Melatonin protects bone against cadmium-induced toxicity via activation of Wnt/β-catenin signaling pathway

Knani, Latifa; Venditti, Massimo; Kechiche, Safa; Bannı, Mohamed; Messaoudi, Imed; Minucci, Sergio

doi:10.1080/15376516.2019.1701595

Cited by 29 publications

(21 citation statements)

References 59 publications

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“…Modulation of Wnt signalling by inhibiting Notum offers an opportunity to target situations when Wnt signalling upregulation may be beneficial, such as Alzheimer's disease and osteoporosis. Our observation that melatonin directly binds to Notum and inhibits its activity suggests a molecular mechanism for previous reports that melatonin can activate Wnt/β‐catenin signalling in neuron cells and osteoblasts …”

Section: Discussionsupporting

confidence: 64%

Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum

Zhao

Ren

Hillier

et al. 2020

Journal of Pineal Research

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The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β‐catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N‐[2‐(5‐fluoro‐1H‐indol‐3‐yl)ethyl]acetamide that is structurally similar to melatonin came to our attention. We then soaked melatonin and its precursor N‐acetylserotonin into Notum crystals and obtained high‐resolution structures (≤1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid, and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 µmol/L), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which upregulation of Wnt signalling may be beneficial.

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Section: Discussionsupporting

confidence: 64%

Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum

Zhao

Ren

Hillier

et al. 2020

Journal of Pineal Research

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“…Considering the remarkable effect of Cd on male fertility, many papers reported the importance of substances that may prevent, counteract, or ameliorate its toxicity to preserve a proper gamete production. Recently, among them, we focused our attention on zinc [ 19 , 20 ] and melatonin (MLT), evaluating their counteractive effects not only in the testis, but also in other tissues targeted by Cd toxicity, such as bone [ 21 ] and ovary [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Altered Expression of DAAM1 and PREP Induced by Cadmium Toxicity Is Counteracted by Melatonin in the Rat Testis

Venditti

Rhouma

Romano

et al. 2021

Genes

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Cadmium (Cd) is one of the most toxic pollutants for health due to its accumulation in several tissues, including testis. This report confirms that Cd increased oxidative stress and apoptosis of germ and somatic cells and provoked testicular injury, as documented by biomolecular and histological alterations, i.e., CAT and SOD activity, the protein level of steroidogenic enzymes (StAR and 3β-HSD), and morphometric parameters. Additionally, it further documents the melatonin (MLT) coadministration produces affects in mitigating Cd-induced toxicity on adult rat testis, as demonstrated by the reduction of oxidative stress and apoptosis, with reversal of the observed histological changes; moreover, a role of MLT in partially restoring steroidogenic enzymes expression was evidenced. Importantly, the cytoarchitecture of testicular cells was perturbed by Cd exposure, as highlighted by impairment of the expression and localization of two cytoskeleton-associated proteins DAAM1 and PREP, which are involved in the germ cells’ differentiation into spermatozoa, altering the normal spermatogenesis. Here, for the first time, we found that the co-treatment with MLT attenuated the Cd-induced toxicity on the testicular DAAM1 and PREP expression. The combined findings provide additional clues about a protective effect of MLT against Cd-induced testicular toxicity by acting on DAAM1 and PREP expression, encouraging further studies to prove its effectiveness in human health.

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“…Tobacco smoking is a major source of Cd intake, a cigarette contains 5 mg of this metal, which could lead to significantly 4–5 times higher levels of Cd in smokers’ blood than that of non‐smokers (Djuric et al, 2015; Takiguchi & Yoshihara, 2006). Generally, the Cd poisoning is the result of a chronic exposure, which is mainly reflected to bone (Järup, Alfvén, Persson, Toss and Elinder, 1998; Knani, Bartolini, et al, 2019; Knani, Venditti, et al, 2019; Xie & Sheng, 2017), kidney (Johri, Jacquillet, & Unwin, 2010; Satarug, 2018), gastrointestinal tract (Tinkov et al, 2018), lung (Ganguly, Levänen, Palmberg, Åkesson, & Lindén, 2018), and testis pathologies, whereas the latest one is the major target organ of Cd toxicity, due to its high sensitivity (Siu, Mruk, Porto, & Cheng, 2009).…”

Section: Introductionmentioning

confidence: 99%

Cadmium‐induced toxicity increases prolyl endopeptidase (PREP) expression in the rat testis

Venditti

Chemek²,

Minucci

et al. 2020

Molecular Reproduction Devel

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During the differentiation of the male gamete, there is a massive remodeling in the shape and architecture of all the cells of the seminiferous epithelium. The cytoskeleton, as well as many associated proteins with it, plays a pivotal role in this process. The testis is particularly susceptible to environmental pollutant, which can lead to injury and impairment of normal spermatozoa production. Cadmium (Cd) is one of the major chemical environmental toxicants in economically developed countries. Food and cigarettes are the main sources of exposure to this element.Here, the protective role of zinc (Zn) to prevent the testicular toxicity in male adult rats after prenatal and during lactation exposure to Cd has been assessed. Altered testicular histology at the interstitial and germinal levels was found, whereas Zn supply completely corrected Cd toxicity. Moreover, the effects of these metals on the testicular expression and localization of the protease prolyl endopeptidase (PREP) were evaluated. Interestingly, the results showed an increase of PREP messenger RNA and protein. Data were corroborated by immunofluorescence. This study raises the possibility of using PREP as a new fertility marker. K E Y W O R D Scadmium, endocrine disruptor, PREP, testis, zinc

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Melatonin protects bone against cadmium-induced toxicity via activation of Wnt/β-catenin signaling pathway

Cited by 29 publications

References 59 publications

Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum

Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum

Altered Expression of DAAM1 and PREP Induced by Cadmium Toxicity Is Counteracted by Melatonin in the Rat Testis

Cadmium‐induced toxicity increases prolyl endopeptidase (PREP) expression in the rat testis

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