Aflatoxin B1 promotes autophagy associated with oxidative stress-related PI3K/AKT/mTOR signaling pathway in mice testis

Huang, Wanyue; Cao, Zheng; Zhang, Jian; Ji, Qiang; Li, Yanfei

doi:10.1016/j.envpol.2019.113317

Cited by 78 publications

(42 citation statements)

References 66 publications

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“…For AKT1, a published study found that the seminiferous tubule diameter in Akt1−/− testes was smaller than that in wild-type mice, and apoptotic sperm were more prevalent in null mice compared to the wild-type mice, whereas the sperm concentration and motility were significantly lower in the null sperm (Kim et al, 2012). The PI3K/AKT signaling pathway also plays an important role in spermatogenesis, targeting this pathway could regulate oxidative stress, apoptosis, sperm motility, as well as Foxo1 nuclear retention in the testis (Sinha et al, 2018;Huang et al, 2019). Inflammation is a significantly factor in testis injury, TNF-α and NF-κB serve as inducers that contribute to spermatogenesis disorders.…”

Section: Discussionmentioning

confidence: 99%

Wuzi Yanzong Pill—Based on Network Pharmacology and In Vivo Evidence—Protects Against Spermatogenesis Disorder via the Regulation of the Apoptosis Pathway

Chen

Ding

et al. 2020

Front. Pharmacol.

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The crisis of male infertility is an issue of human reproductive health worldwide. The Wuzi Yanzong pill (WZYZP) is a traditional Chinese medicine prescription that shows efficacy in kidney reinforcement and essence benefit to ameliorate male reproductive dysfunctions. However, the pharmacological mechanisms of the WZYZP on male infertility have not been investigated and clarified clearly. This study was designed to investigate the effects of the WZYZP on spermatogenesis disorder and explore its underlying pharmacological mechanisms. First, based on a network pharmacology study, 39 bioactive compounds and 40 targets of the WZYZP associated with spermatogenesis disorder were obtained, forming a tight compound-target network. Molecular docking tests showed tight docking of these compounds with predicted targeted proteins. The protein–protein interaction (PPI) network identified TP53, TNF, AKT1, Bcl-XL, Bcl-2, and IκBA as hub targets. The Kyoto Encyclopedia of Genes and Genomes pathway network and pathway-target-compound network revealed that the apoptosis pathway was enriched by multiple signaling pathways and multiple targets, including the hub targets. Subsequently, the chemical characterization of WZYZP was analyzed using liquid chromatography to quadrupole/time-of-flight mass spectrometry, and 40 compounds in positive ion mode and 41 compounds in negative ion mode in the WZYZP were identified. Furthermore, based on the prediction of a network pharmacology study, a rat model of spermatogenesis disorder was established to evaluate the curative role and underlying mechanisms of the WZYZP. The results showed that WZYZP treatment improved rat sperm quality and attenuated serum hormone levels, reversed histopathological damage of the testis, reduced cell apoptosis in testis tissues, and ameliorated the expression of the predicted hub targets (TP53, TNF-α, AKT1, NFκB, and IκBA) and the apoptosis related proteins (Bcl-XL, Bcl-2, Bax, Caspase 3, and Caspase 9). These results indicated that the WZYZP has a protective effect on spermatogenesis disorder, suggesting that it could be an alternative choice for male infertility therapy.

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Section: Discussionmentioning

confidence: 99%

Wuzi Yanzong Pill—Based on Network Pharmacology and In Vivo Evidence—Protects Against Spermatogenesis Disorder via the Regulation of the Apoptosis Pathway

Chen

Ding

et al. 2020

Front. Pharmacol.

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“…16,17 Elucidated mechanisms associated with AFB1-mediated reproductive toxicity include suppression of androgen biosynthetic proteins (17 β-hydroxysteroid dehydrogenase 3, 3β-hydroxysteroid dehydrogenase, and steroidogenic acute regulator), induction of oxidative stress, inhibition of antioxidant defense systems, germ cell apoptosis and autophagy. 18–20 Thus, the potential chemopreventive or chemotherapeutic agents to assuage the deleterious effects of AFB1 in the exposed population are warranted.…”

Section: Introductionmentioning

confidence: 99%

Gallic acid enhances reproductive function by modulating oxido-inflammatory and apoptosis mediators in rats exposed to aflatoxin-B1

Owumi

Adedara

Akomolafe

et al. 2020

Exp Biol Med (Maywood)

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Aflatoxin B1 (AFB1) is reported to elicit adverse reproductive outcomes in animals. Gallic acid (GA) is known to exhibit antioxidant and inflammatory bioactivities. The impact of GA on AFB1-facilitated reproductive dysfunction is nonexistent in literature. This investigation elucidated GA protective effect on AFB1-induced reproductive toxicities in rats, exposed for 28 consecutive days to AFB1 (75 µg/kg), or co-treated with GA (20 or 40 mg/kg) body weight. AFB1 significantly (p < 0.05) reduced testicular function biomarkers, serum hormonal levels, and functional sperm characteristics in experimental animals. GA abated AFB1-induced increases (p < 0.05) in lipid peroxidation and reactive oxygen and nitrogen species, suppressed myeloperoxidase, interleukin-1β, nitric oxide, and tumor necrosis factor-α levels—inflammatory biomarkers—in testes, epididymis, and hypothalamus. Furthermore, GA improved antioxidant defenses and alleviated reduction in interleukin-10, caspase-3 activation, and histological variations in epididymis, testes, and hypothalamus of rats dosed with AFB1. Conclusively, GA enhanced reproductive function in AFB1-exposed rats by modulating inflammatory, oxidative stress, and apoptosis mediators. Impact statement Infertility resulting from reproductive deficiency can be stressful. Exposure to aflatoxin B1, a dietary mycotoxin prevalent in improperly stored grains, is reported to elicit reproductive insufficiencies and infertility. We, therefore, examined the likely beneficial effect of gallic acid (GA) a phytochemical, recognized to exhibit in vitro and in vivo pharmacological bioactivities against oxidative stress and related inflammatory damages in rats, since AFB1 toxicities are predicated on oxidative epoxide formation, in a bid to proffer new evidence to advance the field of nutriceutical application from plant-derived chemopreventive agents. Our findings will advance the field of chemoprevention by presenting data absent in the literature on GA. Our results demonstrate further evidence for GA conferred protection against AFB1-mediated histological lesions in testes, epididymis, and hypothalamus of treated rats; suppresses oxidative damages, relieved inflammatory and apoptotic responses, restored sperm functional characteristics, and hormonal levels relevant for reproductive integrity and function.

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“…Other studies have demonstrated that activation of the PI3K/Akt pathway may protect testicular cells from apoptosis in the offspring of mice after direct maternal exposure to di-(2-ethylhexyl) phthalate (DEHP) [ 52 , 54 ]. In another study, suppression of the PI3K/Akt pathway associated with oxidative stress may lead to aflatoxin B 1 (AFB 1 )-induced testicular damage and promote autophagy [ 55 ]. MAPK, one of the members of the serine/threonine protein kinase family, is involved in many physiological processes, such as cell proliferation, differentiation and growth, and P38, JNK and ERK, three protein genes in the MAPK pathway, are closely related to oligoasthenozoospermia [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

A network pharmacology approach to determine the underlying mechanisms of action of Yishen Tongluo formula for the treatment of oligoasthenozoospermia

Chen

Sun

2021

PLoS ONE

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Oligoasthenozoospermia is a complex disease caused by a variety of factors, and its incidence is increasing yearly worldwide. Yishen Tongluo formula (YSTLF), created by Professor Sun Zixue, has been used to treat oligoasthenozoospermia in clinical practice for several decades with a good therapeutic effect. However, the chemical and pharmacological profiles of YSTLF remain unclear and need to be elucidated. In this study, a network pharmacology approach was applied to explore the potential mechanisms of YSTLF in oligoasthenozoospermia treatment. All of the compounds in YSTLF were retrieved from the corresponding databases, and the bioactive ingredients were screened according to their oral bioavailability (OB) and drug-likeness (DL). The potential proteins of YSTLF were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database and the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) database, while the potential genes of oligoasthenozoospermia were obtained from the GeneCards database and the DisGeNET database. The STRING database was used to construct an interaction network according to the common targets identified by the online tool Venny for YSTLF and oligoasthenozoospermia. The topological characteristics of nodes were visualized and analyzed through Cytoscape. Biological functions and significant pathways were determined and analyzed using the Gene Ontology (GO) knowledgebase, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Metascape. Finally, the disease-formula-compound-target-pathway network was constructed by Cytoscape. A total of 106 bioactive ingredients and 134 potential targets from YSTLF were associated with oligoasthenozoospermia or considered to be therapeutically relevant. Pathway analysis indicated that the PI3K/Akt, MAPK and apoptosis signaling pathways were significant pathways involved in oligoasthenozoospermia. In conclusion, the current study expounded the pharmacological actions and molecular mechanisms of YSTLF in treating oligoasthenozoospermia from a holistic viewpoint. The potential molecular mechanisms were closely related to antioxidative stress, antiapoptosis and anti-inflammation, with TNF, CCND1, ESR1, NFKBIA, NR3C1, MAPK8, and IL6 being possible targets. This network pharmacology prediction may offer a helpful tool to illustrate the molecular mechanisms of the Chinese herbal compound YSTLF in oligoasthenozoospermia treatment.

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Aflatoxin B1 promotes autophagy associated with oxidative stress-related PI3K/AKT/mTOR signaling pathway in mice testis

Cited by 78 publications

References 66 publications

Wuzi Yanzong Pill—Based on Network Pharmacology and In Vivo Evidence—Protects Against Spermatogenesis Disorder via the Regulation of the Apoptosis Pathway

Wuzi Yanzong Pill—Based on Network Pharmacology and In Vivo Evidence—Protects Against Spermatogenesis Disorder via the Regulation of the Apoptosis Pathway

Gallic acid enhances reproductive function by modulating oxido-inflammatory and apoptosis mediators in rats exposed to aflatoxin-B1

A network pharmacology approach to determine the underlying mechanisms of action of Yishen Tongluo formula for the treatment of oligoasthenozoospermia

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