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

Mechanisms Underlying Stage-1 TRPL Channel Translocation in Drosophila Photoreceptors

Background: TRP channels function as key mediators of sensory transduction and other cellular signaling pathways. In Drosophila, TRP and TRPL are the light-activated channels in photoreceptors. While TRP is statically localized in the signaling compartment of the cell (the rhabdomere), TRPL localization is regulated by light. TRPL channels translocate out of the rhabdomere in two distinct stages, returning to the rhabdomere with dark-incubation. Translocation of TRPL channels regulates their availability, and thereby the gain of the signal. Little, however, is known about the mechanisms underlying this trafficking of TRPL channels. Methodology/Principal Findings: We first examine the involvement of de novo protein synthesis in TRPL translocation. We feed flies cycloheximide, verify inhibition of protein synthesis, and test for TRPL translocation in photoreceptors. We find that protein synthesis is not involved in either stage of TRPL translocation out of the rhabdomere, but that re-localization to the rhabdomere from stage-1, but not stage-2, depends on protein synthesis. We also characterize an ex vivo eye preparation that is amenable to biochemical and genetic manipulation. We use this preparation to examine mechanisms of stage-1 TRPL translocation. We find that stage-1 translocation is: induced with ATP depletion, unaltered with perturbation of the actin cytoskeleton or inhibition of endocytosis, and slowed with increased membrane sterol content. Conclusions/Significance: Our results indicate that translocation of TRPL out of the rhabdomere is likely due to protei

Local free light chain expression is increased in chronic rhinosinusitis with nasal polyps

Background Free light chain (FLC) concentrations are demonstrated to be increased in different inflammatory disorders and are proposed to mediate mast celldependent immune responses. A role for mast cells is suggested in chronic rhinosinusitis with nasal polyposis (CRSwNP), which is characterized by a local Th2 inflammatory response. However, clear mast cellactivating factors are not always apparent. In this study, the presence of FLCs in CRS patients with or without nasal polyps (CRSw/sNP) was investigated and the effect of different treatments on FLC expression was analyzed. Methods Nasal tissue, nasal secretion, and serum of control patients, patients with CRSwNP, and CRSsNP were analyzed for the presence of kappa and lambda FLC. The expression of FLCs in nasal polyp tissue was investigated using immunohistochemistry. In addition, FLC was measured in serum and nasal secretion of nasal polyp patients treated with methylprednisolone, doxycycline, anti-IL-5, or placebo. Results Free light chain concentrations were increased in nasal secretion and mucosal tissue homogenates in patients with chronic rhinosinusitis, and this effect was most prominent in CRSwNP patients. Immunohistochemical analysis confirmed the increased FLC concentrations in nasal polyp tissue. In CRSwNP patients, treatment with methylprednisolone or anti-IL-5 resulted in the reduction in systemic or local FLC concentrations, respectively. Conclusion The presence of FLC in CRSwNP and CRSsNP suggests a possible role in mediating the local immune reaction in the paranasal cavities. Furthermore, the decrease in local FLCs after treatment with anti-IL-5 presumes that IL-5 creates an environment that favors FLC production

Elicitation of allergic asthma by immunoglobulin free light chains

The observation that only 50% of patients with adult asthma manifest atopy indicates that other inflammatory mechanisms are likely involved in producing the characteristic features of this disorder; namely reversible airway obstruction, hyperresponsiveness, and pulmonary inflammation. Our recent discovery that antigen-specific Ig free light chains (LCs) mediate hypersensitivity-like responses suggests that these molecules may be of import in the pathophysiology of asthma. Using a murine experimental model of nonatopic asthma, we now have shown that an LC antagonist, the 9-mer peptide F991, can abrogate the development of airway obstruction, hyperresponsiveness, and pulmonary inflammation. Further, passive immunization with antigen-specific LCs and subsequent airway challenge can elicit a mast cell-dependent reaction leading to acute bronchoconstriction. These findings, and the demonstration that the concentration of free K LCs in the sera of patients with adult asthma were significantly increased (as compared with age-matched nonasthmatic individuals), provide previously undescribed insight into the pathogenesis of asthma. In addition, the ability to inhibit pharmacologically LC-induced mast cell activation provides a therapeutic means to prevent or ameliorate the adverse bronchopulmonary manifestations of this incapacitating disorder.</p

Cigarette smoke suppresses the surface expression of c-kit and FC epsilon RI on mast cells

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. COPD is mostly associated with cigarette smoking. Cigarette smoke contains over 4,700 chemical compounds, including free radicals and LPS (a Toll-Like Receptor 4 agonist) at concentrations which may contribute to the pathogenesis of diseases like COPD. We have previously shown that short-term exposure to cigarette smoke medium (CSM) can stimulate several inflammatory cells via TLR4 and that CSM reduces the degranulation of bone-marrow-derived mast cells (BMMCs). In the current study, the effect of CSM on mast cells maturation and function was investigated. Coculturing of BMMC with CSM during the development of bone marrow progenitor cells suppressed the granularity and the surface expression of c-kit and FcεRI receptors. Stimulation with IgE/antigen resulted in decreased degranulation and release of Th1 and Th2 cytokines. The effects of CSM exposure could not be mimicked by the addition of LPS to the culture medium. In conclusion, this study shows that CSM may affect mast cell development and subsequent response to allergic activation in a TLR4-independent manner

Immunoglobulin Free Light Chains in the Pathogenesis of Lung Disorders.

Inflammation is an important component of numerous cancers and chronic diseases and many inflammatory mediators have been shown to have potential prognostic roles. Tumor-infiltrating mast cells can promote tumor growth and angiogenesis, but the mechanism of mast cell activation is unclear. Early studies have shown that immunoglobulin free light chains (FLC) can trigger mast cell activation in an antigen-specific manner. Increased expression of FLC is observed within the stroma of many human cancers including those of breast, colon, lung, pancreas, kidney, and skin. These overexpressed FLCs are co-localized to areas of mast cell infiltration. Importantly, FLC expression is associated with basal-like cancers with an aggressive phenotype. Moreover, FLC is expressed in areas of inflammatory cell infiltration and its expression is significantly associated with poor clinical outcome. In addition, serum and bronchoalveolar fluid FLC concentrations are increased in patients with idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP) compared to control subjects. In this review, we provide an update on the role of FLC in the pathogenesis of several lung disorders and indicate how this may contribute to new therapeutic opportunities