Molecular Mechanism of Polyphenols Promoting Health Based on Life Homeostasis and Gene Expression Regulation

2.1. Polyphenols Hormesis Effects

Hormesis refers to any process in cells or organisms, characterized by biphasic responses to increasing exposure to stress conditions or substance stressors[6,7]. Usually, any stressors within low or moderate doses stimulation zone are beneficial for biological responses, while cell catastrophic damage or apparent toxic occurs at higher doses. Plant polyphenols produced by plants to protect themselves from pests such as bacteria, fungi, and insects, are toxic to these pests, but compared to the maximum dose used in experiments on plants to date, this toxicity has not appeared in mammalians.

However, polyphenols act as stressors on mammalian cells, resulting in the activation of various cellular defense systems achieved controlling the redox environment, protein equilibrium and metabolic homeostasis, inflammatory responses, thereby making cells more resistant to subsequent toxic stimuli[8,9,10][Figure 1]. As regarding us people, hormesis, for examples, the influences of exercise well illustrate the exercise, in which constant and irreversible hurt to skeletal muscle caused oxidative stress lead to increased muscle mass, cardiovascular function, and antioxidant capacity[11]. Furthermore, the optimal hormetic dose concentration responses for luteolin on cell viability of human endothelial is approximately 5000 μM, over 25000 μM causing toxicity[12,13]. In addition to plant polyphenols, including alcohol, most stressors also include physical factors and lifestyle factors, possibly mild oxidative stress, and low dose ultraviolet radiation. Polyphenol hormesis effects contribute to cells restoring physiological homeostasis.

2.2 Polyphenols Regulate Redox Homeostasis Status

The free radical theory of organism aging is one of the most widely recognized theories, which holds that the damage of DNA, protein and lipid caused by excessive free radicals, reactive oxygen species (ROS) and reactive nitrogen in cells is the key factor determining the aging of organisms[14]. Under the homeostasis of organism, the production and quenching of free ROS are in balance, which is beneficial for organism to maintain physiological functions. In the conditions of aging, excessive fatigue, psychological anxiety, depression and pathology, excessive production of human ROS will destroy this balance, and oxidative stress and the resulting oxidative damage occurs[15].

It has been proved that polyphenol compounds can regulate the redox status by reacting with ROS in a stoichiometric manner to form stabilized radicals, following abstraction of hydrogen. First of all, polyphenols directly scavenge ROS because of the existence of phenolic hydroxyl groups on their molecules. Polyphenols possess antioxidant activity by reacting with ROS to form stabilised radicals and eliminate ROS by neutralizing the free radicals. The immediate antioxidant effect of polyphenols consists in neutralizing free radicals through transferring electrons or hydrogen atoms, and reducing the formation of metal dependent hydroxyl radicals via chelation mechanisms.

The capacity of polyphenols to eliminate ROS depends on the number and location of hydroxyl groups, substituents, and glycosylation of phytochemical molecules[16]. Secondly, polyphenols can play an antioxidant role by regulating the production and activity of endogenous antioxidants and antioxidant enzymes[17].

Third, the antioxidant effect of polyphenols can directly or indirectly prevent mitochondrial dysfunction. Fourth, polyphenols may enhance cell antioxidant activity by regulating Nrf2 (Nuclear factor erythroid 2-related factor 2) mediated pathway. Nrf2 is a major transcription factor of many antioxidants and antioxidant enzymes. From insects to humans, Nrf2 is structurally and functionally conservative[18]. Finally, new evidence suggests that polyphenols can antagonize reactive oxygen species by regulating ncRNA[19][Table 1].

2.3. Polyphenols Modulate Protein Homeostasis

Protein homeostasis, also known as proteostasis, is crucial for human life. Protein homeostasis is a strictly controlled biochemical process that achieves protein balance through different mechanisms of protein degradation and synthesis, and its homeostasis process is essential for a healthy lifespan. The proteostasis network requires coordinated action with molecular chaperones and ubiquitin proteasome systems, as well as several types of cellular autophagy, endoplasmic reticulum, and lysosomal cell structures.

Recent evidence implies that the unique role of autophagy is to clear aberrant aggregated proteins keeping protein homeostasis. Interestingly, both oxidative stress and autophagy metabolic pathways interact with target of rapamycin complex 1 (mTORC1) which is an autophagy inhibitor, and AMP activated protein kinase (AMPK) that is an autophagy inducer[20]. In response to acute stress, for example, when starvation or elevated temperatures and physical exercise, excessive ROS interacts with AMPK, following that phosphorylation and activation of tuberous sclerosis complex1/2(TSC ), suppressing mTORC.

As a consequence, typical autophagy pathway, the autophagy inducer, Unc-51 like autophagy activating kinase-1 complex(ULK1), is phosphorylated and activated, transferring to the endoplasmic reticulum for phosphorylation of essential autophagy regulatory protein Beclin-1 [21]. ULK1 translocation and phosphorylation of beclin 1 induce the formation of phosphatidylinositol-3-hydroxy kinase-III (PI3K-III) complex through a cascade reaction, which recruits autophagy related proteins (ATGs) associated with autophagosome formation. Subsequently, the autophagosome membrane assisted by LC3 begins to extend, and LC3-I conjugated with several ATGs and phosphatidylethanolamines to generate lipid, glycosylation, and/or ubiquitination active forms, namely LC3-II, an autophagy marker, which incorporated into the autophagosome[Figure 2]. Eventually, autophagosomes fuse with lysosomes to form autolysosomes, allowing for the degradation and removal of long lived and/or damaged organelles and protein aggregates.

A growing body of evidence demonstrates that activation of autophagy could extend the lifespan of diverse organisms. As above mentioned, other mechanisms that trigger protein homeostasis or maintaining proteostasis involve ubiquitin proteasomal systemm (UPS), molecular chaperones, and in particular the heat shock proteins (HSPs). The protein homeostasis network comprises mechanisms that allow for the accumulation of damaged proteins but must be controlled for the resulting toxicity, ensuring that cellular proteostasis is maintained within strictly regulated pathways of synthesis, folding, conformation, and degradation. In this sense, the system that removes damaged proteins, UPS, central l proteolytic machinery of cells, and the autophagy lysosome system that mediates organelle and large aggregate renewal, are mainly responsible for protein homeostasis[Figure 2].

Many age related diseases and ageing processes are accompanied by uninterrupted UPS dysregulation and autophagy disorders, which prevent the proteostasis system from degrading misfolded proteins, resulting in the accumulation and aggregation of these proteins and ultimately ageing. Molecular chaperones, especially HSPs, are the main line of defense to counteract protein misfolding and subsequent protein deposition, which recognize hydrophobic regions of proteins and promote their refolding or transfer to UPS or autophagy systems. As age increases, proteostasis networks may induce pathological ageing through the accumulation of abnormal proteins, which is a common feature of many oncology, neurodegenerative, metabolic, and cardiovascular diseases[Figure 2].

Many food polyphenols can reduce the aggregation of proteins/peptides implicated in metabolic and neurodegenerative diseases, and can improve the clearance of misfolded proteins by regulating the activity of the proteostasis network. Statistical optimization of Alzheimer's disease revealed that among 17 polyphenols, 10 ligands exhibited drug likeness nature,desirable pharmacokinetic parameters, and low toxicity [22]. Polyphenols consist of various subclasses such as phenolic acids, lignans, tannins, stilbene, hydroxybenzoic acid, hydroxycinnamic acid, and flavonoids, which compounds, as individual entities or combinations, can be used to treat Alzheimer's disease [23]. Several polyphenols, resveratrol in mouse testicles, kaempferol in human cervical cancer KB cell lines, and gallic acid in autophagy of colon cancer cells, enhance autophagy and apoptosis by inhibiting the PI3K/AKT/mTOR pathway [24,25,26].

Resveratrol activates the molecular chaperone Hsp70 in cultured cells, inducing anti-inflammatory response in mouse cells[27]. Curcumins and green tea catechins have been shown to significantly increase the expression of Bax and Caspase 3 pro-apoptotic genes, downregulate the expression of Bcl2 genes[28,29][Table 2][Figure 2].

2.4. Polyphenols Regulate Glucose Metabolism Homeostasis

Glucose metabolism are closely related to human health. The concentration of human blood glucose, especially postprandial blood glucose, is the most important indicator of health. To prevent or ameliorate glucose metabolism disorders, dietary polyphenols have become relevant in regulating glucose and/or lipid metabolism, starch digestibility and absorption homeostasis in humans [30].

Plant polyphenols regulate glucose metabolism by several mechanisms such as reducing gut carbohydrate digestion and glucose absorption, stimulating pancreatic βcells to secret insulin, modulating liver glucose release, activating insulin sensitive tissues in terms of insulin receptors, and glucose uptake. Clinical and animal trials have shown that in patients with chronic cardiovascular diseases and diabetes, and oxidative stress caused by NADPH oxidase are often the direct main causes of postprandial hyperglycemia. It has been proved that polyphenols oleuropein aglycone (OLE) and hydroxytyrosol (HT) in participants modulate hepatic antioxidant enzymes and mitigate NADPH oxidase oxidative stress associated with liver parameters, and bone, joint, and cognitive health[31].

A study on patients with obesity or diabetes reported a correlation between high fat diet and the increase of intestinal derived bacterial lipopolysaccharide (LPS) circulation level, that modification may represent an important activation step of systemic postprandial oxidative stress, and intestinal derived bacterial lipopolysaccharide is responsible for restoring the expression level of anti-inflammatory factor,promoting changes in the composition of the microbiota, increasing the population of the community of beneficial microorganisms [32,33]. Data reports suggest that the consumption of extra virgin olive oil is associated with the down regulation of NADPH oxidase derived oxidative stress, indicating that extra virgin olive oil(EVOO) can lower postprandial blood glucose in patients by reducing postprandial intestinal derived bacterial LPS[34].

Reports indicate that quercetin, myricetin, luteolin, epigallocatechin-3-gallate (EGCG), and resveratrol have inhibitory effects on intestinal carbohydrate digestive enzymes , α-amylase and α-glucosidase, resulting in suppression of postprandial hyperglycemia[35,36,37,38]. Studies have shown that food polyphenols such as tannic acid, quercetin, and myricetin are used to inhibit glucose transporters2 (GLUT2) in cultured intestinal cells, lowering glucose absorption[39,40,41].

In addition, it has been reported that the in vitro catechins of green tea, anthocyanins of grape, bitter melon, EVOO, and black beans play a role in the process mediated by glucose transporters4 (GLUT4) in skeletal muscle cells enhancing insulin mediated glucose uptake[42,43,44,45,46].

Generally, inflammation, saturated fatty acids (SFA), tumor necrosis factor α(TNFα), nuclear factor κ B (NF kB) and c-Jun N-terminal kinase (JNK1/2) pro-inflammatory cytokines are the reason of insulin resistance (IR), easy to cause postprandial hyperglycemia[47].

On the other hand, under conditions of postprandial hyperglycemia, insulin activates the phosphatidylinositol 3-kinase (PI3K)/Akt, AMPK pathway, mediating the the translocation of GLUT pools, glucose transporter storage vesicles (GSV) , in liver and muscle cells to the plasma membrane through insulin receptors (IRS), enhancing blood glucose absorption and reducing postprandial hyperglycemia[48,49]. Dietary polyphenols antioxidant and anti-inflammatory properties can prevent ROS mediated pancreatic β cell damage, consequentially preventing and/or improve IR and glucose intolerance.

It is worth noting that the activation of NF-kB/JNK1/2 pro-inflammatory cytokines inhibits the PI3K/Akt pathway, causing hyperglycemia and glucose intolerance or insulin resistance (IR)[50].

At the same time, polyphenols increase cell ability to absorb glucose through an insulin dependent pathway[Table 3][Figure 2].

3. Polyphenols Regulate Gene Expression

3.1. Food Polyphenols Activate Antioxidant Protection Vitagene Signaling Pathways.

Cytoprotective genes also known as vitagenes that encode proteins involving cellular redox homeostasis, such as the heme-oxygenase-1(HO-1), Hsp70, sirtuins system, and thioredoxin/thioredoxin reductase[51,52]. Polyphenols can evoke cytoprotective genes at multiple levels. All these cell protective vitagene genes can be transcriptionally regulated by the nuclear factor erythroid 2 related factor 2 (Nrf2), which is a key transcription effector that activates a wide range of cytoprotective genes[53]. Nrf2 induces mild stress response through routine transient activity, providing a healthy physiological equilibrium state and prolonging lifespan in different cell and animal models.

However, long term chronic stimulation of Nrf2 in clinical practice may lead to pathophysiological events, so Nrf2 signaling can be considered as a hormone like pathway which is defined as any process in cells or organisms characterized by a biphasic response to increasing exposure to stress conditions or substances stressors. More and more evidences indicate that plant polyphenols activate effective two phases responses , leading to the expression of various Nrf2 dependent antioxidant vitagenes , that effects represent a powerful tool that supports the redox homeostasis under stress conditions and supports the hypothesis that the beneficial properties of polyphenols act through adaptive stress response life sustaining genes[54,55].

3.2. Food Polyphenols Modulate Genomic Stability

Aging and increasing cell division frequency lead to accumulation of genomic instability, genomic damage, and double of somatic mutations[56,57]. Genomic instability has caused many diseases dominated by middle-aged and elderly people, such as cancer, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, stroke, chronic kidney disease, atherosclerosis, osteoporosis，sarcopenia，Alzheimer's disease, Parkinson's disease. Good dietary habits are crucial for maintaining genomic stability. It is well known, diet polyphenols plays a key role in nucleotide synthesis and DNA replication, maintaining DNA methylation and chromosomal stability, preventing DNA oxidation, and recognizing and repairing DNA damage[58].

For example, polyphenols curcumin, EGCG, resveratrol, and quercetin have been shown to decrease DNA damage levels and stimulate DNA damage responses, including the regulation sensors, transducers, and mediators[59]. In this context, it has been proven that resveratrol can upregulate genomic stability of mouse embryonic fibroblasts, protecting cells from mutations in the ARF/p53 pathway. There are also studies indicating that anthocyanins and their microbial metabolites can enhance the expression of DNA repair genes and activate ATM(Ataxia-telangiectasia mutated proteins) and ATR(Ataxia telangiectasia and Rad3-related protein) proteins.

In this regard, the protective effect of polyphenols on genomic instability is evident. These results can be achieved through different mechanisms, such as preventing oxidative damage in DNA, down regulation of DNA double strand breaks and the formation of DNA abnormal modification, giving compounds a promising roles in modulation of pathology or aging hallmarks biomarkers. Telomere shortening is a well known aging mechanism, and with each generation of cells, the efficiency of telomere replication decreases over time, leading to a significant shortening of the region until the critical length is reached[60,61].

The shortens of telomere length leads to genomic instability, which impairs cell cycle function, senescence, and apoptosis, resulting in health harm. At Currently, the use of polyphenols has been widely studied in order to improve telomerase activity, maintain telomere length, and extend lifespan[62]. It has been speculated that polyphenols can effectively prevent telomere shortening based on their antioxidant and anti-inflammatory abilities. The impact of diet on telomere functions show that dietary polyphenol antioxidant activity is an important factor in determining telomere length status. In this sense, studies have shown that in a Mediterranean diet rich in olive oil, leukocyte telomere length can be significantly improved in individuals[63]. In addition, according to descriptions, polyphenols, proanthocyanidins and procyanidins, found in grape seed extracts with recognized antioxidant and anti-inflammatory potential can lower cell apoptosis and prevent reactive oxygen species induced chromosomal damage in human lymphocytes[64].

Furthermore, studies have shown that EGCG and quercetin can prevent myocardial cell apoptosis by preventing telomere shortening and Recombinant Telomeric Repeat Binding Factor 2 (TERF2) expression loss, attributed to the potential antioxidant compounds of these polyphenols [65,66]. A cross study involving men and women suggested that green tea consumption may be protective against telomere shortening reflecting Physiological aging whereas coffee or soft drink consumption may not[67][Table 4].

3.3. Food Polyphenols Improve Epigenetic Function

Environmental factors often regulate gene expression through epigenetic modifications, which mainly include DNA methylation, histone acetylation, methylation, phosphorylation, ubiquitination, and so on. Abnormal changes in epigenetic modifications of human life activities influence the onset and progression of diseases, which are considered fundamental characteristics of different types of cancer, neurodegenerative diseases, metabolic disorders, and skeletal and skeletal diseases.

In principle, drugs reverse the aberrant expression of epigenetic genes，and in this regard, drugs with inhibitory activity against DNA methyltransferase (DNMT) and histone deacetylase (HDAC) have achieved promising results in the treatment of cancer[68]. In recent years, most studies have shown that epigenetic diets, such as several polyphenols, including curcumin, resveratrol, and reportedly catechins, are able to affect NF-kB by modulating the activity of HDACs and DNMTs, and chromatin remodeling [69,70]. Recent studies have provided large amount of data to support the significant impact of plant polyphenols on DNA methylation levels and activity through direct or indirect modifications.

The plant polyphenol genistein in soybeans reduces DNMT activity, forms complexes with it, activates tumor suppressor genes, and may have important implications for cancer prevention and therapy[71]. There is data indicating that resveratrol and quercetin have been shown to have antitumor effects on cancer prevention and treatment, either alone or in combination with other chemotherapeutic drugs, by regulating the histone proteins stability, and DNA methyltransferases (DNMTs) activities[72,73,74,75]. In addition, EGCG obtained from green tea has a remarkable positive effect on the DNMT activity of cancer cells in many tissues and organs of the human body [76]. EGCG not only modifies DNA methylation, but also interferes with HDAC and histone acetyltransferases (HATs) activities. Quercetin, as a HAT inhibitor, inhibits HAT and HDAC activity in human endothelial cells[77]. Previous research has shown that polyphenol diallyl disulfide (DADS) in garlic is a major component that significantly influences histone deacetylases (HDACs) activity and gene expression regulation in human colorectal cancer cell lines Caco-2 and HT-29[78][Table 5].

4. Perspectives

In the past two decades, there has been a significant increase interest in dietary replacement drugs, especially natural products rich in polyphenols, to improve human health and well being. The health problems induced by aging are complex and certainly influenced by dietary habits and genetic background. Considering the tremendous efforts made by researchers in studying the mechanisms of beneficial effects of polyphenols, this review is quite narrow. However, we highlight the evidence of biophysics, biochemical and genetic gene expression regulation, which may provide new insights into the health and dietary effects of polyphenols. Although the application of polyphenols in disease prevention has been proven promising in various model organism based studies, the safety and potential health benefits of their long-term use in humans are still uncertain.

It should be noted that a food may contain at least a few or even hundreds of polyphenols. Some diets, such as the Mediterranean diet, with multiple polyphenol rich foods, together contain about 300 different polyphenols[79,80,81]. Future, to investigate the combination of multiple polyphenols or polyphenol rich foods as polyphenols may have synergistic or additive beneficial effects.

We come into contact with polyphenols from birth, and breast milk contains antioxidant phytochemicals, carotenoids, and polyphenols, both of which derive from the mother's diet[82,83,84]. When it comes to polyphenols, people often consider their antioxidant effects in the human body. However, increasing evidence suggests that due to low bioavailability and fast metabolism of polyphenols, their antioxidant activity in in vivo is much lower than in vitro. Therefore, the continuous daily intake of polyphenols throughout the entire life cycle of the human body can be explained as' chemical training '.

The hormesis effect of polyphenols is actually a form of chemical training, consistent with other training phenomena such as sunbathing, exercise, alcohol consumption, and mental stress, all of which are related to the concept of stimulating and protecting the homeostasis of life. However, the underlying contribution of polyphenol triggered hormesis to its health promotion and disease prevention remains to be further addressed.

Polyphenols enhance cell resistance to stress and senescence, making them an attractive foundation for developing and utilizing novel antioxidants and potential anti-aging agents. However, when dealing with natural or synthetic polyphenol antioxidants, the first consideration should be the significant differences in chemical structure and mode of action on oxidative stress among polyphenols with different structural and functional moieties. Moreover, based on the hormesis biphasic effect characteristic, polyphenols can act as pro oxidants at high doses, which is harmful to humans.

Obesity is related to metabolic disorders of glucose metabolism, and dietary polyphenols show some potential for further development. Throughout the holistic biological anti obesity activities, dietary polyphenols have been demonstrated to stimulate cellular uptake of glucose by increasing insulin sensitivity in the insulin dependent pathway. At the level of biochemistry and biophysics homeostasis, dietary polyphenols also affect lipid metabolism by limiting lipid absorption in the diet, which is not discussed in this article due to length limitations.

In this summary, we reviewed the role of polyphenols in modulating autophagy in various aging neurodegenerative pathologies such as AD, PD. Evidence has revealed that polyphenols can regulate autophagy by modulating crucial autophagy proteins such as beclin-1, LC3 I and II and also act via the mTOR, AMPK, SIRT-1 pathways. In addition, evidence also indicates that ameliorating autophagy processes by polyphenols inhibits neuroinflammation and oxidative stress and upgrades the motor functions and memory in neurodegenerative diseases. However, more researches are deeded to support the use of polyphenols as nutritional products in modulating.

Polyphenolic factors in food and diet may contribute to epigenetic changes, and in some cases are likely to reverse abnormal epigenetic states, restore and maintain human health. Here, we propose a polyphenolic "epigenetic diet" combination recommendation, which focuses on consuming products that can stimulate beneficial epigenetic modifications, including increasing the consumption of fruits, vegetables, and the dietary components described in this article. Nutrigenomics involves studying how genes and dietary polyphenols interact to reveal how people achieve healthy phenotypes based on genetic and nutrition induced DNA and chromatin alterations, while the field of nutriepigenomics involves the lifelong reshaping of our epigenome by nutritional factors[85,86].

5. Conclusions

Polyphenols are not only present in vegetable and grain foods, but also the most important and attractive nutritional components in food, beverage, and fruit wine. Overall, from the perspectives of biochemistry and molecular biology, a plethora of evidence emphasizes the effectiveness of dietary polyphenols in treating illness related to disease progression and preventing aging. The primary benefit of consuming diet rich in polyphenols attributes to their antioxidant properties, with a consequent reduction antioxidative stress closely related to tissue aging.

In recent years, a large number of studies have increasingly supported the positive results of population surveys and clinical trials, which not only reveal to some extent the antioxidant protection mechanisms of polyphenols for health, but also record the molecular basis and cellular correlation of health effects at the level of protein homeostasis/glucose metabolism homeostasis/epigenetic gene expression regulation in organisms.

In this sense, although the molecular mechanism data of polyphenols improving human health in this article is still limited, it is of great significance to provide clues for how plant polyphenols produce so many heterogeneous effects at the cellular level. In summary, an increasing interest in the nutritional pharmacology development of plant polyphenols or their molecular scaffolds, which suggests an understanding of the molecular/cellular determinants of beneficial effects of these molecules in the near future, as well as their potential applications pharmacokinetics and pharmacodynamics, will increase.