CSF2) activity. These changes have recently been confirmed in hepatoma cell lines (HepG2). UNA also mediates upregulation of Chemokine (C-C motif) ligand 21 [CCL21] activity and concurrent downregulation of cholesterol 7alpha-hydroxylase (CYP7A1) activity thereby further mitigating tumor growth in hepatocellular carcinomas. UNA also limits and restricts tumor growth in colorectal malignancies. UNA administration has a positive impact on reactive oxygen species (ROS) production. Bačkorová et al. (2012) have recently demonstrated that similarly UNA modulates Bax and Bcl-2 expression thereby inducing intratumoral apoptosis. In addition, it decreases the ''mitochondrial membrane potential'' significantly. These changes have recently been confirmed in HT-29 cell lines. Besides the above changes, UNA also accentuates caspase-3 activation thus further mitigating tumor growth in colon carcinomas.As is obvious from the above discussion, UNA possesses significant tumor growth limiting properties. It appears to be a promising antineoplastic agent, and further research is recommended to fully evaluate these effects of UNA. ReferencesBačkorová, M., Jendželovský , R., Kello, M., Bačkor, M., Mikeš, J., and Fedoročko, P. (2012). Lichen secondary metabolites are...

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(+)-Usnic Acid-induced Myocardial Toxicity in Rats

Cited by 12 publications

References 40 publications

Comprehensive Evaluation of (+)-Usnic Acid–induced Cardiotoxicity in Rats by Sequential Cross-omics Analysis

Comprehensive Evaluation of (+)-Usnic Acid–induced Cardiotoxicity in Rats by Sequential Cross-omics Analysis

(+)-Usnic Acid Isolated from the Lichen Cladonia substellata Impairs Myocardial Contractility

Usnic Acid and Its Evolving Role as a Potent Antineoplastic Agent

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