Interactions of NADPH oxidase, renin–angiotensin–aldosterone system and reactive oxygen species in mequindox-mediated aldosterone secretion in Wistar rats

Huang, Xian-Ju; Wang, Xu; Ihsan, Awais; Liu, Qin; Xue, Xi-Juan; Su, Shijia; Yang, Chunhui; Wei, Zhou; Zhang, Yuan

doi:10.1016/j.toxlet.2010.05.013

Cited by 34 publications

(27 citation statements)

References 41 publications

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“… Huang et al (2009) reported the dose-dependent long-term toxicity of MEQ on adrenal gland in male rats, and its mechanism may involve in oxidative stress and steroid hormone biosynthesis pathway. Then, they found the complex interactions of MEQ metabolism, renin–angiotensin–aldosterone system, NADPH oxidase and oxidative stress in response to MEQ-induced tissue toxicity and aldosterone secretion ( Huang et al, 2010a ). Wang et al (2015a) estimated the adrenal cell damage induced by QCT and its bidesoxy-QCT (B-QCT) metabolite, and suggested that its toxic effects resulted from N -oxide groups, and its toxic mechanism might involve the interference of the steroid hormone biosynthesis pathway.…”

Section: Toxicological Effects Of Qdnosmentioning

confidence: 99%

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Cheng

Cao

et al. 2016

Front. Pharmacol.

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Quinoxaline 1,4-di-N-oxides (QdNOs) have manifold biological properties, including antimicrobial, antitumoral, antitrypanosomal and antiinflammatory/antioxidant activities. These diverse activities endow them broad applications and prospects in human and veterinary medicines. As QdNOs arouse widespread interest, the evaluation of their medicinal chemistry is still in progress. In the meantime, adverse effects have been reported in some of the QdNO derivatives. For example, genotoxicity and bacterial resistance have been found in QdNO antibacterial growth promoters, conferring urgent need for discovery of new QdNO drugs. However, the modes of actions of QdNOs are not fully understood, hindering the development and innovation of these promising compounds. Here, QdNOs are categorized based on the activities and usages, among which the antimicrobial activities are consist of antibacterial, antimycobacterial and anticandida activities, and the antiprotozoal activities include antitrypanosomal, antimalarial, antitrichomonas, and antiamoebic activities. The structure-activity relationship and the mode of actions of each type of activity of QdNOs are summarized, and the toxicity and the underlying mechanisms are also discussed, providing insight for the future research and development of these fascinating compounds.

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Section: Toxicological Effects Of Qdnosmentioning

confidence: 99%

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Cheng

Cao

et al. 2016

Front. Pharmacol.

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“…In the previous studies, adrenal toxicity was observed in the following delivery of MEQ in rats ( Huang et al, 2009 , 2010a ; Ihsan et al, 2010 ). MEQ was reported to reduce the output of adrenal aldosterone ( Huang et al, 2010b ), and cause the damage of the adrenal with the decrease of the aldosterone concentration in plasma ( Huang et al, 2010a ). The concentrations of Na + , K + , UA, and BUN in the serum are controlled by the kidney and adrenal glands ( Huang et al, 2010a , b ).…”

Section: Discussionmentioning

confidence: 95%

“…Mequindox, a relative new compound in QdNOs, is widely applied in livestock owing to its strong inhibitory activities against microbes in China ( Liu et al, 2012 ; Wu et al, 2012 ; Li et al, 2014 ; Wang et al, 2016b ). Early findings have demonstrated that adrenal toxicity ( Huang et al, 2009 ), testicular toxicity ( Ihsan et al, 2011 ; Liu et al, 2017c , b ), kidney and liver toxicity ( Huang et al, 2010a ; Liu et al, 2017d ) induced by MEQ in vivo . CBX ( World Health Organization [WHO], 1991a ) and OLA ( World Health Organization [WHO], 1991b ), structural analogs of MEQ, were prohibited in food-producing animals due to its potential mutagenic and carcinogenic effects ( Wu et al, 2007 ; Liu et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Mequindox Induced Genotoxicity and Carcinogenicity in Mice

Liu

Lei

et al. 2018

Front. Pharmacol.

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Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo, and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice.

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“…8 Nicotinamide adenine dinucleotide phosphate (NADPH) is a major source of ROS generation in both physiologic and pathophysiologic situations. 9 It is now widely accepted that oxidative stress acts as one of central mechanisms for development of type 2 diabetes. 8,10 ROS can induce dysfunction and apoptosis in pancreatic β-cells.…”

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confidence: 99%

Advanced oxidation protein products promote NADPH oxidase-dependent β-cell destruction and dysfunction through the Bcl-2/Bax apoptotic pathway

Liang

Lou

et al. 2017

Laboratory Investigation

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The accumulation of plasma advanced oxidation protein products (AOPPs) has been linked with diverse disorders, including diabetes, chronic kidney disease, obesity, and metabolic syndrome. The aim of the present study was to evaluate the pathophysiological relevance of AOPPs in β-cell destruction and dysfunction. Exposure of cultured rat β-cells (INS-1) to AOPPs induced an increase in Bax expression, caspase-3 activity, and apoptosis as well as a decrease in Bcl-2 expression in a dose- and time-dependent manner. AOPP challenge rapidly increased the production of intracellular superoxide by activation of NADPH oxidases, demonstrated by p47 translocation and interaction with p22 and gp91, and this in turn led to apoptosis. AOPPs treatment resulted in β-cell apoptosis, AOPPs accumulation, and decreased insulin content in pancreas and plasma in unilateral nephrectomized rats. Chronic inhibition of NADPH oxidase by apocynin prevented β-cell apoptosis and ameliorated insulin deficiency in AOPP-challenged rats. This study demonstrates for the first time that accumulation of AOPPs promotes NADPH oxidase-dependent β-cell destruction and dysfunction by the Bcl-2/Bax-caspase apoptotic pathway. This finding may provide a mechanistic explanation for β-cell destruction and dysfunction in patients with diverse disorders.

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Interactions of NADPH oxidase, renin–angiotensin–aldosterone system and reactive oxygen species in mequindox-mediated aldosterone secretion in Wistar rats

Cited by 34 publications

References 41 publications

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Mequindox Induced Genotoxicity and Carcinogenicity in Mice

Advanced oxidation protein products promote NADPH oxidase-dependent β-cell destruction and dysfunction through the Bcl-2/Bax apoptotic pathway

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