For years, the aging brain has directly been linked with manifestations of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson's disease (PD). These were characterized by anomalies in the synthesis of proteins and a conglomeration of misfolded proteins as a result of altered signaling pathways by epigenetic manipulations (Shukla et al., 2019). These disorders otherwise associated with low levels of melatonin were significantly reversed when melatonin was administered and its receptors triggered (Bondy and Sharman, 2007).

Type 1 diabetes (T1D) also known as insulin-dependent diabetes mellitus is an autoimmune condition characterized by inflammatory responses due to the influx of immune response cells in the pancreas, leading to the destruction of insulin-producing beta cells (Tai et al., 2016). Interaction between environmental and genetic factors has caused alteration of gene expression through epigenetic regulations in T1D (Cerna, 2019). Several studies point to the involvement of inflammatory inducers such as cytokines and lipopolysaccharides, which damage cellular and molecular components (Pestana et al., 2016) as among the causative agents of T1D. Cyclooxygenase-2 (COX-2) and inducible Nitric Oxide Synthase (iNOS) expressions have been vindicated in this inflammatory induced response (Chen et al., 2016b). These inflammatory inducible proteins have been reported as upstream factors of T1D via activation of transcription factors through binding of the kappa beta (NF-кB) promoter regions resulting in modulation of epigenetic chromatin remodeling (Hu et al., 2016a). Changes in DNA methylation were observed at the insulin region in the islets as a result of cross-talk between the β-cells affiliated with DNA methylation and the immune response which suggested that an increase in immune response such as cytokines, can result in an increase in DNA methylation and decrease in insulin levels, a phenomenon observed in T1D (Rui et al., 2016). Histone modification via hyperacetylation was implicated in T1D associated with COX-2 expression, whereby monocyte acetylated histone H4 levels were remarkably elevated in diabetic patients relative to non-diabetic patients (Chen et al., 2009). The same study furthermore highlighted how these hyperacetylations were restricted to patients who had no complications further suggesting the potential protective effect of histone hyperacetylation in T1D patients with complications such as endothelial and vascular dysfunctions (Chen et al., 2009).

Though inadequately studied, the association between miRNAs and immune cells has been established in T1D. Studies have found that dysregulation of expressed miRNAs which correlates with immune cells such as T cells and B lymphocytes was linked to the onset of T1D and that these miRNAs when manipulated to participate in the preservation of cells of the pancreas as reviewed by Mohammad Taheri et al. (2020).

The importance of melatonin in immune cells has been established through modulation of responses of pancreatic cells whereby melatonin exerted beneficial effects in type 1 diabetes through suppression of T cell proliferation in the islets (Lin et al., 2009). Wu Guo Deng et al. demonstrated melatonin’s anti-inflammatory mechanism via suppression of the expression of pro-inflammatory genes COX-2 and iNOS through epigenetic modulation (Deng et al., 2006). They showed how melatonin can reduce the p52 binding to the chromatin of COX-2 and iNOS promoter regions through inhibition of p300 HAT activity (Figure 1). The study further established that increase in p300 HAT activity consequently increased histone acetylation of p52 which increased the expression of the pro-inflammatory mediators. Several lines of studies have explained the relationship between the action of p300 HAT and that of iNOS and COX-2, that is, a decrease in p300 HAT activity leads to a decrease in transcriptional activities of the iNOS and COX-2 and vice versa (Deng et al., 2003). The exact mechanism by which melatonin inhibits p300 HAT activity is still elusive. However, overexpression of p300 protein interacts with the promoter regions, enhancing the transcriptional signal which results in the optimization of pro-inflammatory activation (Shi et al., 2012). Usually, these inflammatory mediators are bound by the p52 domain due to p300 HAT activity (and eventually increased histone acetylation of p52), which results in the opening up of the chromatin structures, making them available to trans-activators hence enabling their transcription (Deng et al., 2006), intensifying inflammation. However, this process was inhibited by melatonin, suggesting its regulatory role in pro-inflammatory genes by transcriptional mechanisms (Shi et al., 2012). Kellogg et al. (2008) postulated that the COX-2 pathway may provide a potential therapeutic alternative in diabetic peripheral neuropathy. In normal conditions, p52 is a transcriptional repressor protein generated from p100 under a tightly controlled process (Vallabhapurapu et al., 2015). The nexus of how transcription is activated through the p100 route via epigenetic mechanism is still a mystery and further investigations may provide a better therapeutic strategy in the development of target-specific drugs.

P300 has further been investigated in Type 2 diabetes through different epigenetic modulated mechanisms to that of T1D. P300 protein has been implicated in insulin secretion patterns in the beta cells of the pancreas. Bompada et al. (2016) illustrated how p300 knockout led to misshapen secretion of insulin (a typical feature of T2D) and apoptosis of beta cells of pancreases, marked by a decrease in p300 acetylation in presence of high glucose, and an increase in acetylation when an HDAC inhibitor was introduced. Melatonin has been shown to promote beta cell survival by preventing glucotoxicity-induced beta cells loss via p38 MAPK inhibition. In the pancreases, it has been reported that phosphorylation of Akt and/or p38 MAPK plays an important role in beta-cell survival (Wijesekara et al., 2010). On the other hand, diabetes is characterized by dysfunction of pancreatic beta cells and the development of apoptosis due to raised levels of glucose above normal (Butler et al., 2003). Moreover, glucotoxicity and other inflammation-inducing agents have been implicated in the phosphorylation of p300 due to the activation of p38 MAPK in the pancreatic beta cells, leading to cell degradation and apoptosis (Ruiz et al., 2018). However, this process was reversed as the activation of pro-apoptotic factor p38 MAPK was blocked when melatonin was administered (Saldeen et al., 2001).

Overwhelming evidence shows activation of p38 MAPK in insulin-releasing cells causes a damaging effect on the beta cells. Natalia Makeeva et al. (2006) reported that upon activation of p38 MAPK due to the high levels of cytokines like iNOS, p38 MAPK was maintained at a hyper-phosphorylated state, the beta cells producing insulin was driven into apoptosis and eventually cell death. Melatonin signaling was shown to alleviate induced-cell apoptosis and improved the deleterious effects caused by insulin resistance (Figure 1) due to glucotoxicity and oxidative stress in human beta cells (Costes et al., 2015), through inhibition of the apoptotic factor p38 MAPK (Park et al., 2014) and reduction of p38 MAPK phosphorylation (Choi et al., 2018). In addition, Xiongfei Xu et al. (2018) demonstrated melatonin’s ability to attenuate LPS-induced inflammation in macrophages through Akt phosphorylation signaling. Akt phosphorylation has been reported severally as a critical modulator of GLUT 4 translocation (an effector of glucose uptake in tissues) thereby enhancing the effects of insulin on target tissues (Choi et al., 2018).

COX-2 is an iso-enzyme responsible for the formation of prostanoids such as prostaglandins and thromboxanes, whose overexpression has been reported not only in inflammatory diseases but in the induction of numerous types of cancer as well (Roelofs et al., 2014). Melatonin on the other hand has been reported severally as an inhibitor of COX-2 in cancer cells (Yi et al., 2014; Shrestha et al., 2017). Several explanations have been explicated including the epigenetic approach which involves the regulation of trans-activator and co-activator genes. For instance, the Factor Nuclear kappa B (NF-ĸB) is a transcriptional factor located in the cell cytoplasm functioning to regulate gene expressions involved in cell survival, proliferation, inflammatory responses, and metastasis (Taniguchi and Karin, 2018). In normal cells, NF-ĸB is usually in a resting/inactive state in the cytosol and its activation is often regulated to maintain the cell homeostasis, and activation of immune responses thereby protecting the cell from environmental factors that would otherwise destroy it (Liu et al., 2017). In cancer cells, NF-ĸB is constitutively activated due to aberrant protein expression or alterations in normal regulation by the regulatory proteins leading to mutation (Park and Hong, 2016).

NF-ĸB activation has been reviewed in the inhibition of apoptosis, and induction of tumorigenic enhancing genes such as MMP-9, Bcl-xl, XIAP, and cyclin D1, leading to metastasis (Fuchs, 2013). Through suppression of NF-ĸB (p65) gene expression (Figure 2), melatonin can inhibit its activation and subsequent translocation to the nucleus (Qin et al., 2012), preventing metastasis in cancer cells (Gao et al., 2017). Huaiqiang Ju et al. attributed this to melatonin’s ability to decrease NF-ĸB protein activity via phosphorylation. The inhibitory protein, IкBα which usually binds to NF-кB, causes the latter to migrate into the nucleus when the IK kinase enzyme phosphorylates IкBα and is subsequently degraded by proteasomal enzyme 26S via ubiquitination, leading to NF-ĸB translocation into the nucleus. They concluded that melatonin administration to pancreatic ductal adenocarcinoma cells led to a decrease in phosphorylation of IкBα which helped to explain the low levels of p65 protein in the nucleus of melatonin treated groups (Ju et al., 2016). Further evidence on pancreatic cancer cells shows that upon activation (as a result of abnormal activation of p65 binding with p50 protein), a heterodimer is formed which enters the nucleus to begin the process of transcription and eventually tumor development and progression (Ling et al., 2012b). Zhen Wei Zou et al. (2018), reported that activation of NF- ĸB signaling evidenced by elevated levels of phosphorylated p65 and other gene products that enhance the invasion of cancer cells, was eradicated upon treatment with melatonin. Additionally, melatonin showed synergistic effects to 5-fluorouracil (5-FU) enhancing its antitumor activity by facilitating the migration of p50/p65 from the nucleus to the cytoplasm, reducing NF-кB dependent cancer development and progression (Gao et al., 2017). It is therefore evident that inhibition of the NF-ĸB pathway by targeting p65 protein could be a breakthrough in the discovery of drug therapy for various types of cancer. Melatonin offers a promising and noble target in this perspective, as far as drug efficacy and safety are concerned.

In the treatment of cancer, the actual mechanism underlying the association between miRNAs and melatonin remains elusory. In recent times, there has been a surge in the involvement of miRNAs in the advancement of tumors which has attracted attention in the field of research. These miRNAs have been demonstrated to regulate the expression of genes by inactivating messenger RNA by either preventing ribosomal binding or cutting the mRNA which is further destroyed by the cell leading to less or no translation of mRNA, a process resulting in gene silencing (Hammond et al., 2001). The study on miR-152 has been on the rise due to its tumor-suppressing activity. Constant overexpression of miR-152 in cancer cell lines caused a remarkable decline in cell proliferation and angiogenesis (Li et al., 2016b). Sun et al. (2017b) showed that miR-152-3p inhibited invasion and development of glioblastoma cells by down expressing DNA methyltransferase thereby hindering hypermethylation of neurofibromatosis 2 (NF2). Treatment with melatonin showed elevated levels of miR-152-3p in breast cancer cells when compared to control groups (Marques et al., 2018), suggesting melatonin’s role in cancer suppression.

Another miRNA, miR-483 overexpression has been recently shown to play an oncogenic role in thyroid cancer (Zhang et al., 2019), breast cancer (Huang and Lyu, 2018), colorectal cancer (Liang et al., 2019), esophageal squamous cell carcinoma (Ma et al., 2016), ovarian cancer (Arrighetti et al., 2016), hepatocellular (Lupini et al., 2016), and pancreatic ductal adenocarcinoma (Wang et al., 2015). Earlier on, Clokie et al. (2012) had shown how the addition of miR-483-3p antagonist led to an increase in the synthesis of melatonin by the pineal gland and eventual attenuation of tumor invasion and progression. Thus, inhibition of miR-483-3p and subsequent elevation of melatonin present a promising tumor therapeutic target.

MiR-155 has been a gene of interest implicated in the development of cancer, just a while ago. Studies performed on hepatocellular carcinoma showed elevated levels of miR-155 which acted as an oncogene thereby promoting cell proliferation, progression of the cell cycle, and inhibition of apoptosis (Liao et al., 2018). Zhang et al. (2016) explained that this phenomenon was a result of the downregulation of ARID2, a tumor suppressor gene, which subsequently activated the Akt phosphorylation signaling pathway leading to cancer progression. Accruing evidence shows melatonin’s prowess in arresting cell cycle progression in hepatocellular carcinoma by downregulation of p-Akt dependent pathway (Long et al., 2017). Activation of the Akt pathway has been shown to cause oncogenic transcription factors to bind and inactivate phosphorylated Rb protein leading to the transcription factor E2 promoter-binding-protein-dimerization partner protein (E2F-DP) release, pushing the cell into the synthesis phase, a process that is reversed by melatonin (Long et al., 2017). On the same note, melatonin has been reported to inhibit miR-155 in glioma (Gu et al., 2017) and glioblastoma cells through suppression of Akt phosphorylation, inhibiting its epigenetic modified oncogenic transcriptional activity (Chen et al., 2016a).

Studies pointed towards miR-16-5p are the latest in trying to explain the epigenetic mechanism in cancer by the non-coding RNA molecules that regulate gene translation in various types of cancers. Studies reveal that aberrant expression of miR-16-5p resulted in malignancies including gastric (Zhang et al., 2015), (Krell et al., 2018), breast (Rinnerthaler et al., 2016), (Zhang et al., 2018a), bone (Sang et al., 2017), ovarian (Dwivedi et al., 2016), hepatic (Wu et al., 2015), prostate (Wang et al., 2019b), cervical (Wang et al., 2008), and lymphatic system (Calin et al., 2002). Treatment with melatonin suppressed gastric cancer (Figure 3) via upregulation of miR-16-5p expression and downregulation of SMAD3 (Zhu et al., 2018), indicating that the TGF-β/SMAD pathway might be a possible molecular mechanism by which melatonin precludes cancer progression. TGF-β is a protein known to control cell functions including cell growth, proliferation, and apoptosis (Lustri et al., 2017). Pathologically, the TGF-β/SMAD signaling pathway has been associated with migration, invasion, and metastasis (Ji et al., 2015). Here, the TGF-βI trans-phosphorylates type II (TGF-βII) induces phosphorylation of SMAD3, consequently activating the formation of a complex with SMAD4 which migrates and accumulates in the nucleus where they interact with transcription cofactors and promoters which in turn regulates transcription of target genes, eventually enhancing cell proliferation and metastasis (Ji et al., 2015). Melatonin exposure significantly attenuated gastric cancer by enhancing miR-16-5p expression which targeted SMAD3 and resulted in negative regulation of its abundance (Zhu et al., 2018). Elsewhere, melatonin was reported to alleviate liver fibrosis through TGF-β1/SMAD signaling pathway (Wang et al., 2018b). Hongliang Jiang et al. further demonstrated that miR-16-5p played a tumor suppressor role via downregulation of SMAD3 (Zhang et al., 2018a). How melatonin interacts with miR-16-5p to impart its cancer-suppressing activity still needs further clarification and future studies to confirm the molecular mechanism are vital. This approach puts melatonin and miR-16-5p/TGF-β/SMAD pathway as a possible candidate for therapeutic target and possibly understanding of the etiology of different types of cancer.

Epidemiological studies show a strong association between artificial light and the prevalence of cancer (Garcia-Saenz et al., 2018). Modern artificial lights especially those with blue light emissions have been reported to cause a litany of health problems with cancer being among them (Kamat et al., 2016). The suprachiasmatic nucleus (SCN) functions to regulate the circadian cycle which is controlled by the external environment (day and night clock). Several reviews have been put forth trying to explain how environmental factors such as artificial light can cause circadian disruptions by causing desynchronization of the circadian pacemaker (SCN), resulting in decreased levels of melatonin secretions from the pineal gland (Benke and Benke, 2012). Concerns have been raised regarding the effects of the artificial light at night associated with hormonal imbalances (melatonin) and impaired circadian rhythms (Russart and Nelson, 2018), causing a myriad of diseases including cancer. Studies show that melatonin attenuates the effects of breast, prostate, liver, and skin cancers associated with ill-timed light exposures (early morning, late evening, night) (Dauchy et al., 2018). In the recent past, epigenetic modification affecting the circadian rhythm has been used to explain melatonin’s mechanism of action. Through the activation of the MT1 receptor, melatonin was able to prevent invasion and metastasis of breast cancer (Hill et al., 2015). Agbaria et al. (2019) demonstrated that, when artificial light at night (ALAN) with increased irradiances was administered in rats’ breast cancer, melatonin levels were significantly decreased, while the levels remained normal in the control group. This had been confirmed earlier by Sánchez et al. (2018) who implicated that melatonin resynchronized dysregulated circadian rhythm by preventing SIRT1 from binding to CLOCK/BMAL1 dimer which would otherwise cause deacetylation of BMAL1 resulting in less transcription and degradation of the period (PER) proteins. Earlier, SIRT1 had been implicated in the regulation of the circadian cycle through the deacetylation of PER2 protein (Asher et al., 2008). The CLOCK protein has been reported to exhibit histone acetylation activity necessary in the modulation of circadian rhythm in cancer animal models (Sun et al., 2017a).

It was also found that melatonin upregulated Casein Kinase 1 (CK1) protein levels, increasing the binding sites available for phosphorylation to the transcription factors (Sánchez et al., 2018). These findings together support melatonin’s effects on hepatocellular cells which might also have contributed to its protective activity through modulation of the circadian rhythm.

Cardiac fibrosis is a common manifestation of chronically stressed myocardial tissues characterized by abnormal thickening of the valves of the heart due to the proliferation of the fibroblasts (Kong et al., 2014). The functioning heart muscles are replaced by the thick dysfunctional fibrotic tissues resulting in heart failure and sometimes death. Currently, though there exists no convincing therapy that can prevent the onset and progression of this condition, understanding the pathophysiology of this process may prove crucial and beneficial.

Strides have been made in the interest of employing epigenetic therapies to arrest myocardial fibrotic degeneration through stimulation of human cardiac fibroblasts to suppress or express pro-fibrotic protein genes which have the effect of modulating DNA-methylating genes such as DNMT1 and DNMT3a/3b (Yu and Xu, 2015). Activated myocardial fibroblasts in the rat model resulted in an increase in DNMT3a which in turn led to overexpression of ERK1/2 coupled with suppression of RASAL1 (a Ras-GTPase-activating protein) genes, causing fibroblast activation and cardiac fibrosis (Grimaldi et al., 2017). A DNA methylation inhibitor 5-azacytidine has been reported in the sumoylation of interferon regulatory factor-1 (IRF-1) causing improvements in cardiac fibrosis (Jeong et al., 2015).

The protective effects of melatonin have been previously investigated, effectively alleviating cardiac fibroblast-induced cardiac fibrosis via inhibition of mitochondrial oxidative injury and regulation of SIRT3-mediated SOD2 deacetylation (Jiang et al., 2020). Melatonin also exerted anti‐fibrosis effects in all phases of fibrotic pathogenesis including inhibition of epithelial cell injury, blockading of inflammatory cytokine release, reduction in activation and proliferation of fibrogenic effector cells, and decrease in deposition of ECM (GAG and collagen I and III) (Hu et al., 2016b).

Big strides have been made in understanding melatonin-induced epigenetics on cardiac fibrosis and towards the identification of therapeutic targets. One such study conducted by Crespo et al. (2015) postulated that the development of fibrosis greatly depended on the pro-fibrogenic cytokine TGF- β, directly linked with hyperphosphorylation of SMAD3. TGF-β1/SMAD pathway has been associated with fibrosis in the kidney (Wang et al., 2016), heart (Bansal et al., 2017) liver (Lee et al., 2018b) skin (Qin et al., 2018), and lungs (Jia et al., 2019). They demonstrated that through downregulation of TGF-β and subsequent decrease in phosphorylation of SMAD3, melatonin abrogated the transcription of target genes induced by the TGF-β1/SMAD signaling pathway (Crespo et al., 2015). TGF-β is a well-known collagen synthesis enhancer (Qin et al., 2018). Additionally, melatonin significantly attenuated the fibrosis process by suppressing the activation of TGF-β1/SMAD signaling in heart (Yeung et al., 2015), which resulted in the reduction of collagen deposition in the heart tissues. Similarly, melatonin produced anti-fibrotic effects through activation of TGF-β1/SMAD signaling pathways as a result of down-regulation of lncRNA MALAT1 and knock-down of miR-141 (Che et al., 2020). Elsewhere, the elevated expression of histone deacetylases in cardiac fibrosis in juveniles was attributed to decreasing melatonin levels resulting in heart failure, a condition that was reversed when external melatonin was administered and playing an inhibitory role to the HDACs. Earlier on, Wu et al. (2018) had postulated that melatonin could prevent programmed hypertension by inhibiting HDACs (Wu et al., 2014). However, the underlying molecular mechanism behind this inhibition needs further elucidation.

The in-depth knowledge of the renal-angiotensin-aldosterone system (RAAS) alongside in vivo and in vitro studies have suggested possible epigenomic-related mechanisms underlying the etiology of hypertension. Unusual activation of RAAS by the associated genes has been previously reported to cause an increase in blood pressure (Crowley et al., 2006). Angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) have been reported as the main genes which code to the angiotensinogen protein and angiotensin-converting enzyme respectively, regulating the RAAS pathway and eventually blood pressure (Pei et al., 2015). Moreover, activation of RAAS genes due to impaired functioning of the RAAS system has been associated with pathophysiological conditions including essential hypertension. One such gene 11-Betahydroxysteroid dehydrogenase type-2 (HSD11B2), performed in a rat model demonstrated a positive association between hypermethylation and hypertension (Baserga et al., 2010). Similar findings were reported in newborn babies whereby hypermethylation of the (HSD11B2) promoter gene was linked to a high risk of essential hypertension (Zhao et al., 2014). Elsewhere, hypomethylation of promoter gene coding AGT in rat adipose tissues (Wang et al., 2014) and hypomethylation of ACE during pregnancy (Goyal et al., 2010) both led to the occurrence of hypertension. Studies on non-coding RNA demonstrated repressed levels of AGT and elevated expression of ACE in hypertensive individuals (Litwin et al., 2013). MiR-27a/b and 21 have been linked with the expression of RAAS-regulated AGT and ACE genes respectively, both leading to hypertension (Zou et al., 2020).

Melatonin has been implicated in the epigenomic regulation of hypertension by decreasing the mRNA expression levels of agt1, ace, and agtr1 which promoted vasodilation and alleviating hypertension (Tain et al., 2017). Tain et al. (2016), demonstrated that melatonin could decrease renal levels of ace2, agt, and agtra1 genes. Additionally, melatonin attenuated hypertension through suppression of the renin-angiotensin system (Ohashi et al., 2019b). Recently, it has been reported and reviewed by several researchers, that aberrant methylation patterns of ACE and AGTR-1 promoter regions might be one of the underlying epigenetic mechanisms behind hypertension (Pei et al., 2015).

The non-coding RNAs could also play a role in the development and progression of hypertension through epigenetic modulations. Melatonin has been shown to regulate these non-coding RNAs thereby modulating the occurrence or progression of hypertension. Real-time PCR and western blotting results clearly illustrate how the overexpression of H19 and miR-675-3p coupled with downregulation of miR-200a in melatonin-treated rats (previously induced with hypertension) led to an increase in the expression of PDCD4 and a decrease in expression of IGFR1 proteins (Wang et al., 2018c). Changes in these two proteins eventually can result in apoptosis and suppression of smooth muscles of the pulmonary artery, a condition associated with the alleviation of hypertension (Liu et al., 2010). DNA-methylation induced by a methyl-donor diet resulted in programmed hypertension in women during the pregnancy period by altering renal transcriptomes, a condition that was reversed when maternal melatonin therapy was conducted. It was then reported that melatonin therapy could offer protective activity in adult male offspring against programmed hypertension mechanistically by regulating DNA-methylation (Tain et al., 2018) or playing a HDACs inhibitor role. To date, the actual nexus between melatonin and epigenetics in the pathophysiology of hypertension is still unknown. A deeper understanding of how the non-coding RNAs and DNA-methylation stimulates the RAAS, AGT, and ACE genes of the renal system leading to the development of hypertension, would be a step closer to better understanding the actual mechanism by which melatonin works to alleviate hypertension, making it easier to design and develop melatonin-based therapies.

MiR-200 family is a target molecule in the pathology of heart failure. Liu et al. (2018) premised that upregulation of miR-200a due to increased secretion of protein CTRP3 (a paralog of adiponectin) in melatonin treated groups, led to activation of Nrf-2 and eventually abrogation of obesity-related heart failure. Contrarily, it was reported elsewhere that melatonin downregulated the expression of miR-200a which subsequently increased the apoptotic genes PDCD4 resulting in amelioration of pulmonary artery hypertension (Wang et al., 2018c). MiR-200 has also been implicated in arrhythmias (Daimi et al., 2015) and hypercholesterolemia associated with atherosclerosis (Martino et al., 2015).

Angiotensin II a well-known pro-inflammatory regulator has been implicated in cardiac dysfunction of a failing heart through its association with reactive oxygen species (ROS) (Zablocki and Sadoshima, 2013) and phosphorylation of p65/RelA when overly expressed as seen in heart failure (Kim et al., 2012). The result is an activated p65 which binds to the promoter site of NF-кB in the human antigen R (HuR) (Kong et al., 2017) eliciting a binding activation to the MMP2, leading to collagen degradation and eventual heart failure. An increase in hypomethylation of MMP2 has been previously reported in blood samples and cardiac tissues of heart failure patients (Glezeva et al., 2019). Additionally, the multifaceted sites of MMP2 available for phosphorylation contain NF-кB sites in the promoter domains which have been previously demonstrated to cause modulation in its activities (Sariahmetoglu et al., 2007; Jacob-Ferreira et al., 2013). Melatonin on the other hand has been shown to downregulate MMP2 protein expression (Figure 4) through inhibition of the NF-кB signaling pathway and via ROS scavenging (Kong et al., 2017). Although post-translational modulations such as phosphorylation can regulate MMP2 expression, melatonin involvement in this regulation is yet to be demystified.

Atherosclerosis is a condition characterized by the buildup of plaques from cholesterol, deposited on the inner walls of the endothelium, causing stenosis and heart attack, and sometimes death (Insull, 2009). Endothelium dysfunction due to degeneration causes the formation of these plaques which upon rupture have been reported to cause sudden coronary death, myocardial infarction, and heart attack (Hsiao et al., 2015). Therefore, plaque stabilization is an important approach in the pharmacotherapy of heart diseases stemming from atherosclerotic plaque. Changing the morphology and content of the atherosclerotic plaque could help alter the function of the plaque in the endothelium by either preventing or reducing its stringent effects when it ruptures (Libby and Aikawa, 2003).

Increasing the fibrous content through collagen synthesis is the basic idea of stabilizing atherosclerotic plaque. Recently, Li et al. (2019b) demonstrated this phenomenon by using the smooth muscle cells from ApoE^−/− mice. They found out that at high doses, melatonin was able to cause significant stabilization of atherosclerotic plaque. They further explained this occurrence to be caused by melatonin-induced Akt phosphorylation of the specificity protein 1 (Sp1), which cleaved to the promoter site and elevated the expression of the PH4alpha-1 gene. The PH4alpha-1 gene has been associated with the formation of a major component of the extracellular matrix known as 4- hydroxyproline in collagens (Abrams and Andrew, 2002). Sp1 is a ubiquitously expressed transcription factor illustrated to be activated through Akt phosphorylation (Chuang et al., 2013). Earlier on, Sp1 was shown to cause transactivation of the VEGF promoter region via Akt phosphorylation (Pore et al., 2004). Additionally, the pineal hormone has been implicated in the downregulation of MMPs and interstitial increase in collagen, leading to stabilization of the atherosclerotic plaque, as a result of elevated levels of fibrous tissues (Aikawa et al., 1998). An increase in MMPs has been widely reported to degrade and suppress collagen synthesis (Bertelsen et al., 2018). This reduction of collagen due to degradation can lead to the weakening of the plaque, inevitably causing its rupture (Braganza and Bennett, 2001). Computational chemistry studies showed that melatonin could inhibit the enzymatic activity of MMP-9 by docking on its active site preventing further action of the enzyme (Rudra et al., 2013). This pineal hormone has also been premised to cause an upswing in collagen synthesis in the experimental model (Drobnik et al., 2008), which could unwind the process of plaque rupture.

Different experimental reports have deduced molecular pathways involving inflammatory processes leading to atherosclerosis (Moriya, 2019). The role of miR-223 in the regulation of atherosclerosis has been studied in the recent past with a growing body of evidence reporting exciting findings on the association of miR-223 with inflammation-induced atherosclerosis (You et al., 2022). Tang et al. (2015) explained that through suppression of TLR4 and its subsequent downstream gene NF-кB, they managed to cease inflammation-induced atherosclerotic plaque. Lately, miR-223 has been linked to the inhibition of inflammatory processes related to endothelium dysfunction in atherosclerosis (Cavallari et al., 2019). The expression of tissue factor (TF) also known as thromboplastin was reportedly suppressed by miR-223, suggesting a possible anti-thrombogenesis mechanism in the formation of atherosclerotic plaque (Li et al., 2014). We have previously reported the progression of atherosclerosis through the pyroptotic process via lncRNA-MEG3/miR-223/NLRP3 pathway. Any attempts of knocking down miR-223 led to the blocking of melatonin’s inhibitory effects on pyroptosis, suggesting that there is a nexus between miR-223 and melatonin in the alleviation of atherosclerotic plaque (Zhang et al., 2018b). Although it is not yet defined how melatonin directly collaborates with miR-223 to impact anti-atherosclerosis action, the recent research findings on melatonin seem to corroborate its putative actions against atherosclerotic plaque.

The concept of aging and growing old seems not to go down well with many people; some people believe once they grow old, they might lose their worth, good looks, or importance in society. For a long period, several factors majorly environmental stimuli had been attributed to aging. In recent decades, scientists have been able to demonstrate that aging is hugely dependent and associated with genetic and epigenetic pathways which influence lifespan. Senescence involves a prolonged condition requiring the adaptation of the cell to a stressful microenvironment initiated by a deep epigenetic reconditioning response resulting in irreparable DNA damage. For instance, when mitochondrial DNA methylation was examined during the senescence period, a study concluded that hypomethylation of the mitochondrial CpG region was directly linked to cellular senescence as a result of oxidative stress (Yu et al., 2017). Likewise, the histone deacetylase inhibitor enzymes were intensely involved in the promotion of cellular senescence as a result of the upregulation of p16 and p21 gene expression via potent stimulation of cardiac fibroblasts (Tao et al., 2016). MiRNAs have also been involved in the physiological process of cellular senescence and aging. Through the TGF-β signaling pathway, miR-29 negatively regulates H4K20me3, an epigenetic target that leads to the progression of senescence (Lyu et al., 2018). These epigenetic alterations could be identified as targets for epigenetic therapies, from suppression of senescence-inducing triggers to positive activation of signaling pathways associated with anti-senescence.

Melatonin has been used substantially in many vital life processes, and its secretion and circulation decline gradually over time. For instance, Lahiri postulated that the levels of melatonin in the serum decreased significantly with age, in body tissues including the heart (Lahiri et al., 2004), and that chronic treatment with melatonin exhibited anti-senescence effects and also reduced deteriorative and oxidative changes associated with cardiac aging (Guo et al., 2017). Although a relatively new area of research, the role played by miRNAs in aging has gained interest among researchers in an attempt to prolong human life. Studies on these miRNAs associated with cardiac senescence and aging have shed much light on prospects, as to how they can be regulated to slow down cardiac senescence processes. LncRNA H19 has recently been implicated in the promotion of cardiomyocytes senescence by regulating the aging markers p53 and p21 (Zhuang et al., 2021). The lncRNA H19 silenced the MALAT1 and MIAT in fibrosis-related cardiac hypertrophy resulting in increasing in senescence protein markers p53 and p21 (Su et al., 2021). Melatonin on the hand actively produced antifibrotic action in cardiac fibrosis through inhibition of MALAT1 (Che et al., 2020). Additionally, H19-derived miR-675 has been implicated as a regulator of cellular senescence in aging-induced vascular dysfunction (Han et al., 2019). MiR-675 overexpression exhibited anti-senescence activity in cardiac progenitor cells in presence of melatonin through regulation of transcriptional factors p53 and p21 (Cai et al., 2016). Further, accumulation of p53 and p21 proteins have been reported in cardiovascular studies as promulgators of senescence through p53/p21 DNA-induced damage and cell cycle arrest rendering the cells senescence (Li et al., 2019c), a function that was reversed by exposure to melatonin (Cai et al., 2016). Altogether, these findings provide basic evidence of melatonin’s cardio-protective action, especially in an aging state.