Effects of the polyunsaturated fatty acids, EPA and DHA, on hematological malignancies: a systematic review

Omega-3 polyunsaturated fatty acids (PUFAs) have well established anti-cancer properties. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among this biologically active family of macromolecules for which various anti-cancer effects have been explained. These PUFAs have a high safety profile and can induce apoptosis and inhibit growth of cancer cells bothin vitroandin vivo, following a partially selective manner. They also increase the efficacy of chemotherapeutic agents by increasing the sensitivity of different cell lines to specific anti-neoplastic drugs. Various mechanisms have been proposed for the anti-cancer effects of these omega-3 PUFAs; however, the exact mechanisms still remain unknown. While numerous studies have investigated the effects of DHA and EPA on solid tumors and the responsible mechanisms, there is no consensus regarding the effects and mechanisms of action of these two FAs in hematological malignancies. Here, we performed a systematic review of the beneficial effects of EPA and DHA on hematological cell lines as well as the findings of relatedin vivostudies and clinical trials. We summarize the key underlying mechanisms and the therapeutic potential of these PUFAs in the treatment of hematological cancers. Differential expression of apoptosis-regulating genes and Glutathione peroxidase 4 (Gp-x4), varying abilities of different cancerous and healthy cells to metabolize EPA into its more active metabolites and to uptake PUFAS are among the major factors that determine the sensitivity of cells to DHA and EPA. Considering the abundance of data on the safety of these FAs and their proven anti-cancer effects in hematological cell lines and the lack of related human studies, further research is warranted to find ways of exploiting the anticancer effects of DHA and EPA in clinical settings both in isolation and in combination with other therapeutic regimens

До питання про походження імені язичеської богині Мокоша

Приводяться екстралінгвістичні та лінгвістичні докази, що Мокоша пов’язана з водою. Виявлено лексична спорідненість цього ім’я не тільки з індоєвропейськими, але й семітськими мовами. На основі аналізу структурних компонентів слів, які мають спільну сему “вода” та подібність у звучанні, у досліджуваному слові виділено етимологічний корінь о-(а), префікс м- і суфікси -к - і -ош(а). Ключові слова: глубинна етимологія, Мокоша, загальна сема, подібні структурні компоненти, індоєвропейські, семітські мови.Приводятся экстралингвистические и лингвистические доказательства, что Мокоша связана с водой. Обнаружено лексическое родство этого имени не только с индоевропейскими, но и семитскими языками. На основе анализа структурных компонентов слов, которые имеют общую сему “вода” и сходство в звучании, в исследуемом слове выделено этимологический корень о-(а-), префикс м- и суффиксы -к - и -ош(а). Ключевые слова: глубинная этимология, Мокоша, общая сема, похожие структурные компоненты, индоевропейские, семитские языки.Extra-linguistic and linguistic arguments are adduced that Mokosha is connected with water. The lexical affinity of this name was established both with Indo-European and Semitic languages. On the basis of the analysis of structural components of the words which have the common seme “water” and show resemblance in sounding, the etymological root o-(a-), prefix m- and suffixes -k- and -osh(a) were singled out in the investigated word. Keywords: deep etymology, Mokosha, common seme, similar structural components, Indо- European, Semitic languages

Українська діаспора Кабардино-Балкарії

Кабардино-Балкарська республіка – суб’єкт Російської Федерації. За даними статистичного управління за 2000 рік, у республіці проживало близько 15 тисяч етнічних українців. З них в Нальчику - 5725 чоловік

Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures

Extracellular vesicles (EV) in breast milk carry immune relevant proteins and could play an important role in the instruction of the neonatal immune system. To further analyze these EV and to elucidate their function it is important that native populations of EV can be recovered from (stored) breast milk samples in a reproducible fashion. However, the impact of isolation and storage procedures on recovery of breast milk EV has remained underexposed. Here, we aimed to define parameters important for EV recovery from fresh and stored breast milk. To compare various protocols across different donors, breast milk was spiked with a well-defined murine EV population. We found that centrifugation of EV down into density gradients largely improved density-based separation and isolation of EV, compared to floatation up into gradients after high-force pelleting of EV. Using cryo-electron microscopy, we identified different subpopulations of human breast milk EV and a not previously described population of lipid tubules. Additionally, the impact of cold storage on breast milk EV was investigated. We determined that storing unprocessed breast milk at −80°C or 4°C caused death of cells present in breast milk, leading to contamination of the breast milk EV population with storage-induced EV. Here, an alternative method is proposed to store breast milk samples for EV analysis at later time points. The proposed adaptations to the breast milk storage and EV isolation procedures can be applied for EV-based biomarker profiling of breast milk and functional analysis of the role of breast milk EV in the development of the neonatal immune system

Immunoglobulin free light chains are biomarkers of poor prognosis in basal-like breast cancer and are potential targets in tumor-associated inflammation

Inflammation is an important component of various cancers and its inflammatory cells and mediators have been shown to have prognostic potential. Tumor-infiltrating mast cells can promote tumor growth and angiogenesis, but the mechanism of mast cell activation is unclear. In earlier studies, we demonstrated that immunoglobulin free light chains (FLC) can trigger mast cells in an antigen-specific manner. Increased expression of FLC was observed within stroma of various human cancers including those of breast, colon, lung, pancreas, kidney and skin, and FLC expression co-localized with areas of mast cell infiltration. In a large cohort of breast cancer patients, FLC expression was shown associated with basal-like cancers with an aggressive phenotype. Moreover, lambda FLC was found expressed in areas of inflammatory infiltration and its expression was significantly associated with poor clinical outcome. Functional importance of FLCs was shown in a murine B16F10 melanoma model, where inhibition of FLC-mediated mast cell activation strongly reduced tumor growth. Collectively, this study identifies FLCs as a ligand in the pro-tumorigenic activation of mast cells. Blocking this pathway may open new avenues for the inhibition of tumor growth, while immunohistochemical staining of FLC may be helpful in the diagnosis and prognosis of cancer

Mast cells—fetal mast cells crosstalk with maternal interfaces during pregnancy: Friend or foe?

Mast cells (MC) are hematopoietic immune cells that play a major role during allergic reactions in adults by releasing a myriad of vasoactive and inflammatory mediators. MC seed all vascularized tissues and are most prominent in organs with a barrier function such as skin, lungs, and intestines. These secreted molecules cause mild symptoms such as localized itchiness and sneezing to life-threatening symptoms (i.e., anaphylactic shock). Presently, despite the extensive research on Th2-mediated immune responses in allergic diseases in adults, we are still unable to determine the mechanisms of the role of MC in developing pediatric allergic (PA) disorders. In this review, we will summarize the most recent findings on the origin of MC and discuss the underappreciated contribution of MC in the sensitization phase to maternal antibodies during pregnancy in allergic reactions and other diseases such as infectious diseases. Then, we will lay out potential MC-dependent therapeutic strategies to be considered in future investigations to understand the remaining gaps in MC research for a better quality of life for these young patients

A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes

The generation of bispecific antibodies (bsAbs) targeting two different antigens opens a new level of specificity and, compared to mAbs, improved clinical efficacy in cancer therapy. Currently, the different strategies for development of bsAbs primarily focus on IgG isotypes. Nevertheless, in comparison to IgG isotypes, IgE has been shown to offer superior tumor control in preclinical models. Therefore, in order to combine the promising potential of IgE molecules with increased target selectivity of bsAbs, we developed dual tumor-associated antigen-targeting bispecific human IgE antibodies. As proof of principle, we used two different pairing approaches - knobs-into-holes and leucine zipper-mediated pairing. Our data show that both strategies were highly efficient in driving bispecific IgE formation, with no undesired pairings observed. Bispecific IgE antibodies also showed a dose-dependent binding to their target antigens, and cell bridging experiments demonstrated simultaneous binding of two different antigens. As antibodies mediate a major part of their effector functions through interaction with Fc receptors (FcRs) expressed on immune cells, we confirmed FcεR binding by inducing in vitro mast cell degranulation and demonstrating in vitro and in vivo monocyte-mediated cytotoxicity against target antigen-expressing Chinese hamster ovary cells. Moreover, we demonstrated that the IgE bsAb construct was significantly more efficient in mediating antibody-dependent cell toxicity than its IgG1 counterpart. In conclusion, we describe the successful development of first bispecific IgE antibodies with superior antibody-dependent cell toxicity-mediated cell killing in comparison to IgG bispecific antibodies. These findings highlight the relevance of IgE-based bispecific antibodies for clinical application

Esterified derivatives of DHA and EPA increase bortezomib cytotoxicity in human multiple myeloma cells

BACKGROUND & AIMS: Although the proteasome inhibitor bortezomib has greatly improved the clinical outcome of patients with multiple myeloma (MM), acquired drug resistance remains the greatest obstacle on the road of treating MM. We previously showed that omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) with the chemotherapeutic agent bortezomib can overcome its chemoresistance in MM cells. However, most DHA/EPA are esterified shortly after oral administration, which may affect their bioactivity. This study was to evaluate the cytotoxicity of ethyl ester-DHA/EPA in human MM cells. The mechanisms relevant for the cytotoxicity of these esterified-fatty acids were further investigated. METHODS: Human MM cell lines L363, OPM2, U266 were treated with ethyl ester-DHA/EPA with or without bortezomib. The percentage of dead cells and intracellular reactive oxygen species (ROS) levels were analyzed by flow cytometry. RESULTS: Ethyl ester-DHA and -EPA were much more potent than DHA/EPA to induce cytotoxicity in MM cells, even in DHA/EPA-resistant MM cells. Pretreating MM cells with esterified-DHA/EPA before bortezomib potently increased its cytotoxicity. Additionally, intracellular ROS levels were upregulated in MM cells after treatment with ethyl ester-DHA/EPA, which reflected the enhanced oxidative stress in treated cells. CONCLUSIONS: This study provides evidence that ethyl ester-DHA/EPA in combination with bortezomib may improve the overall efficacy in MM cells, similar to DHA/EPA, relieving the concern that esterification of DHA/EPA may affect its bioactivity and further supporting the potential clinical use of fatty acids DHA/EPA for combating drug resistance during MM therapy