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Exosomes are extracellular microvesicles released from cells, which are involved in many biological and pathological processes, mainly because of their role in intercellular communication. Exosomes derived from colorectal cancer (CRC) cells are related to oncogenesis, tumor cell survival, chemo-resistance, and metastasis. The role of the exosomes in these processes involves the transfer of proteins, RNAs, or mutant versions of proto-oncogenes to the target cells. In recent years, great efforts have been made to identify useful biomarkers in CRC exosomes for diagnosis, prediction of prognosis, and treatment response. This review focuses on recent studies on CRC exosomes, considering isolation, cargo, biomarkers, and the effects of exosomes on the development and progression of CRC, including resistance to antitumor therapy.
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Neoplasias Colorrectales/patología , Exosomas/fisiología , Biomarcadores de Tumor , Carcinogénesis , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Humanos , Mutación , Proteínas de Neoplasias/metabolismo , Pronóstico , Transporte de Proteínas , Proto-Oncogenes/genética , ARN Neoplásico/metabolismoRESUMEN
The in vitro antiproliferative activities of some taiwaniaquinoids and related compounds with functionalized A, B, or C rings against human breast (MCF-7), colon (T-84), and lung (A-549) tumor cell lines were assayed. The most potent compounds, 16, 27, and 36, were more effective than the naturally occurring taiwaniaquinones A (4) and F (5) in all three cell lines. The structure-activity relationship study of these new taiwaniaquinoids highlighted the correlation between the bromo substituent and the antiproliferative activity, especially in MCF-7 cells. These findings indicate that some of the taiwaniaquinoids might be useful as cytostatic agents against breast, colon, and lung cancer cell lines.
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Antineoplásicos/farmacología , Terpenos/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Estructura Molecular , Estereoisomerismo , Taiwán , Terpenos/químicaRESUMEN
Taiwaniaquinoids are a unique family of diterpenoids predominantly isolated from Taiwania cryptomerioides Hayata. Previously, we evaluated the antiproliferative effect of several synthetic taiwaniaquinoids against human lung (A-549), colon (T-84), and breast (MCF-7) tumor cell lines. Herein, we report the in vitro and in vivo antitumor activity of the most potent compounds. Their cytotoxic activity against healthy peripheral blood mononuclear cells (PBMCs) has also been examined. We underscore the limited toxicity of compound C36 in PBMCs and demonstrate that it exerts its antitumor effect in MCF-7 cells (IC50 = 1.8 µM) by triggering an increase in reactive oxygen species, increasing the cell population in the sub-G1 phase of the cell cycle (90 %), and ultimately activating apoptotic (49.6 %) rather than autophagic processes. Western blot results suggested that the underlying mechanism of the C36 apoptotic effects was linked to caspase 9 activation and a rise in the Bax/Bcl-2 ratio. In vivo analyses showed normal behavior and hematological parameters in C57BL/6 mice post C36 treatment. Moreover, no significant impact was observed on the biochemical parameters of these animals, indicating that C36 did not induce liver toxicity. Furthermore, C36 demonstrated a significant reduction in tumor growth in immune-competent C57BL/6 mice implanted with E0771 mouse mammary tumor cells, effectively improving survival rates. These findings position taiwaniaquinoids, particularly compound C36, as promising therapeutic candidates for human breast cancer.
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Antineoplásicos , Neoplasias de la Mama , Animales , Humanos , Ratones , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Leucocitos Mononucleares/metabolismo , Apoptosis , Ensayos de Selección de Medicamentos Antitumorales , Ratones Endogámicos C57BL , Línea Celular Tumoral , Células MCF-7 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Proliferación CelularRESUMEN
A comprehensive characterization of the phytochemicals present in a blackberry fruit extract by HPLC-TOF-MS has been carried out. The main compounds in the extract were ursane-type terpenoids which, along with phenolic compounds, may be responsible for the bioactivity of the extract. In vitro antioxidant capacity was assessed through Folin-Ciocalteu (31.05 ± 4.9 mg GAE/g d.w.), FRAP (637.8 ± 3.2 µmol Fe2+/g d.w.), DPPH (IC50 97.1 ± 2.4 µg d.w./mL) and TEAC (576.6 ± 8.3 µmol TE/g d.w.) assays. Furthermore, the extract exerted remarkable effects on in vitro cellular antioxidant activity in HUVEC cells at a concentration of 5 mg/mL. Antimicrobial activity of the extract was also tested. Most sensible microorganisms were Gram-positive bacteria, such as E. faecalis, B. cereus and Gram-negative E. coli (MBC of 12.5 mg/mL). IC50 values against colon tumoral cells HT-29 (4.9 ± 0.2 mg/mL), T-84 (5.9 ± 0.3 mg/mL) and SW-837 (5.9 ± 0.2 mg/mL) were also obtained. Furthermore, blackberry extract demonstrated anti-inflammatory activity inhibiting the secretion of pro-inflammatory IL-8 cytokines in two cellular models (HT-29 and T-84) in a concentration-dependent manner. These results support that blackberry fruits are an interesting source of bioactive compounds that may be useful in the prevention and treatment of different diseases, mainly related to oxidative stress.
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Increasing rates of cancer incidence and the side-effects of current chemotherapeutic treatments have led to the research on novel anticancer products based on dietary compounds. The use of Allium metabolites and extracts has been proposed to reduce the proliferation of tumor cells by several mechanisms. In this study, we have shown the in vitro anti-proliferative and anti-inflammatory effect of two onion-derived metabolites propyl propane thiosulfinate (PTS) and propyl propane thiosulfonate (PTSO) on several human tumor lines (MCF-7, T-84, A-549, HT-29, Panc-1, Jurkat, PC-3, SW-837, and T1-73). We observed that this effect was related to their ability to induce apoptosis regulated by oxidative stress. In addition, both compounds were also able to reduce the levels of some pro-inflammatory cytokines, such as IL-8, IL-6, and IL-17. Therefore, PTS and PTSO may have a promising role in cancer prevention and/or treatment.
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Allium , Humanos , Propano , Dieta , Cebollas , Antiinflamatorios/farmacologíaRESUMEN
Vaccinium myrtillus L. (bilberry) leaves are an important by-product of berry production that may be used as a source of phenolic compounds which have a positive effect on human health. Therefore, an ultrasound-assisted extraction via sonotrode has been used for the first time to recover bioactive compounds from bilberry leaves. The extraction has been optimized using a Box-Behnken design. The influence of ethanol:water ratio (v/v), time of extraction (min) and amplitude (%) were evaluated considering total phenolic content (TPC) and antioxidant capacity (DPPH and FRAP assays) as dependent variables in a response surface methodology (RSM). Optimum values for the independent factors were 30:70 ethanol/water (v/v), 5 min of extraction and 55% amplitude. The empirical values of the independent variables using the optimized conditions were 217.03 ± 4.92 mg GAE/g d.w. (TPC), 271.13 ± 5.84 mg TE/g d.w. (DPPH) and 312.21 ± 9.30 mg TE/g d.w. (FRAP). The validity of the experimental design was confirmed using ANOVA and the optimal extract was characterized using HPLC-MS. A total of 53 compounds were tentatively identified, of which 22 were found in bilberry leaves for the first time. Among them, chlorogenic acid was the most abundant molecule, representing 53% of the total phenolic compounds identified. Additionally, the antimicrobial and anticancer activities of the optimum extract were tested. Gram-positive bacteria demonstrated high sensitivity to bilberry leaves extract in vitro, with MBC values of 6.25 mg/mL for Listeria monocytogenes, Listeria innocua and Enterococcus faecalis, and 0.8 mg/mL for Staphylococcus aureus and Bacillus cereus. Furthermore, bilberry leaves extract exerted in vitro antiproliferative activity against HT-29, T-84 and SW-837 colon tumor cells with IC50 values of 213.2 ± 2.5, 1140.3 ± 5.2 and 936.5 ± 4.6 µg/mL, respectively. Thus, this rapid ultrasound-assisted extraction method has demonstrated to be an efficient technique to obtain bilberry leaves extract with in vitro antioxidant, antimicrobial and anticancer capacities that may be useful for the food industry as natural preservative or even for the production of functional foods or nutraceuticals.
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Among the alternatives to control avian coccidiosis, alliaceous extracts stand out due to their functional properties. Despite this, most of the references are focused just on garlic. In this study, we analyze the in vitro effects of propyl-propane thiosulfinate (PTS) and propyl-propane thiosulfonate (PTSO), two organosulfur compounds from onion, on MDBK cells infected with sporozoites of Eimeria acervulina. To this aim, two different experiments were performed. In the first experiment, sporozoites were previously incubated for 1 h at 1, 5 and 10 µg/mL of PTS or PTSO and added to MDBK cells. In the second experiment, MDBK cells were first incubated for 24 h at different concentrations of PTS or PTSO and then infected with E. acervulina sporozoites. Then, 24 h after inoculation, the presence of E. acervulina was quantified by qPCR. MDBK viability was measured at 72 h post-infection. Sporozoites incubated at 10 µg/mL of PTS and PTSO inhibited the capability to penetrate the cells up to 75.2% ± 6.44 and 71.7% ± 6.03, respectively. The incubation of MDBK with each compound resulted in a preventive effect against sporozoite invasion at 1 µg/mL of PTS and 1 and 10 µg/mL of PTSO. Cells incubated with PTSO obtained similar viability percentages to uninfected cells. These results suggest that the use of PTS and PTSO is a promising alternative to coccidiosis treatment, although further in vivo studies need to be performed.
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Dietary changes affect the composition and structure of gut microbiota (GM) in animals and humans. One of the beneficial effects of consuming products derived from plants is the positive influence on immunity and gastrointestinal health. Species belonging to the genus Allium contain many organosulfur compounds (OSCs) that have been widely studied showing their biological properties and beneficial effects on intestinal health and GM. This is the first systematic review of OSCs from Allium performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and it is based on the evidence that we found in literature about the benefits on the GM and intestinal health demonstrated by OSCs from Allium, and specifically from onion. OSCs from Allium cepa have shown a significant antibacterial activity against a broad spectrum of antibiotic-resistant Gram-positive and Gram-negative bacteria. In addition, the intake of OSCs from onion was able to modulate the composition of GM, increasing the beneficial bacterial populations in animal models. Moreover, the beneficial effects observed in murine models of colitis suggest that these compounds could be suitable candidates for the treatment of inflammatory bowel disease (IBD) or reverse the dysbiosis caused by a high-fat diet (HFD). Despite the evidence found both in vitro and in vivo, we have not found any article that tested OSCs different from allicin in clinical trials or dietary intervention studies in humans. In this sense, it would be interesting to conduct new research that tests the benefits of these compounds in human GM.
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Few studies have examined the use of animal models to evaluate the in-vivo toxicity of antimicrobial peptides, but such research is essential to their safe use in foods. This study was performed to evaluate any adverse effects of enterocin AS-48, a circular bacteriocin produced by Enterococcus strains, when administered to BALB/c mice at concentrations of 50, 100, and 200â¯mg/kg in the diet for 90 days. Animals dosed with nisin at a dietary concentration of 200â¯mg/kg served as a reference treated group. There were no deaths in any of the animal groups, and the AS-48 treatment produced no abnormalities or clinical signs on body weights, food consumption, urinalysis, haematology, or blood biochemistry. Furthermore, there were no significant differences in the weights of liver, spleen, heart, kidneys, and intestines between control mice and those treated with AS-48 or nisin. The histopathological study showed moderate vacuolar degeneration in hepatocytes of some animals fed 100 or 200â¯mg/kg AS-48 (3/10 and 2/10 respectively). However, this anomaly was lower than in the group treated with nisin (5/10). Conclusively, no toxicologically significant changes were associated in BALB/c mice fed with 50, 100, and 200â¯mg/kg enterocin AS-48 for 90 days.
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Proteínas Bacterianas/toxicidad , Enterococcus faecalis/metabolismo , Péptidos/toxicidad , Animales , Proteínas Bacterianas/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Ratones Endogámicos BALB C , Tamaño de los Órganos/efectos de los fármacos , Péptidos/administración & dosificación , Pruebas de Toxicidad SubcrónicaRESUMEN
The synthesis of podocarpanes, including 12,19-dihydroxy-13-acetyl-8,11,13-podocarpatriene (23), isolated from Gaultheria yunnanensis and not previously synthesized, and totarane-type terpenoids, starting from the natural labdane trans-communic acid (15), is described. Their antiproliferative activities against MCF-7, T-84 and A-549 human tumoural cell lines are studied. An antiproliferative effect was induced by compounds 23, 27 and 28, with IC50â¯<â¯10⯵M in two (27) or three cell lines (23 and 28). No correlation with log P values was observed. The totarane o-quinone 27, and especially the catechol 28, which is readily oxidisable to compound 27, were the most active compounds, highlighting the functional groups present in C11 and C12. Compound 28 showed limited toxicity in normal peripheral blood mononuclear cells (78.5% cell viability versus non-treated control cultures at 10⯵M), and appeared to exert an antiproliferative effect in A-549â¯cells (IC50 0.6⯵M) through a mechanism that involves the induction of apoptosis mediated by an increased Bax/Bcl-2 ratio. The results of the present study indicate that compound 28, at least, might be useful as an antitumoral agent. Further studies are required to elucidate the cellular and molecular elements involved in its effect, and the activity/toxicity in preclinical models.
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Abietanos/química , Abietanos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Diterpenos/química , Diterpenos/farmacología , Abietanos/síntesis química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diterpenos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
Saponins are potential wide-spectrum antitumor drugs, and copper(I) catalyzed azide-alkyne 1,3-dipolar cycloaddition is a suitable approach to synthesizing saponin-like compounds by regioselective glycosylation of the C2/C3 hydroxyl and C28 carboxylic groups of triterpene aglycones maslinic acid (MA) and oleanolic acid (OA). Biological studies on the T-84 human colon carcinoma cell line support the role of the hydroxyl groups at C2/C3, the influence of the aglycone, and the bulky nature of the substituents in C28. OA bearing a α-d-mannose moiety at C28 (compound 18) focused our interest because the estimated inhibitory concentration 50 was similar to that reported for ginsenoside Rh2 against colon cancer cells and it inhibits the G1-S phase transition affecting the cell viability and apoptosis. Considering that triterpenoids from natural sources have been identified as inhibitors of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling, docking studies were conducted to evaluate whether NF-κB may be a potential target. Results are consistent with the biological study and predict a similar binding mode of MA and compound 18 to the p52 subunit from NF-κB but not for OA. The fact that the binding site is shared by the NF-κB inhibitor 6,6-dimethyl-2-(phenylimino)-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one supports the result and points to NF-κB as a potential target of both MA and compound 18.
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The role of the induction of oxidative stress as the mechanism of action of many antitumor drugs is acquiring an increasing interest. In such cases, the antitumor therapy success may be conditioned by the antioxidants present in our own body, which can be synthesized de novo (endogenous) or incorporated through the diet and nutritional supplements (exogenous). In this paper, we have reviewed different aspects of antioxidants, including their classification, natural sources, importance in diet, consumption of nutritional supplements, and the impact of antioxidants on health. Moreover, we have focused especially on the study of the interaction between antioxidants and antitumor therapy, considering both radiotherapy and chemotherapy. In this regard, we found that the convenience of administration of antioxidants during cancer treatment still remains a very controversial issue. In general terms, antioxidants could promote or suppress the effectiveness of antitumor treatment and even protect healthy tissues against damage induced by oxidative stress. The effects may depend on many factors discussed in the paper. These factors should be taken into consideration in order to achieve precise nutritional recommendations for patients. The evidence at the moment suggests that the supplementation or restriction of exogenous antioxidants during cancer treatment, as appropriate, could contribute to improving its efficiency.
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Antioxidantes/uso terapéutico , Neoplasias/dietoterapia , Política Nutricional , Animales , HumanosRESUMEN
BACKGROUND: Around 20%-30% of breast cancers overexpress the proto-oncogene human epidermal growth receptor 2 (HER2), and they are characterized by being very invasive. Therefore, many current studies are focused on testing new therapies against tumors that overexpress this receptor. In particular, there exists major interest in new strategies to fight breast cancer resistant to trastuzumab (Tmab), a humanized antibody that binds specifically to HER2 interfering with its mitogenic signaling. Our team has previously developed immunostimulating complexes (ISCOMs) as nanocapsules functionalized with lipid vinyl sulfones, which can incorporate protein A and bind to G immunoglobulins that makes them very flexible nanocarriers. METHODS AND RESULTS: The aim of this in vitro study was to synthesize and evaluate a drug delivery system based on protein A-functionalized ISCOMs to target HER2-overexpressing cells. We describe the preparation of ISCOMs, the loading with the drugs doxorubicin and paclitaxel, the binding of ISCOMs to alkyl vinyl sulfone-protein A, the coupling of Tmab, and the evaluation in both HER2-overexpressing breast cancer cells (HCC1954) and non-overexpressing cells (MCF-7) by flow cytometry and fluorescence microscopy. Results show that the uptake is dependent on the level of overexpression of HER2, and the analysis of the cell viability reveals that targeted drugs are selective toward HCC1954, whereas MCF-7 cells remain unaffected. CONCLUSION: Protein A-functionalized ISCOMs are versatile carriers that can be coupled to antibodies that act as targeting agents to deliver drugs. When coupling to Tmab and loading with paclitaxel or doxorubicin, they become efficient vehicles for the selective delivery of the drug to Tmab-resistant HER2-overexpressing breast cancer cells. These nanoparticles may pave the way for the development of novel therapies for poor prognosis resistant patients.