Summary of miRNAs bioactive compounds and miRNAs expression in human pathology.
MicroRNAs (miRNAs) are a class of non-coding endogenous RNA molecules that are involved in post-transcriptional gene silencing via binding to their target messenger RNA, leading to mRNA degradation or translational repression. MicroRNAs can be modulated by several factors including hormones, transcription factors, and dietary compounds. These biologically active compounds have positive impact on the progression of human pathology including non-communicable diseases, which indicating that administration of diet may have potential as therapeutic agents in modulating the risk of chronic diseases. Interestingly, evidence emerging in recent years suggests that dietary miRNAs can be absorbed in human circulation, modulated human gene expression and biological functions. The exploitation of the miRNA functioning within different origins, cellular miRNAs and dietary miRNAs will help us to understand the molecular machinery as well as the regulatory mechanisms involved in fundamentally important biological processes. Therefore, this knowledge may be applied of natural bioactive compounds in preventive or therapeutic approaches.
- functional foods
- dietary microRNAs
- chronic diseases
- non-communicable diseases
1. Introduction - Origin, biogenesis and functions of microRNAs
MicroRNAs or miRNAs are a class of small non-coding RNA approximately 21–25 nucleotides that modulate on gene expression post-transcriptionally via binding to the 3′ untranslated region (3′-UTR) of the target messenger RNA (mRNA), resulting in mRNA degradation or translational repression. The first miRNA, lin-4, was discovered by Ambro and his research group in 1993 and it was found to be related with larva development in
miRNAs are normally transcribed by RNA polymerase II from miRNA genes. This transcription leads to generate a primary miRNA transcript (pri-miRNA). Then, pri-miRNA is further cleaved by a microprocessor complex, which consists of Drosha, the double-stranded RNase III enzyme and DiGeorge syndrome critical region 8 (DGCR8), important cofactor, into a hairpin structure precursor miRNA (pre-miRNA) in the nucleus (Figure 1). The double strand pre-miRNAs with 70 nucleotides are then exported to the cytoplasm by the process of nuclear export factor exportin-5. The pre-miRNA is then processed by RNase III, Dicer, thereby generating a mature miRNA:miRNA duplex approximately 22 nucleotides in length and without a hairpin structure. The helicase enzyme cleaves miRNA duplexes into single-stranded miRNAs and incorporated into the Argonaute (AGO), TRBP and PACT proteins to form the RNA-induced silencing complex (RISC). Usually, other single strand called passenger strand or the star (*) strand will be degraded, while single strand mature miRNA is able to bind with its target mRNA and mediating translational inhibition or mRNA degradation, along with their sequence complementarity to the target [1, 3]. In plants, target mRNA will be degraded if miRNA has perfect or near-perfect complementarity to its target. In contrast to mammal, miRNAs bind to partially complementary sites in the 3′-UTRs of target mRNA, which leading to translational repression . the target mRNA is either blocked (imperfect complementary) or degraded (perfect complementary) of the ribosomal translation, which sequentially impacts the cellular functions.
Phytochemicals are major plant-derived compounds that naturally found in vegetables, fruits, medicinal plants or other plants with medicinal properties including antioxidant, anti-diabetic, anti-inflammatory, antimicrobial, antidepressant, anticancer and prevention in other chronic non-communicable diseases [5, 6, 7]. Phenolic and flavonoid compounds are the most important group of bioactive compounds and second metabolites in plants which comprise of essential molecules of human diet [6, 8]. It has been shown that bioactive compounds can modulate the endogenous miRNAs expression [1, 9, 10, 11, 12]. Recently, some studies have revealed that plant-derived miRNAs (dietary miRNAs) as new bioactive compounds in plants can affect the synthesis of endogenous miRNAs [13, 14, 15]. Strikingly, miRNAs do not function only their origins but they are able to regulate the gene expression in cross-kingdom. Therefore, bioactive compounds present in functional foods are potentially regulate endogenous miRNAs expression.
2. Dietary compounds and endogenous miRNAs
Extensive studies have been performed to understand the molecular mechanism of bioactive compounds with a positive effect on chronic diseases or non-communicable diseases such as arthritis, cancer, cardiovascular diseases, diabetes and obesity [1, 16]. Emerging evidences confirm that alteration of endogenous miRNAs expression can be influenced by bioactive compounds in functional foods [16, 17] (Figure 2 and Table 1).
|Dietary compound||miRNA expression||Target of miRNA||Diseases||References|
|Acetyl-11-Keto-β-Boswellic Acid||miR-27a miR-34a||Unknown||Colorectal cancer|||
|Cinnamic acid derivatives||miR-143||MAPK/Erk5||Colon cancer|||
|Curcumin||miR-15a, miR-16, miR-34a, miR-146b-5p|
|miR-19a miR-19b||Unknown||Breast cancer|||
|miR-101, miR-200b, miR-200c, miR-141 miR-429||miR-21||Unknown||Colorectal cancer||[39, 40]|
miR-1908 miR-3127 miR-3178 miR-3198
|miR-23b*, miR-183 miR-193b* miR-210 miR-222* miR-494 miR-664*|
|miR-181b||CXCL1 CXCL2||Breast cancer|||
|miR-124 miR-155||Unknown||Neurodegenerative disorder|||
|Sox4 Cdc25A||Breast cancer||[48, 49]|
|let-7b, let-7c, let-7d, let-7e, and miR-200b/c||ZEB-1,|
|let-7a miR34a||c-Myc||Hepatocellular carcinoma|||
|miR-29 miR-210||miR-125b miR-203||Unknown||Cervical cancer|||
|miR-10b miR-181a miR-221||Unknown||Liver fibrosis|||
|miR-1260b||sRRP1 Smad4||Prostate cancer|||
|miR-1260b||sFRP1, Dkk2, Smad4||Renal cancer|||
|miR-451||Unknown||Chronic liver disease|||
miR-298 miR-2218 miR-1502 miR-2117
|Unknown||Oxidative stress in pheochromocytoma|||
miR-1283, miR-3714 miR-6867-5p
|Silymarin||miR-203||class 1 HDAC proteins and ZEB1||Lung cancer|||
|miR-122 miR-192 miR-194||Unknown||Liver damage|||
|Sulforaphane||miR-23b miR-92b miR-381 miR-382||Unknown||Breast cancer|||
|miR-9 miR-326||Unknown||Gastric cancer|||
2.1 Acetyl-11-keto-β-boswellic acid
3-acetyl-11-keto- β -boswellic acid (AKBA) is pentacyclic triterpene acids that mainly found in
Arctigenin (AR) is a phenylpropanoid dizbenzylbutyrolactone lignin and was first identified in
2.3 Cinnamic acid derivatives
Cinnamic acid derivatives can occur naturally in plants and their structure composing of benzene ring and acrylic acid group. Several compounds of cinnamic acid derivatives have been identified including artepilin C, baccharin, drupanin, ferulic acid, curcumin, caffeic acid, p-hydroxycinnamic acid, coumaric and chlorogenic acids, etc. [30, 31]. Medicinal activities of cinnamic acid derivatives have been reported such as anti-inflammatory, anti-oxidant, anti-viral, anti-microbial, anti-diabetic, neuroprotective and anti-tumor activities [30, 31, 32]. Cinnamic acid derivatives from propolis significantly induced colon cancer cell apoptosis through TRAIL/DR4/5 and/or FasL/Fas death-signaling pathways and via the upregulated miR-143 expression, resulting in decreased the target gene MAPK/Erk5 expression and its downstream target c-Myc . Moreover, Li et al. demonstrated that cinnamic acid derivatives decreased gastric cancer cell proliferation through the up-regulation of miR-145 and down-regulation P13K/Akt signaling pathway . Therefore, cinnamic acid derivatives have a potential as therapeutic agents for cancer.
Curcumin[(1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptane-3,5-dione] is well known as natural polyphenol and derived from the rhizome of turmeric or
3,3′-diindolylmethane (DIM) is a naturally active compound found in stomach, which derived from indole-3-carbinol (I3C) that present in cruciferous vegetables. DIM has been reported to regulate several miRNAs expression in cancer. Tumor suppressor miRNAs was upregulated by DIM in prostate cancer cells including let-7, miR-34a and miR-150-5p by targeting EZH2, Notch1 and AR and Ahr, respectively . DIM also upregulated tumor suppressor miR-200, which led to inhibit the expression of FoxM1 in breast cancer cells . miR-212/132 cluster and miR-21 were upregulated by DIM, which downregulated the expression of Sox4 and Cdc25A, respectively in breast cancer [48, 49]. Moreover, DIM upregulated let-7b, let-7c, let-7d, let-7e, and miR-200b/c expression, which led to inhibit the expression of ZEB-1, E-cadherin in pancreatic cancer cells . It has been reported miR-146a was upregulated upon treated with DIM and suppressed the expression of MTA2, NF-κB, IRAK1, EGFR in pancreatic cancer cells .
DIM showed the modulation of miRNAs expression in other inflammatory diseases. The expression of miR-106a, miR-20b, and miR-125b-5p were increased after treatment with DIM and suppressed the expression of IRAK4 and TNF-α to limit responses to TLRs activated by LPS in acute liver failure (ALF) animal model . DIM significantly upregulated miR-200c, miR-146a, miR-16, miR-93, and miR-22 in brain CD4+ T cells and inhibited the expression of cyclin E1 and B-cell lymphoma-2 in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis .
(−)-Epigallocatechin-3-Gallate or EGCG is a major polyphenol compound in green tea (
EGCG showed the protective effect against myocardial ischemia/reperfusion (I/R) injury through up-regulation of miR-384-mediated autophagy by targeting Beclin-1 via activating the PI3K/Akt signaling pathway . EGCG also demonstrated the anti-arthritic effects by inhibited IL-1β-induced ADAMTS5 expression and up-regulated the expression of miR-140-3p in osteoarthritis chondrocytes . EGCG treatment has potential role of preventing toxin-induced fibrosis by suppression of osteopontin expression and up-regulation of miR-10b, miR-181a and miR-221 in liver hepatocellular carcinoma cells .
Genistein belongs to isoflavone family and presents in soybeans with antiangiogenic, anti-metastasis, anti-inflammatory, anti-oxidant, cell cycle arrest and induction of apoptosis effects . Genistein can regulate the expression of miRNAs in several call types . It has been reported that treatment of genistein up-regulated miR-23b and inhibited breast cancer cell growth . Genistein also exhibited anti-tumor effect by down-regulated miR-1260b and targeting sRRP1 and Smad4 through DNA methylation or histone modifications in prostate cancer cells . The same research group reported that miR-1260b was highly expressed in renal cancer cells and miR-1260b was down-regulated in genistein treated renal cancer cells . The treatment of miR-1260b inhibitor inhibited the expression of its target genes, sFRP1, Dkk2, Smad4 . Treatment with genistein induced non-small lung cancer cell apoptosis, caspase-3/9 activation and inhibited cell proliferation via up-regulation of miR-27a -mediated MET signaling . Co-encapsulate miR-29b with genistein in hybrid nanoparticles (GMLHN) has been studied to treat effectively in non-small lung cancer cell and GMLHN showed the anti-proliferative effect by down-regulation of phosphorylated AKT (pAKT) and phosphorylated phosphoinositide-3 kinase (p-PI3K) .
Genistein promoted myoblast proliferation and differentiation through down-regulated miR-222 expression, resulting in increased expression of its target genes, MyoG, MyoD, and ERα . Interestingly, genistein up-regulated miR-451 expression and inhibited IL1β expression and inflammation in chronic liver disease nonalcoholic steatohepatitis (NASH) mice model .
Quercetin is bioactive flavonoids that can be found in fruits and vegetables including onion, kale, apple, many berries, citrus fruits and tea . Anti-cancer, anti-inflammatory, antioxidant, anti-diabetes, anti-atherosclerosis and anti-viral effects have been reported in different in vitro studies for quercetin . Several studies have focused on quercetin and miRNAs modulation for therapeutic approaches. miR-200b-3p was up-regulated in pancreatic cancer cells when treated with quercetin, resulting in inhibition of self-renewal and decrease of proliferation through Notch1 signaling pathway . Quercetin significantly inhibited breast cancer cell proliferation and invasion via up-regulated miR-146a expression and targeting EGFR . Quercetin inhibited cell viability, migration and invasion by up-regulated miR-16 and targeting HOXA10 in oral cancer cells . In addition, quercetin decreased oral cancer cell viability and increased cell apoptosis via miR-22/WNT1/β-catenin pathway .
Recently, quercetin modulated 34 miRNAs expression (5 upregulated and 29 downregulated) and novel miR-97, miR-298, miR-2218, miR-1502, and miR-2117 were identified in pheochromocytoma of the rat adrenal medulla that responded for protective effect against oxidative stress through PI3K-AKT signaling pathway . Treatment of quercetin inhibited proliferation of endometriosis through up-regulated miR-503-5p, miR-1283, miR-3714 and miR-6867-5p by targeting CCND1 . TGFβ1 is a fibrosis inducer and quercetin significantly down-regulated miR-21 and TGFβ1 and up-regulated miR-122 in liver fibrosis . Protection of cardiomyocyte against hypoxia caused insults of quercetin has been reported by up-regulation of miR-199 mediated sirt1 expression and AMPK phosphorylation .
Silymarin is a flavonolignans extracted from the milk thistle
β-Sitosterol-d-glucoside is bioactive compounds that has been isolated from
Sulforaphane is dietary compounds in broccoli (
Sulforaphane has potential to inhibit hepatic fibrosis by downregulating miR-423-5p in hepatic stellate cell . Sulforaphane showed the protective effect in microglia-mediated neurotoxicity by inhibited LPS-induced expression of inflammatory miRNA, miR-155 .
3. Dietary miRNA and human gene regulation
Several evidences demonstrated the direct modulation of cellular signaling pathways by dietary compounds could decrease the risk of chronic diseases . Interestingly, it has been reported that small non-coding RNA including miRNAs can be transferred across Kingdoms, for example dietary miRNAs have been found in human body fluids and these circulating miRNAs are likely to regulate human gene expression [15, 102, 103, 104, 105, 106, 107]. The uptake of plant derived miRNAs could be in the form of raw and cooked plants in capable of stability forms [107, 108]. Due to high temperature cooking process, low pH and enzymes in digestive tract as well as enzymes in blood circulation, miRNAs might be destroyed before their functions with target mRNAs . Strikingly, GC base content, 2’-O-methylation on the 3′-terminal, unique nucleotide sequence of dietary miRNAs and extracellular vesicles (exosome and microvesicle) are preventive features of plant derived miRNAs in harmful conditions [109, 110, 111, 112, 113, 114].
There are numerous studies to support the functional roles of dietary miRNAs in cross kingdom gene regulation. Rice miR156a and miR168a were detected in human serum and miR168a down-regulated low-density lipoprotein receptor adapter protein 1 (LDLRAP1) expression, resulted in an increase of plasma LDL cholesterol level, Table 2 . miR2910 from
|Plants||Plant derived-miRNAs||Human target gene/ Disease||References|
|14 miRNAs||Cancer (breast, lung and leukemia)|||
|Ras-MAPK signaling pathway, Alzheimer disease,|
breast cancer, cardiomyopathy, HIV, lung cancer,
several neurological disorders
|cabbage, spinach and lettuce||miR156a||Cardiovascular disease|||
|Cancer, cardiovascular and neurodegenerative diseases|||
The abundantly expressed miRNA in dietary green vegetable, miR156a which was detected in human serum and targeted the junction adhesion molecule-A (JAM-A) . The JAM-A was up-regulated in atherosclerotic lesions from cardiovascular disease patients and miR156a could suppressed inflammatory cytokine-induced monocytes adhesion by targeting JAM-A . The very recently report using a computational approach to predict the potential target of rice miRNAs including miR156-5p, miR164-5p, miR168-5p, miR395-3p, miR396-3p, miR396-5p, miR444-3p, miR529-3p, miR1846-3p, miR2907-3p, which can bind to the human mRNA . Most of these target genes were associated with cancer, cardiovascular and neurodegenerative diseases . miR14 derived from
It has been widely known that functional foods and their bioactive compounds have the capacity for human health benefits. To date, miRNAs have been shown a significant effect on gene expression and modulate the cellular biological functions in physiological and pathological conditions. There is emerging evidence suggesting that dietary bioactive compounds can be effective in human diseases as a result of altering miRNAs expression levels, resulting in modulation of cellular signaling pathway. Additional research the possibility of bioactive compounds for developing as novel drugs with less side effects is required
This study has been supported by University of Phayao Research Grant (Grant no. FF64-RIM037) and School of Medical Sciences Research Grant (Grant no. MS 632001), University of Phayao.