Regulation of main ncRNAs by polyphenols: A novel anticancer therapeutic approach.

BACKGROUND: Plant polyphenols have shown promising applications in oncotherapy. Increasing evidence reveals that polyphenols possess the antitumor potential for multiple cancers. Non-coding RNAs (ncRNAs), mainly including small ncRNAs (microRNA) and long ncRNAs (lncRNAs), play critical roles in cancer initiation and progression. PURPOSE: To establish the modulation of ncRNAs by polyphenols as a novel and promising approach in anticancer treatment. STUDY DESIGN: The present research employed ncRNA, miRNA, lncRNA, and regulatory mechanism as keywords to retrieve the literature from PubMed, Web of Science, Science direct, and Google Scholar, in a 20-year period from 2003 to 2023. This study critically reviewed the current literature and presented the regulation of prominent ncRNAs by polyphenols. A comprehensive total of 169 papers were retrieved on polyphenols and their related ncRNAs in cancers. RESULTS: NcRNAs, mainly including miRNA and lncRNA, play critical roles in cancer initiation and progression, which are potential modulatory targets of bioactive polyphenols, such as resveratrol, genistein, curcumin, EGCG, quercetin, in cancer management. The mechanism involved in polyphenol-mediated ncRNA regulation includes epigenetic and transcriptional modification, and post-transcriptional processing. CONCLUSION: Regulatory ncRNAs are potential therapeutic targets of bioactive polyphenols, and these phytochemicals could modulate the level of these ncRNAs directly and indirectly. A better comprehension of the ncRNA regulation by polyphenols in cancers, their functional outcomes on tumor pathophysiology and regulatory molecular mechanisms, may be helpful to develop effective strategies to fight the devastating disease.

Advanced glycation end products in diabetic retinopathy and phytochemical therapy.

Advanced glycation end products (AGEs) are generated by the nonenzymatic glycation of proteins or lipids. Diabetic retinopathy (DR) is one common complication in patients with diabetes. The accumulation of AGEs in retinal cells is strongly associated with the development of DR. AGEs can induce the breakdown of redox balance and then cause oxidative stress in retinal cells, exerting cytopathic effects in the progression of DR. The interaction between AGEs and the receptor for AGE (RAGE) is involved in multiple cellular pathological alterations in the retina. This review is to elucidate the pathogenetic roles of AGEs in the progression of DR, including metabolic abnormalities, lipid peroxidation, structural and functional alterations, and neurodegeneration. In addition, disorders associated with AGEs can be used as potential therapeutic targets to explore effective and safe treatments for DR. In this review, we have also introduced antioxidant phytochemicals as potential therapeutic strategies for the treatment of DR.

Decitabine enhances targeting of AML cells by NY-ESO-1-specific TCR-T cells and promotes the maintenance of effector function and the memory phenotype.

NY-ESO-1 is a well-known cancer-testis antigen (CTA) with re-expression in numerous cancer types, but its expression is suppressed in myeloid leukemia cells. Patients with acute myeloid leukemia (AML) receiving decitabine (DAC) exhibit induced expression of NY-ESO-1 in blasts; thus, we investigated the effects of NY-ESO-1-specific TCR-engineered T (TCR-T) cells combined with DAC against AML. NY-ESO-1-specific TCR-T cells could efficiently eliminate AML cell lines (including U937, HL60, and Kasumi-1cells) and primary AML blasts in vitro by targeting the DAC-induced NY-ESO-1 expression. Moreover, the incubation of T cells with DAC during TCR transduction (designated as dTCR-T cells) could further enhance the anti-leukemia efficacy of TCR-T cells and increase the generation of memory-like phenotype. The combination of DAC with NY-ESO-1-specific dTCR-T cells showed a superior anti-tumor efficacy in vivo and prolonged the survival of an AML xenograft mouse model, with three out of five mice showing complete elimination of AML cells over 90 days. This outcome was correlated with enhanced expressions of IFN-γ and TNF-α, and an increased proportion of central memory T cells (CD45RO+CD62L+ and CD45RO+CCR7+). Taken together, these data provide preclinical evidence for the combined use of DAC and NY-ESO-1-specific dTCR-T cells for the treatment of AML.

Development and evaluation of a novel nanofibersolosome for enhancing the stability, in vitro bioaccessibility, and colonic delivery of cyanidin-3-O-glucoside.

The development of colon-specific carrier systems using polysaccharides for oral delivery of nutraceuticals is of great importance for the treatment and/or prevention of inflammatory bowel diseases. In this study, self-assembly with the assistance of vortexing and pulsed-ultrasonication was employed to develop a Fibersol®-2 (a digestion-resistant polysaccharide) and lipoid S75 based novel nanocarrier (denoted as nanofibersolosome) for the colonic delivery of cyanidin-3-O-glucoside (C3G). A series of nanofibersolosome formulations (CFS-0.5-4, 0.5-4 represent the ratios of Fibersol®-2:lipoid S75) were developed and their performance was compared with Fibersol®-2-free reference lipid formulation (CFS-0). The nanofibersolosomes (<150 nm) were spherical and unilamellar with high negative surface charge (-38 to -51 mV) and good encapsulation efficiency (EE > 90%). They performed much better than CFS-0 in retaining their physical properties during freeze drying, preventing particle aggregation, and retaining C3G during storage (4 and 25 ℃) and thermal treatments (40, 60, and 80 ℃). They also exhibited significantly higher stability during simulated gastrointestinal digestion than CFS-0. These desirable features of the nanofibersolosomes (especially CFS-0.5 and CFS-1) led to the efficient delivery of higher concentrations of C3G to the colon than CFS-0. Moreover, gastrointestinal-digested and colonic-fermented nanofibersolosome samples exhibited significantly higher DPPH radical scavenging activity and stronger promoting effect on short-chain fatty acid generation than CFS-0. These in vitro findings indicate that the novel nanofibersolosome possesses great potential for the colonic delivery of C3G and likely other hydrophilic labile phytochemicals that merits further evaluation in in vivo models.

Oral administration of EGCG solution equivalent to daily achievable dosages of regular tea drinkers effectively suppresses miR483-3p induced metastasis of hepatocellular carcinoma cells in mice.

The effect of non-cytotoxic doses of epigallocatechin-3-gallate (EGCG) on the metastatic capability of human hepatocellular carcinoma (HCC) cells was investigated in vitro and in vivo. miR483-3p, a microRNA whose expression correlates inversely with survival and positively with disease progression in HCC patients, was found to promote HCC cell migration and invasion in vitro as well as lung metastasis in nude mice established by the tail-vein injection of HCC cells. The induction of reactive oxygen species (ROS) and downregulation of antioxidant defense factors Nrf2 and SOD2 appeared to be an important underlying mechanism and treatment with a non-cytotoxic dose of EGCG effectively reversed the miR483-3p-induced enhancement of HCC cell migration and invasion in vitro. Moreover, administration through drinking water at doses (0.1% and 0.5% EGCG solution, respectively) equivalent to the intake of regular to heavy tea drinkers could also significantly inhibit lung metastasis of HCC cells based on the estimation from the USDA Database for the Flavonoid Content of Selected Foods and FDA guidelines for the conversion of animal dose to human equivalent dose. EGCG also significantly counteracted the miR483-3p-induced alteration in the expression of epithelial-mesenchymal transition (EMT) markers, E-cadherin and vimentin, and downregulated the endogenous expression of miR483-3p in HCC cells through an epigenetic mechanism that led to the hypermethylation of the miR483-3p promoter region. The data from our study illustrate that miR483-3p promotes HCC metastasis likely through the induction of oxidative stress and uncover a novel role of EGCG for protection against miR483-3p-mediated HCC metastasis via the epigenetic modulation of miR483-3p expression. These findings therefore provide further evidence supporting that regular tea consumption may contribute to protection against miR-483-3p-induced ROS and the associated HCC progression.

A novel potent inhibitor of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) formation from Chinese chive: Identification, inhibitory effect and action mechanism.

Differential solvent extraction and phytochemical profiling of Chinse chive were employed to identify its principal PhIP-formation inhibitory constituents. Six compounds (mangiferin, isorhamnetin, luteolin, rosmarinic acid, 6-methylcoumarin, and cyanidin-3-glucoside) were further analyzed in a PhIP-producing chemical model to identify the dominant inhibitor. Its inhibitory mechanism was investigated by assessing the contribution of antioxidation and scavenging of key PhIP precursor/intermediate. No significant correlation was observed between PhIP inhibition rates and antioxidant activities. Further evaluation of the novel potent inhibitor mangiferin revealed a highly significant correlation between its dose-dependent inhibition of PhIP formation and phenylacetaldehyde scavenging. Finally, the proposed mechanism was corroborated through organic synthesis and structural elucidation of the mangiferin-phenylacetaldehyde adduct. This study has identified a potent novel inhibitor of the most abundant HA in heat-processed food and characterized its action mechanism. These findings may provide insight for future studies on mitigation of dietary exposure to toxic Maillard products by polyphenolic phytochemicals.

Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications.

Oxidative stress, a cytopathic outcome of excessive generation of ROS and the repression of antioxidant defense system for ROS elimination, is involved in the pathogenesis of multiple diseases, including diabetes and its complications. Retinopathy, a microvascular complication of diabetes, is the primary cause of acquired blindness in diabetic patients. Oxidative stress has been verified as one critical contributor to the pathogenesis of diabetic retinopathy. Oxidative stress can both contribute to and result from the metabolic abnormalities induced by hyperglycemia, mainly including the increased flux of the polyol pathway and hexosamine pathway, the hyper-activation of protein kinase C (PKC) isoforms, and the accumulation of advanced glycation end products (AGEs). Moreover, the repression of the antioxidant defense system by hyperglycemia-mediated epigenetic modification also leads to the imbalance between the scavenging and production of ROS. Excessive accumulation of ROS induces mitochondrial damage, cellular apoptosis, inflammation, lipid peroxidation, and structural and functional alterations in retina. Therefore, it is important to understand and elucidate the oxidative stress-related mechanisms underlying the progress of diabetic retinopathy. In addition, the abnormalities correlated with oxidative stress provide multiple potential therapeutic targets to develop safe and effective treatments for diabetic retinopathy. Here, we also summarized the main antioxidant therapeutic strategies to control this disease.

Resveratrol: Evidence for Its Nephroprotective Effect in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Dietary habits play a major role in determining the onset and progression of DM-related disorders and a proper diet (rich in fruits and vegetables) can delay or prevent the process of DM pathogenesis. Thus, increasing attention has been paid to polyphenols and polyphenol-rich foods since their increased intake has been associated with a reduced incidence of DM and its associated complications. Resveratrol is a polyphenolic phytoalexin that is mainly found in grapevines and berries. It is available in various pharmaceutical dosages and is widely recommended as a dietary supplement due to its beneficial effects. Remarkably, resveratrol's capability to effectively lower blood glucose levels without any side effects has been amply demonstrated in many in vitro and in vivo studies. Herein, we comprehensively review and discuss the nephroprotective effect of resveratrol during DN and its associated mechanisms. Resveratrol exerts its nephroprotective effects via various mechanisms including reducing oxidative stress and advanced glycation end-product (AGE) production, stimulating autophagy, inhibiting endoplasmic reticulum (ER) stress and inflammation, ameliorating lipotoxicity, activating the AMP kinase (AMPK) pathway, and modulating angiogenesis. Moreover, the use of resveratrol as an adjuvant to conventional antidiabetic therapies could be an effective approach to manage DN in humans. However, evidence is scarce to support whether resveratrol has beneficial effects in humans during DN. Therefore, clinical studies are warranted to elucidate resveratrol's role against DN.

6-C-(E-Phenylethenyl)Naringenin Attenuates the Stemness of Hepatocellular Carcinoma Cells by Suppressing Wnt/ß-Catenin Signaling.

The effect of a novel semi-natural derivative of naringenin, 6-C-(E-phenylethenyl)naringenin (6-CEPN) on hepatocellular carcinoma (HCC) stemness was evaluated both in vitro and in vivo. 6-CEPN reduced HCC cell viability, inhibited sphere formation, cell migration and invasion, and blocked epithelial-mesenchymal transition. It was equally effective against NANOG+ cells sorted from cultured HCC cells that was accompanied by downregulation of stemness-associated transcription factors and attenuated HIF-1 activity. Furthermore, 6-CEPN significantly enhanced the sensitivity of HCC cells to therapeutic drugs, and inhibited HCC tumor growth and lung metastasis of HCC cells. 6-CEPN suppressed Wnt/ß-catenin signaling by inducing ß-catenin degradation and inhibiting its nuclear translocation. Upregulation of GSK3ß appeared to be crucial for 6-CEPN's inhibitory activity in the signaling pathway. These findings indicate that 6-CEPN has a strong effect against liver cancer, which is mediated, at least in part, by suppressing the stemness of HCC cells through an action mechanism involving Wnt/ß-catenin signaling.

Chronic exposure to tetrabromodiphenyl ether (BDE-47) aggravates hepatic steatosis and liver fibrosis in diet-induced obese mice.

Exposure to polybrominated diphenyl ethers (PBDEs), is closely associated with the occurrence of obesity and non-alcoholic fatty liver disease (NAFLD), yet their pathological effects and underlying mechanisms remain unclear. To examine the role of 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) in the progression of NAFLD under obese condition, male C57BL/6 J mice were fed with diet interaction for 15 weeks and subcutaneously injected with BDE-47 (7 mg/kg or 70 mg/kg) or the vehicle weekly. BDE-47 exposure (70 mg/kg) significantly elevated the body weight and worsened hepatic steatosis along with increased inflammation in high fat diet (HFD) fed mice. Furthermore, integration analysis of lipidomics and gene expression revealed that BDE-47 up-regulated triglyceride synthesis but suppressed lipid exportation and ß oxidation, aggravating the accumulation of hepatic lipid in HFD fed mice. In addition, the increase of liver fibrosis, serum transaminase levels, as well as lipid peroxidation have been observed in mice co-treated with BDE-47 and HFD. Moreover, BDE-47-induced fibrogenic responses in hepatocytes were suppressed by antioxidants, which confirmed that BDE-47-induced liver fibrosis was tightly associated with oxidative stress. In conclusion, these results provided new and robust evidence for revealing the hepatoxicity of BDE-47 under obese condition and illustrated the underlying mechanism of BDE-47 induced liver fibrosis.

A framework for identifying dysregulated chromatin regulators as master regulators in human cancer.

MOTIVATION: Chromatin regulators (CRs) are frequently dysregulated to reprogram the epigenetic landscape of the cancer genome. However, the underpinnings of the dysregulation of CRs and their downstream effectors remain to be elucidated. RESULTS: Here, we designed an integrated framework based on multi-omics data to identify candidate master regulatory CRs affected by genomic alterations across eight cancer types in The Cancer Genome Atlas. Most of them showed consistent activated or repressed (i.e. oncogenic or tumor-suppressive) roles in cancer initiation and progression. In order to further explore the insight mechanism of the dysregulated CRs, we developed an R package ModReg based on differential connectivity to identify CRs as modulators of transcription factors (TFs) involved in tumorigenesis. Our analysis revealed that the connectivity between TFs and their target genes (TGs) tended to be disrupted in the patients who had a high expression of oncogenic CRs or low-expression of tumor-suppressive CRs. As a proof-of-principle study, 14 (82.4%) of the top-ranked 17 driver CRs in liver cancer were able to be validated by literature mining or experiments including shRNA knockdown and dCas9-based epigenetic editing. Moreover, we confirmed that CR SIRT7 physically interacted with TF NFE2L2, and positively modulated the transcriptional program of NFE2L2 by affecting ∼64% of its TGs. AVAILABILITY AND IMPLEMENTATION: ModReg is freely accessible at http://cis.hku.hk/software/ModReg.tar.gz. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MICMIC: identification of DNA methylation of distal regulatory regions with causal effects on tumorigenesis.

Aberrant promoter methylation is a common mechanism for tumor suppressor inactivation in cancer. We develop a set of tools to identify genome-wide DNA methylation in distal regions with causal effect on tumorigenesis called MICMIC. Many predictions are directly validated by dCas9-based epigenetic editing to support the accuracy and efficiency of our tool. Oncogenic and lineage-specific transcription factors are shown to aberrantly shape the methylation landscape by modifying tumor-subtype core regulatory circuitry. Notably, the gene regulatory networks orchestrated by enhancer methylation across different cancer types are seen to converge on a common architecture. MICMIC is available on https://github.com/ZhangJlab/MICMIC .

High expression of long non-coding RNA H19 is required for efficient tumorigenesis induced by Bcr-Abl oncogene.

Dysregulation of non-coding RNA H19 has been observed in various tumors. However, it remains unknown whether H19 is involved in Bcr-Abl-induced leukemia. Here, we demonstrate a critical requirement for H19 in Bcr-Abl-mediated tumorigenesis. H19 was highly expressed in Bcr-Abl-transformed cell lines and primary cells derived from patients in a Bcr-Abl kinase-dependent manner. Silencing H19 expression sensitized leukemic cells to undergo imatinib-induced apoptosis and inhibited Bcr-Abl-induced tumor growth. Furthermore, H19 was shown to be regulated by c-Myc in Bcr-Abl-expressing cells. These results reveal an important role H19 plays in Bcr-Abl-mediated transformation and provide novel insights into complex mechanisms underlying Bcr-Abl-induced cancers.