Euphorbia damarana L.C.Leach, also known as Damara milk bush, grows only in the north-western desert areas of Namibia and southern Angola. It is often the only vegetation in these desert regions and ...the local inhabitants know very well that it is extremely poisonous to humans and animals. During the 1960s, twenty-seven migrating mineworkers used its dead branches as firewood for their barbecue with deadly consequences. They all passed away after consuming meat that was infused with toxic volatiles in the smoke. We report in this study, on the isolation of the toxic triterpenoid, euphol that is present in high concentrations in the stems and smoke of E. damarana. Small concentrations of compounds with phorbol ester skeletons were also detected in this species. The cytotoxicity of euphol in the smoke and stem extracts of E. damarana was determined by the sulfo-rhodamine-B stain (SRB) assay on eight human cell lines (A549, PC-3, HeLa, HepG2, MCF-7, MCF-12A, MRC-5 and HaCaT). Significant cytotoxic activity was observed from the purified euphol, stem and smoke extracts with IC50 values ranging from 1.99 to 3.99 μg/mL, 5.00 to 20.00 μg/mL and from 11.75 to 40.00 μg/mL respectively, on all the tested human cell lines. Since euphol is the primary compound (concentration 10.3 mg/g) in the smoke extract and toxic to all cell lines tested at a significantly low IC50 level, it can be considered as the main toxin in E. damarana and responsible for the deaths of the miners.
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•Euphorbia species were traditionally used for arrowhead poisoning.•Euphorbia damarana demonstrated cytotoxic activity in vitro against all tested human cell lines.•Euphol was isolated as the main toxin.•Euphol demonstrated significant cytotoxic activity in vitro against all tested human cell lines.•Euphorbia damarana has the potential to be considered for anticancer drug development.
Summary
Natural killer (NK) cells express an array of germ‐line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signalling ...molecules. The presence of many activating receptors and many members of a given family of signalling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signalling molecules. NK cells express many MHC‐I‐specific inhibitory receptors. Signals from MHC‐I‐specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity.
“Natural killer (NK) cells utilize an array of germ‐line encoded activating and inhibitory receptors to sense their surroundings. The signals from activating receptors trigger, and those from inhibitory receptors prevent, NK cell cytotoxicity. This review provides a brief overview of the events that underlie NK cell cytotoxicity, and discusses how inhibitory receptors control NK cell cytotoxicity to prevent inappropriate responses.”
Mucosa-associated invariant T (MAIT) cells represent a large innate-like evolutionarily conserved antimicrobial T-cell subset in humans. MAIT cells recognize microbial riboflavin metabolites from a ...range of microbes presented by MR1 molecules. MAIT cells are impaired in several chronic diseases including HIV-1 infection, where they show signs of exhaustion and decline numerically. Here, we examined the broader effector functions of MAIT cells in this context and strategies to rescue their functions. Residual MAIT cells from HIV-infected patients displayed aberrant baseline levels of cytolytic proteins, and failed to mobilize cytolytic molecules in response to bacterial antigen. In particular, the induction of granzyme B (GrzB) expression was profoundly defective. The functionally impaired MAIT cell population exhibited abnormal T-bet and Eomes expression patterns that correlated with the deficiency in cytotoxic capacity and cytokine production. Effective antiretroviral therapy (ART) did not fully restore these aberrations. Interestingly, IL-7 was capable of arming resting MAIT cells from healthy donors into cytotoxic GrzB+ effector T cells capable of killing bacteria-infected cells and producing high levels of pro-inflammatory cytokines in an MR1-dependent fashion. Furthermore, IL-7 treatment enhanced the sensitivity of MAIT cells to detect low levels of bacteria. In HIV-infected patients, plasma IL-7 levels were positively correlated with MAIT cell numbers and function, and IL-7 treatment in vitro significantly restored MAIT cell effector functions even in the absence of ART. These results indicate that the cytolytic capacity in MAIT cells is severely defective in HIV-1 infected patients, and that the broad-based functional defect in these cells is associated with deficiency in critical transcription factors. Furthermore, IL-7 induces the arming of effector functions and enhances the sensitivity of MAIT cells, and may be considered in immunotherapeutic approaches to restore MAIT cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we ...describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.
Magnetic nanocomposites containing iron oxide and gold components take great attention last years because of their relative biocompatibility and the ability to combine the magnetic properties of iron ...and the chemical bonding properties of gold for the possible drug delivery or diagnostics for various diseases. However, such particles have some toxicity to living cells, and the effect depends on many factors, including size, shape, the ratio of components in the composites, and the type of cells affected. And thus, the search for compositions and technologies for producing iron-gold particles with improved properties and reduced cytotoxicity remains relevant. The aim of the study was to synthesize and characterize Fe3O4/Au nanocomposites and evaluate their influence on living cells using the example of cell line HEK293.
Fe3O4 nanoparticles (NPs) were synthesized by co-precipitation of Fe2+/Fe3+ water solution in alkaline conditions and then boiled with HAuCl4 in 0.1 M sodium citrate. The NPs properties were estimated by transmission electron microscopy (TEM), vibration magnetometry and ferromagnetic resonance (FMR).
According to magnetometric measurements, nanoparticles are mainly in a superparamagnetic state. By fitting magnetization curves, the magnetic characteristics of nanoparticles were determined: saturation magnetization (59.3 emu/g) and magnetic anisotropy constant (K = 0.86·105 erg/cm3). The average particle size estimated from magnetic measurements was 8.7 nm. Considering the presence of a magnetically dead layer, this is in good agreement with the TEM results. The temperature dependence of the FMR linewidth was analyzed using two models. As a result, the parameters MSV and K/MS were determined. The models used showed good agreement. The values of the anisotropy constant (K = 1.06·105 erg/cm3) and the average particle size (6.8 nm) are estimated.
The effect of the NPs on the HEK293 cells was studied by MTT-assay, flow cytometry and RT-PCR. The exposure with the NPs lead to a significant decrease of cell metabolic activity in HEK293 cell culture, but this effect was not accompanied by cell death. It was shown that the expression of antioxidant enzymes SOD1 and GPX1 was reduced at the mRNA stage. So the NPs synthesized may affect gene expression and metabolism of HEK293 cells, but this does not have fatal consequences for cell viability.
•Magnetic nanocomposites of Fe3O4/Au were synthesized.•Magnetic properties of nanoparticles were studied using magnetometry and FMR.•Magnetic Fe3O4/Au particles can reduce metabolic activity of living cells.•Fe3O4/Au nanocomposites affect the mRNA level of SOD1 and GPX1 genes.
Teaching an old dog new tricks: The case of Fenbendazole Vlachou, Ioanna; Parsonidis, Panagiotis; Mamagkaki, Alexandra ...
Cancer treatment and research communications,
2022, 2022-00-00, 20220101, 2022-01-01, Letnik:
32
Journal Article
Recenzirano
Odprti dostop
•Fenbendazole has similar mechanism of action to some anticancer drugs.•Qualitative and quantitative analysis of formulated fenbendazole indicates some formulation issues that hinder ...distribution.•Fenbendazole exhibits cytotoxic effect against human cancer cell lines.
The objective of this study is the assessment of the cytotoxic effect of fenbendazole and its commercially available formulation, which is used for its antihelmintic properties. The formulation was tested for its efficacy as well as the determination of the ingredients with proliferation assays and analytical techniques. HPLC, LC-MS and NMR confirmed the stated amount of active ingredient on the label. Dissolution studies were performed to simulate the ability of fenbendazole to dissolve adequately in the fluids of the Gastrointestinal tract, be absorbed in the circulation and reach certain areas of the human body. However, dissolution studies showed that both brands possess issues in their distribution. The in vitro drug screening exhibited potential cytotoxic effect in different types of human cancer cell lines and MDA-MB-231 human breast adenocarcinoma cells appeared to be the most sensitive with IC50 value lower than 10 μM.
The chemical composition of PM2.5 and cellular effects from exposure to fine aerosol extracts were studied for samples collected in Beijing, Tianjin, Shijiazhuang, and Hengshui, China in winter 2015. ...Effects of priority polycyclic aromatic hydrocarbons (PAHs) and their oxygenated derivatives (OPAHs) in PM2.5 on cell cultures were a major focus of the study. Total quantified PAHs and OPAHs at Shijiazhuang and Hengshui were higher than at Beijing and Tianjin, and benz(a)anthracene, chrysene and 1,8-naphthalic anhydride were the most abundant species. Exposure to PM2.5 extracts caused a concentration-dependent decline in cell viability and a dose-dependent increase in nitric oxide production. Two cytokines, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), also increased when A549 test cells were exposed to PM2.5 extracts. PAHs and OPAHs in PM2.5 can potentially cause cell damage and induce cytotoxicity and pro-inflammatory responses: benzo(a)anthracene-7,12-dione was highly correlated with NO production, dibenz(a,h)anthracene and 1,4-chrysenequinone were correlated with TNF-α production, and 1-naphthaldehyde was significantly correlated with IL-6 production. The study provides a new approach for evaluating relationships between air-quality and cell toxicity with respect to specific chemicals.
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•PAHs and OPAHs were qualified in Beijing-Tianjin-Hebei region.•Cell viability of A549 exposed to PM2.5 showed a concentration-dependent decline.•PM2.5 exhibited dose-dependent increases in NO, TNF-α and IL-6 productions.•DBA and 1,4-CRQ were well correlated with TNF-α, and 1-NAD was correlated with IL-6.
Exposure to PAHs and OPAHs associated with fine aerosol particles may induce cytotoxic and pro-inflammatory responses in vitro.
Adoptive cellular immunotherapy (ACI) is a promising treatment for a number of cancers. Cytokine-induced killer cells (CIKs) are considered to be major cytotoxic immunologic effector cells. Usually ...cancer cells are able to suppress antitumor responses by secreting immunosuppressive factors. CIKs have significant antitumor activity and are capable of eradicating tumors with few side effects. They are a very encouraging cell population used against hematological and solid tumors, with an inexpensive expansion protocol which could yield to superior clinical outcome in clinical trials employing adoptive cellular therapy combination. In the last decade, clinical protocols have been modified by enriching lymphocytes with CIK cells. They are a subpopulation of lymphocytes characterized by the expression of CD3+ and CD56+ wich are surface markers common to T lymphocytes and natural killer NK cells. CIK cells are mainly used in two diseases: in hematological patients who suffer relapse after allogeneic transplantation and in patients with hepatic carcinoma after surgical ablation to eliminate residual tumor cells. Dendritic cells DCs could play a pivotal role in enhancing the antitumor efficacy of CIKs.
Gamma delta T (γδT) lymphocytes are primed for rapid function, including cytotoxicity toward cancer cells, and are a component of the immediate stress response. Following activation, they can ...function as professional antigen-presenting cells. Chimeric antigen receptors (CARs) work by focusing T cell function on defined cell surface tumor antigens and provide essential costimulation for robust activation. Given the natural tropism of γδT cells for the tumor microenvironment, we hypothesized that their transduction with CARs might enhance cytotoxicity while retaining their ability to migrate to tumor and act as antigen-presenting cells to prolong the intratumoral immune response. Using a GD2-targeting CAR as a model system, we showed that γδT cells of both Vδ1 and Vδ2 subsets could be expanded and transduced to sufficient numbers for clinical studies. The CAR added to the cells’ innate cytotoxicity by enhancing GD2-specific killing of GD2-expressing cancer cell lines. Migration toward tumor cells in vitro was not impaired by the presence of the CAR. Expanded CAR-transduced Vδ2 cells retained the ability to take up tumor antigens and cross presented the processed peptide to responder alpha beta T (αβT) lymphocytes. γδ CAR-T cell products show promise for evaluation in clinical studies of solid tumors.
Chimeric antigen receptors (CARs) have been successfully expressed in human T cells to redirect their cytotoxic effector function against cancer antigens. A rare subset of T cells called gamma delta T cells is shown to be amenable to genetic modification by CARs and to retain the additional functional characteristic of antigen cross presentation.
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