Variability in the Clinical Effects of the Omega-3 Polyunsaturated Fatty Acids DHA and EPA in Cardiovascular Disease-Possible Causes and Future Considerations.

Cardiovascular disease (CVD) that includes myocardial infarction and stroke, is the leading cause of mortality worldwide. Atherosclerosis, the primary underlying cause of CVD, can be controlled by pharmacological and dietary interventions, including n-3 polyunsaturated fatty acid (PUFA) supplementation. n-3 PUFA supplementation, primarily consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has shown promise in reducing atherosclerosis by modulating risk factors, including triglyceride levels and vascular inflammation. n-3 PUFAs act by replacing pro-inflammatory fatty acid types in cell membranes and plasma lipids, by regulating transcription factor activity, and by inducing epigenetic changes. EPA and DHA regulate cellular function through shared and differential molecular mechanisms. Large clinical studies on n-3 PUFAs have reported conflicting findings, causing confusion among the public and health professionals. In this review, we discuss important factors leading to these inconsistencies, in the context of atherosclerosis, including clinical study design and the differential effects of EPA and DHA on cell function. We propose steps to improve clinical and basic experimental study design in order to improve supplement composition optimization. Finally, we propose that understanding the factors underlying the poor response to n-3 PUFAs, and the development of molecular biomarkers for predicting response may help towards a more personalized treatment.

Key genes expressed in mitochondria­endoplasmic reticulum contact sites in cancer (Review).

Cell fate is critically affected by mitochondrial activity, from ATP production to metabolism, Ca2+ homeostasis and signaling. These actions are regulated by proteins expressed in mitochondria (Mt)­endoplasmic reticulum contact sites (MERCSs). The literature supports the fact that disruption to the physiology of the Mt and/or MERCSs can be due to alterations in the Ca2+ influx/efflux, which further regulates autophagy and apoptosis activity. The current review presents the findings of numerous studies with regard to the involvement of proteins positioned in MERCSs and how they express anti­ and pro­apoptotic properties by adjusting Ca2+ across membranes. The review also explores the involvement of mitochondrial proteins as hot spots in cancer development, cell death and/or survival, and the method via which they can potentially be targeted as a therapeutic option.

Aberrant Expression and Prognostic Potential of IL-37 in Human Lung Adenocarcinoma.

Interleukin-37 (IL-37) is a relatively new IL-1 family cytokine that, due to its immunoregulatory properties, has lately gained increasing attention in basic and translational biomedical research. Emerging evidence supports the implication of this protein in any human disorder in which immune homeostasis is compromised, including cancer. The aim of this study was to explore the prognostic and/or diagnostic potential of IL-37 and its receptor SIGIRR (single immunoglobulin IL-1-related receptor) in human tumors. We utilized a series of bioinformatics tools and -omics datasets to unravel possible associations of IL-37 and SIGIRR expression levels and genetic aberrations with tumor development, histopathological parameters, distribution of tumor-infiltrating immune cells, and survival rates of patients. Our data revealed that amongst the 17 human malignancies investigated, IL-37 exhibits higher expression levels in tumors of lung adenocarcinoma (LUAD). Moreover, the expression profiles of IL-37 and SIGIRR are associated with LUAD development and tumor stage, whereas their high mRNA levels are favorable prognostic factors for the overall survival of patients. What is more, IL-37 correlates positively with a LUAD-associated transcriptomic signature, and its nucleotide changes and expression levels are linked with distinct infiltration patterns of certain cell subsets known to control LUAD anti-tumor immune responses. Our data indicate the potential value of IL-37 and its receptor SIGIRR to serve as biomarkers and/or immune-checkpoint therapeutic targets for LUAD patients. Further, the data highlight the urgent need for further exploration of this cytokine and the underlying pathogenetic mechanisms to fully elucidate its implication in LUAD development and progression.

Amygdalin as a chemoprotective agent in co-treatment with cisplatin.

Amygdalin is a naturally occurring glycoside used in traditional Chinese medicine and is known to have anti-cancer properties. Even though the anti-cancer properties of amygdalin are well known, its effect on normal cells has not been thoroughly investigated. The aim of the present study was to investigate a possible chemo-protective role of amygdalin against the cytotoxic effects of chemotherapy for normal human cells. Specifically, it was tested in combination with a strong chemotherapeutic drug cisplatin. Human non-tumorigenic MCF12F epithelial cell line, human fibroblasts cells, human breast cancer MCF7 and MDA-MB-231 cells were treated with cisplatin in a dose- and time-depended manner in the absence or presence of amygdalin. When MCF12F cells and fibroblasts underwent pre-treatment with amygdalin followed by cisplatin treatment (24 h amygdalin + 24 h cisplatin), the cell viability was increased (22%, p < 0.001) as indicated using MTT assay. As attested by flow cytometry, combination treatment was associated with decreased the percentage of late apoptotic cells compared with monotherapy (fold-change of decrease = 1.6 and 4.5 for 15 and 20 µΜ, respectively). Also, the proteins expression of PUMA, p53, phospho-p53 and Bax decreased, when a combination treatment was used vs. cisplatin alone, while the proapoptotic proteins Bcl-2 and Bcl-xL exhibited an increased tendency in the presence of amygdalin. Moreover, the levels of pro-apoptotic genes PUMA, p53, and BAX mRNA were significantly downregulated (∼83%, ∼66%, and ∼44%, respectively) vs. cisplatin alone, while the mRNA levels of anti-apoptotic genes BCl-2 and Bcl-XL were upregulated (∼44.5% and ∼51%, respectively), vs. cisplatin alone after 24 h of combination treatment. The study on the Combination index (CI) assay indicated that amygdalin could be possibly considered as an antagonist to cisplatin (2.2 and 2.3) for MCF12F and fibroblast cells, respectively. In contrast, for the breast cancer MCF7 and MDA-MB-231 cells, amygdalin and cisplatin indicated a synergistic effect (0.8 and 0.65), respectively. Our present findings suggest that amygdalin has chemo-modulatory effect when used in co-treatment with cisplatin and is able to protect normal breast cells as well as the fibroblasts during chemotherapy treatment, indicating a strong selective chemoprotective ability and may contribute to a better quality of life for cancer patients.

Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach.

Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG, rs11108094 on USP44, rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, may affect the expression patterns of metabolic genes, such as USP44, METAP2, PPARG, TIMP4 and RPS6KA1, in adipose tissue, skeletal muscle, liver, pancreas and whole blood. Most importantly, a set of 86 AML/T2D common susceptibility genes was found to be significantly associated with metabolic cellular processes, including purine, pyrimidine, and choline metabolism, as well as insulin, AMPK, mTOR and PI3K signaling. Moreover, it was revealed that the whole blood of AML patients exhibits deregulated expression of certain T2D-related genes. Our findings support the existence of common metabolic perturbations in AML and T2D that may account for the increased risk for AML in T2D patients. Future studies may focus on the elucidation of these pathogenetic mechanisms in AML/T2D patients, as well as on the assessment of certain susceptibility variants and genes as potential biomarkers for AML development in the setting of T2D. Detection of shared therapeutic molecular targets may enforce the need for repurposing metabolic drugs in the therapeutic management of AML.

The Role of Tumor-Associated Myeloid Cells in Modulating Cancer Therapy.

Myeloid cells include various cellular subtypes that are distinguished into mononuclear and polymorphonuclear cells, derived from either common myeloid progenitor cells (CMPs) or myeloid stem cells. They play pivotal roles in innate immunity since, following invasion by pathogens, myeloid cells are recruited and initiate phagocytosis and secretion of inflammatory cytokines into local tissues. Moreover, mounting evidence suggests that myeloid cells may also regulate cancer development by infiltrating the tumor to directly interact with cancer cells or by affecting the tumor microenvironment. Importantly, mononuclear phagocytes, including macrophages and dendritic cells (DCs), can have either a positive or negative impact on the efficacy of chemotherapy, radiotherapy as well as targeted anti-cancer therapies. Tumor-associated macrophages (TAMs), profusely found in the tumor stroma, can promote resistance to chemotherapeutic drugs, such as Taxol and Paclitaxel, whereas the suppression of TAMs can lead to an improved radiotherapy outcome. On the contrary, the presence of TAMs may be beneficial for targeted therapies as they can facilitate the accumulation of large quantities of nanoparticles carrying therapeutic compounds. Tumor infiltrating DCs, however, are generally thought to enhance cytotoxic therapies, including those using anthracyclines. This review focuses on the role of tumor-infiltrating and stroma myeloid cells in modulating tumor responses to various treatments. We herein report the impact of myeloid cells in a number of therapeutic approaches across a wide range of malignancies, as well as the efforts toward the elimination of myeloid cells or the exploitation of their presence for the enhancement of therapeutic efficacy against cancer.

Mechanisms of Metastatic Tumor Dormancy and Implications for Cancer Therapy.

Metastasis, a multistep process during which tumor cells disseminate to secondary organs, represents the main cause of death for cancer patients. Metastatic dormancy is a late stage during cancer progression, following extravasation of cells at a secondary site, where the metastatic cells stop proliferating but survive in a quiescent state. When the microenvironmental conditions are favorable, they re-initiate proliferation and colonize, sometimes years after treatment of the primary tumor. This phenomenon represents a major clinical obstacle in cancer patient care. In this review, we describe the current knowledge regarding the genetic or epigenetic mechanisms that are activated by cancer cells that either sustain tumor dormancy or promote escape from this inactive state. In addition, we focus on the role of the microenvironment with emphasis on the effects of extracellular matrix proteins and in factors implicated in regulating dormancy during colonization to the lungs, brain, and bone. Finally, we describe the opportunities and efforts being made for the development of novel therapeutic strategies to combat metastatic cancer, by targeting the dormancy stage.