Heme metabolism genes Downregulated in COPD Cachexia.

IntroductionCachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.MethodsWe analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m2) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m2 among women and < 17 kg/m2 among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.ResultsThe prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).DiscussionSeveral replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage

Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes

Breast cancer (BC) is a nearly ubiquitous malignancy that effects the lives of millions worldwide. Recently, nutritional prevention of BC has received increased attention due to its efficacy and ease of application. Chief among chemopreventive compounds are plant-based substances known as dietary phytochemicals. Sulforaphane (SFN), an epigenetically active phytochemical found in cruciferous vegetables, has shown promise in BC prevention. In addition, observational studies suggest that the life stage of phytochemical consumption may influence its anticancer properties. These life stages, called critical periods (CPs), are associated with rapid development and increased susceptibility to cellular damage. Puberty, a CP in which female breast tissue undergoes proliferation and differentiation, is of particular interest for later-life BC development. However, little is known about the importance of nutritional chemoprevention to CPs. We sought to address this by utilizing two estrogen receptor-negative [ER(-)] transgenic mouse models fed SFN-containing broccoli sprout extract during the critical period of puberty. We found that this treatment resulted in a significant decrease in tumor incidence and weight, as well as an increase in tumor latency. Further, we found significant alterations in the long-term expression of cancer-associated genes, including p21, p53, and BRCA2. Additionally, our transcriptomic analyses identified expressional changes in many cancer-associated genes, and bisulfite sequencing revealed that the antiproliferation-associated gene Erich4 was both hypomethylated and overexpressed in our experimental group. Our study indicates that dietary interventions during the CP of puberty may be important for later-life ER(-) BC prevention and highlights potential important genetic and epigenetic targets for treatment and study of the more deadly variants of BC

Impact of Stilbenes as Epigenetic Modulators of Breast Cancer Risk and Associated Biomarkers

With the recent advancement of genetic screening for testing susceptibility to mammary oncogenesis in women, the relevance of the gene−environment interaction has become progressively apparent in the context of aberrant gene expressions. Fetal exposure to external stressors, hormones, and nutrients, along with the inherited genome, impact its traits, including cancer susceptibility. Currently, there is increasing interest in the role of epigenetic biomarkers such as genomic methylation signatures, plasma microRNAs, and alterations in cell-signaling pathways in the diagnosis and primary prevention of breast cancer, as well as its prognosis. Polyphenols like natural stilbenes have been shown to be effective in chemoprevention by exerting cytotoxic effects that can stall cell proliferation. Besides possessing antioxidant properties against the DNA-damaging effects of reactive oxygen species, stilbenes have also been observed to modulate cell-signaling pathways. With the increasing trend of early-life screening for hereditary breast cancer risks, the potency of different phytochemicals in harnessing the epigenetic biomarkers of breast cancer risk demand more investigation. This review will explore means of exploiting the abilities of stilbenes in altering the underlying factors that influence breast cancer risk, as well as the appearance of associated biomarkers

Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes

Breast cancer (BC) is a nearly ubiquitous malignancy that effects the lives of millions worldwide. Recently, nutritional prevention of BC has received increased attention due to its efficacy and ease of application. Chief among chemopreventive compounds are plant-based substances known as dietary phytochemicals. Sulforaphane (SFN), an epigenetically active phytochemical found in cruciferous vegetables, has shown promise in BC prevention. In addition, observational studies suggest that the life stage of phytochemical consumption may influence its anticancer properties. These life stages, called critical periods (CPs), are associated with rapid development and increased susceptibility to cellular damage. Puberty, a CP in which female breast tissue undergoes proliferation and differentiation, is of particular interest for later-life BC development. However, little is known about the importance of nutritional chemoprevention to CPs. We sought to address this by utilizing two estrogen receptor-negative [ER(-)] transgenic mouse models fed SFN-containing broccoli sprout extract during the critical period of puberty. We found that this treatment resulted in a significant decrease in tumor incidence and weight, as well as an increase in tumor latency. Further, we found significant alterations in the long-term expression of cancer-associated genes, including p21, p53, and BRCA2. Additionally, our transcriptomic analyses identified expressional changes in many cancer-associated genes, and bisulfite sequencing revealed that the antiproliferation-associated gene Erich4 was both hypomethylated and overexpressed in our experimental group. Our study indicates that dietary interventions during the CP of puberty may be important for later-life ER(-) BC prevention and highlights potential important genetic and epigenetic targets for treatment and study of the more deadly variants of BC

Combinatorial Epigenetics Impact of Polyphenols and Phytochemicals in Cancer Prevention and Therapy

Polyphenols are potent micronutrients that can be found in large quantities in various food sources and spices. These compounds, also known as phenolics due to their phenolic structure, play a vital nutrient-based role in the prevention of various diseases such as diabetes, cardiovascular diseases, neurodegenerative diseases, liver disease, and cancers. However, the function of polyphenols in disease prevention and therapy depends on their dietary consumption and biological properties. According to American Cancer Society statistics, there will be an expected rise of 23.6 million new cancer cases by 2030. Due to the severity of the increased risk, it is important to evaluate various preventive measures associated with cancer. Relatively recently, numerous studies have indicated that various dietary polyphenols and phytochemicals possess properties of modifying epigenetic mechanisms that modulate gene expression resulting in regulation of cancer. These polyphenols and phytochemicals, when administrated in a dose-dependent and combinatorial-based manner, can have an enhanced effect on epigenetic changes, which play a crucial role in cancer prevention and therapy. Hence, this review will focus on the mechanisms of combined polyphenols and phytochemicals that can impact various epigenetic modifications such as DNA methylation and histone modifications as well as regulation of non-coding miRNAs expression for treatment and prevention of various types of cancer

The Epigenetic Link between Polyphenols, Aging and Age-Related Diseases

Aging is a complex process mainly categorized by a decline in tissue, cells and organ function and an increased risk of mortality. Recent studies have provided evidence that suggests a strong association between epigenetic mechanisms throughout an organism’s lifespan and age-related disease progression. Epigenetics is considered an evolving field and regulates the genetic code at several levels. Among these are DNA changes, which include modifications to DNA methylation state, histone changes, which include modifications of methylation, acetylation, ubiquitination and phosphorylation of histones, and non-coding RNA changes. As a result, these epigenetic modifications are vital targets for potential therapeutic interventions against age-related deterioration and disease progression. Dietary polyphenols play a key role in modulating these modifications thereby delaying aging and extending longevity. In this review, we summarize recent advancements linking epigenetics, polyphenols and aging as well as critical findings related to the various dietary polyphenols in different fruits and vegetables. In addition, we cover studies that relate polyphenols and their epigenetic effects to various aging-related diseases such as cardiovascular diseases, neurodegenerative diseases, autoimmune disorders, diabetes, osteoporosis and cancer

Genome-Wide Analysis on Transcriptome and Methylome in Prevention of Mammary Tumor Induced by Early Life Combined Botanicals

Breast cancer (BC) is the most common malignancy and the second leading cause of cancer death among women in the United States. The consumption of natural dietary components such as broccoli sprouts (BSp) and green tea polyphenols (GTPs) has demonstrated exciting potential in reducing the risk of BC through the regulation of epigenetic mechanisms. However, little is known about their impacts on reversing epigenomic aberrations that are centrally involved in the initiation and progression of BC. Previously, we have determined the efficacy of combined BSp and GTPs treatment on the inhibition of the growth of a mammary tumor in a transgenic Her2/neu mouse model. We sought to extend our previous study to identify universal biomarkers that represent common mechanistic changes among different mouse models in response to this dietary regime by including a new transgenic mouse model, C3(1)-SV40 TAg (SV40). As a result, we identified novel target genes that were differentially expressed and methylated in response to dietary botanicals when administered singly (BSp and GTPs) and in combination (BSp + GTPs) in both mouse models. We discovered more differentially expressed and methylated genes in the combination treatment group compared to the singly administered groups. Subsequently, several biological pathways related to epigenetic regulations were identified in response to the combination treatment. Furthermore, when compared to the BSp and GTPs treatment alone, the combinatorial treatment showed a more significant impact on the regulation of the epigenetic modifier activities involved in DNA methylation and histone modifications. Our study provides key insights about the impact of the combined administration of BSp and GTPs on BC using a multi-omics analysis, suggesting a combinatorial approach is more efficacious in preventing and inhibiting BC by impacting key tumor-related genes at transcriptomic and methylomic levels. Our findings could be further extrapolated as a comprehensive source for understanding the epigenetic modifications that are associated with the effects of these dietary botanicals on BC prevention.https://doi.org/10.3390/cells1201001

Genome-Wide Analysis on Transcriptome and Methylome in Prevention of Mammary Tumor Induced by Early Life Combined Botanicals

Breast cancer (BC) is the most common malignancy and the second leading cause of cancer death among women in the United States. The consumption of natural dietary components such as broccoli sprouts (BSp) and green tea polyphenols (GTPs) has demonstrated exciting potential in reducing the risk of BC through the regulation of epigenetic mechanisms. However, little is known about their impacts on reversing epigenomic aberrations that are centrally involved in the initiation and progression of BC. Previously, we have determined the efficacy of combined BSp and GTPs treatment on the inhibition of the growth of a mammary tumor in a transgenic Her2/neu mouse model. We sought to extend our previous study to identify universal biomarkers that represent common mechanistic changes among different mouse models in response to this dietary regime by including a new transgenic mouse model, C3(1)-SV40 TAg (SV40). As a result, we identified novel target genes that were differentially expressed and methylated in response to dietary botanicals when administered singly (BSp and GTPs) and in combination (BSp + GTPs) in both mouse models. We discovered more differentially expressed and methylated genes in the combination treatment group compared to the singly administered groups. Subsequently, several biological pathways related to epigenetic regulations were identified in response to the combination treatment. Furthermore, when compared to the BSp and GTPs treatment alone, the combinatorial treatment showed a more significant impact on the regulation of the epigenetic modifier activities involved in DNA methylation and histone modifications. Our study provides key insights about the impact of the combined administration of BSp and GTPs on BC using a multi-omics analysis, suggesting a combinatorial approach is more efficacious in preventing and inhibiting BC by impacting key tumor-related genes at transcriptomic and methylomic levels. Our findings could be further extrapolated as a comprehensive source for understanding the epigenetic modifications that are associated with the effects of these dietary botanicals on BC prevention

Repositioning drugs by targeting network modules: a Parkinson’s disease case study

Abstract Background Much effort has been devoted to the discovery of specific mechanisms between drugs and single targets to date. However, as biological systems maintain homeostasis at the level of functional networks robustly controlling the internal environment, such networks commonly contain multiple redundant mechanisms designed to counteract loss or perturbation of a single member of the network. As such, investigation of therapeutics that target dysregulated pathways or processes, rather than single targets, may identify agents that function at a level of the biological organization more relevant to the pathology of complex diseases such as Parkinson’s Disease (PD). Genome-wide association studies (GWAS) in PD have identified common variants underlying disease susceptibility, while gene expression microarray data provide genome-wide transcriptional profiles. These genomic studies can illustrate upstream perturbations causing the dysfunction in signaling pathways and downstream biochemical mechanisms leading to the PD phenotype. We hypothesize that drugs acting at the level of a gene expression module specific to PD can overcome the lack of efficacy associated with targeting a single gene in polygenic diseases. Thus, this approach represents a promising new direction for module-based drug discovery in human diseases such as PD. Results We built a framework that integrates GWAS data with gene co-expression modules from tissues representing three brain regions—the frontal gyrus, the lateral substantia, and the medial substantia in PD patients. Using weighted gene correlation network analysis (WGCNA) software package in R, we conducted enrichment analysis of data from a GWAS of PD. This led to the identification of two over-represented PD-specific gene co-expression network modules: the Brown Module (Br) containing 449 genes and the Turquoise module (T) containing 905 genes. Further enrichment analysis identified four functional pathways within the Br module (cellular respiration, intracellular transport, energy coupled proton transport against the electrochemical gradient, and microtubule-based movement), and one functional pathway within the T module (M-phase). Next, we utilized drug-protein regulatory relationship databases (DMAP) and developed a Drug Effect Sum Score (DESS) to evaluate all candidate drugs that might restore gene expression to normal level across the Br and T modules. Among the drugs with the 12 highest DESS scores, 5 had been reported as potential treatments for PD and 6 hold potential repositioning applications. Conclusion In this study, we present a systems pharmacology framework which draws on genetic data from GWAS and gene expression microarray data to reposition drugs for PD. Our innovative approach integrates gene co-expression modules with biomolecular interaction network analysis to identify network modules critical to the PD pathway and disease mechanism. We quantify the positive effects of drugs in a DESS score that is based on known drug-target activity profiles. Our results illustrate that this modular approach is promising for repositioning drugs for use in polygenic diseases such as PD, and is capable of addressing challenges of the hindered gene target in drug repositioning approaches to date

Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms

Consumption of dietary natural components such as genistein (GE) found in soy-rich sources is strongly associated with a lower risk of breast cancer. However, bioactive dietary component-based therapeutic strategies are largely understudied in breast cancer treatment. Our investigation sought to elucidate the potential mechanisms linking bioactive dietary GE to its breast cancer chemotherapeutic potential in a special subtype of aggressive breast cancer—triple-negative breast cancer (TNBC)—by utilizing two preclinical patient-derived xenograft (PDX) orthotopic mouse models: BCM-3204 and TM00091. Our study revealed that administration of GE resulted in a delay of tumor growth in both PDX models. With transcriptomics analyses in TNBC tumors isolated from BCM-3204 PDXs, we found that dietary soybean GE significantly influenced multiple tumor-regulated gene expressions. Further validation assessment of six candidate differentially expressed genes (DEGs)—Cd74, Lpl, Ifi44, Fzd9, Sat1 and Wwc1—demonstrated a similar trend at gene transcriptional and protein levels as observed in RNA-sequencing results. Mechanistically, GE treatment-induced Cd74 downregulation regulated the NF-κB/Bcl-xL/TAp63 signal pathway, which may contribute to soybean GE-mediated therapeutic effects on TNBC tumors. Additionally, our findings revealed that GE can modify expression levels of key epigenetic-associated genes such as DNA methyltransferases (Dnmt3b), ten-eleven translocation (Tet3) methylcytosine dioxygenases and histone deacetyltransferase (Hdac2), and their enzymatic activities as well as genomic DNA methylation and histone methylation (H3K9) levels. Collectively, our investigation shows high significance for potential development of a novel therapeutic approach by using bioactive soybean GE for TNBC patients who have few treatment options