Beneficial Effects of Manilkara zapota-Derived Bioactive Compounds in the Epigenetic Program of Neurodevelopment

Abstract

Gestational diet has a long-dated effect not only on the disease risk in offspring but also on the occurrence of future neurological diseases. During ontogeny, changes in the epigenetic state that shape morphological and functional differentiation of several brain areas can affect embryonic fetal development. Many epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs control brain gene expression, both in the course of neurodevelopment and in adult brain cognitive functions. Epigenetic alterations have been linked to neuro-evolutionary disorders with intellectual disability, plasticity, and memory and synaptic learning disorders. Epigenetic processes act specifically, affecting different regions based on the accessibility of chromatin and cell-specific states, facilitating the establishment of lost balance. Recent insights have underscored the interplay between epigenetic enzymes active during embryonic development and the presence of bioactive compounds, such as vitamins and polyphenols. The fruit of Manilkara zapota contains a rich array of these bioactive compounds, which are renowned for their beneficial properties for health. In this review, we delve into the action of each bioactive micronutrient found in Manilkara zapota, elucidating their roles in those epigenetic mechanisms crucial for neuronal development and programming. Through a comprehensive understanding of these interactions, we aim to shed light on potential avenues for harnessing dietary interventions to promote optimal neurodevelopment and mitigate the risk of neurological disorders.

Keywords: maternal health outcomes; microbiota; neurodevelopment assessments; phytochemicals; vitamins.

Figure 1

Phytochemical profile of Manilkara zapota fruit. Main structural formulas of bioactive compounds in the Manilkara zapota, like polyphenols, vitamins, minerals, and flavonoids.

Figure 2

Potential influence of bioactive compounds of the Manilkara zapota fruit on DNA methylation. Bioactive compounds of the Manilkara zapota fruit contribute to the production of SAM and are linked to epigenetic mechanisms, favoring DNA methylation. Supplementation during pregnancy and lactation can influence embryonic development, genomic imprinting, and aging. Abbreviations: SAM (S-adenosyl-L-methionine); SAH S-adenosylhomocysteine.

Figure 3

Molecular mechanisms of vitamin B complex and vitamin C involved in brain epigenetic phenomena. Abbreviation: 5-HTR2C (5-hydroxytryptamine receptor 2C); ALKB (alkylation repair enzyme AlkB homolog 1); FOXA2 (forkhead box protein A2); H3K4ME (histone H3 lysine 4 methylation); HCT metabolism (histidine catabolism metabolism); HDAC (histone deacetylase); HDM (histone demethylase); 5-HTR2A (5-hydroxytryptamine receptor 2A); LDS1 (lysine demethylase 1); LMX1A (LIM homeobox protein 1A); NGN2 (neurogenin 2); NRF2 (nuclear factor (erythroid-derived 2)-like 2); NURR1 (nuclear receptor related 1); PGC1A (peroxisome proliferator–activated receptor gamma coactivator 1 alpha); PITX3 (paired homeobox protein 3); PPAR-γ (peroxisome proliferator–activated receptor gamma); RXR-RAR (retinoid X receptor–retinoic acid receptor); SAM (S-adenosylmethionine); SIRTS (sirtuin family of proteins).

Figure 4

Molecular mechanism of polyphenols involved in brain epigenetic phenomena. Abbreviation: AMPK (AMP-activated protein kinase); BBB (blood–brain barrier); CAT (catalase); DNMT (DNA methyltransferase); GPx (glutathione peroxidase); HDAC (histone deacetylase); NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells); KEAP1 (Kelch-like ECH-associated protein 1); NRF2 (nuclear factor (erythroid-derived 2)-like 2); PI3K/AKT (phosphatidylinositol 3-kinase/AKT); SIRT1 (sirtuin 1); SOD (superoxide dismutase).

Figure 5

Molecular mechanism of phenolic acids involved in brain epigenetic phenomena. Abbreviations: BDNF (brain-derived neurotrophic factor); CREB (CAMP response element binding protein); DNMT1 (DNA methyltransferase 1); HDAC (histone deacetylase); HMT (histone methyltransferase); NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells); PI3K/AKT/mTOR (phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin); PKA (protein kinase A); SIRT1 (sirtuin 1).

Figure 6

Molecular mechanism of flavonoids involved in brain epigenetic phenomena. Abbreviation: BAX (Bcl-2-associated X protein); CAT (catalase); HO1 (heme oxygenase 1); KEAP1 (Kelch-like ECH-associated protein 1); NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells); NQO1 (NAD(P)H:quinone oxidoreductase 1); NRF2 (nuclear factor (erythroid-derived 2)-like 2); PI3K/AKT (phosphatidylinositol 3-kinase/AKT); SIRT1 (sirtuin 1); SOD (superoxide dismutase).