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1.
Chem Biol Interact ; 333: 109325, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33221320

RESUMO

Previous studies revealed that direct contact with graphene oxide (GO) induced cytotoxic effects, but the importance of involvement of metabolic pathways, in particular lipid metabolism pathways, might be overlooked. In this study, human umbilical vein endothelial cells (HUVECs) were exposed to GO with large size (denoted as GO-L) or small size (denoted as GO-S), and transcriptomics were used to understand the mechanisms of cytotoxicity of GO at systemic levels. It was shown that GO-L more significantly induced cytotoxicity compared with GO-S. Transcriptomic analysis revealed that compared with GO-S, GO-L had larger impact on gene ontology terms related with mitochondrial function as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related with cell death and growth. But GO-S showed greater influence on KEGG pathways related with lipid metabolism. Both types of GO showed minimal impact on oxidative stress but increased de novo lipogenesis protein fatty acid synthase (FASN). However, only GO-S significantly promoted acyl-CoA synthetase 3 (ACSL3), a key enzyme responsible for esterification of free fatty acids and lipid droplet biogenesis. Not surprisingly, GO-L but not GO-S impaired lipid droplet biogenesis, and increasing lipid levels by oleic acid or α-linolenic acid reduced the cytotoxicity of GO-L to HUVECs. Combined, the results from this study suggested that impaired lipid droplet biogenesis was involved in GO-induced cytotoxicity in HUVECs, and inducing lipid droplet biogenesis could prevent the cytotoxicity of GO.


Assuntos
Citotoxinas/toxicidade , Perfilação da Expressão Gênica , Grafite/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Coenzima A Ligases/genética , Ácido Graxo Sintase Tipo I/genética , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
2.
Nat Commun ; 11(1): 5818, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199689

RESUMO

Cholesterol-dependent cytolysins (CDCs) are pore-forming proteins that serve as major virulence factors for pathogenic bacteria. They target eukaryotic cells using different mechanisms, but all require the presence of cholesterol to pierce lipid bilayers. How CDCs use cholesterol to selectively lyse cells is essential for understanding virulence strategies of several pathogenic bacteria, and for repurposing CDCs to kill new cellular targets. Here we address that question by trapping an early state of pore formation for the CDC intermedilysin, bound to the human immune receptor CD59 in a nanodisc model membrane. Our cryo electron microscopy map reveals structural transitions required for oligomerization, which include the lateral movement of a key amphipathic helix. We demonstrate that the charge of this helix is crucial for tuning lytic activity of CDCs. Furthermore, we discover modifications that overcome the requirement of cholesterol for membrane rupture, which may facilitate engineering the target-cell specificity of pore-forming proteins.


Assuntos
Membrana Celular/metabolismo , Citotoxinas/química , Citotoxinas/metabolismo , Antígenos CD59/metabolismo , Membrana Celular/ultraestrutura , Microscopia Crioeletrônica , Citotoxinas/genética , Humanos , Modelos Biológicos , Modelos Moleculares , Mutação/genética , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
3.
Afr Health Sci ; 20(2): 822-832, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33163049

RESUMO

Introduction: Breast cancer is one of the leading cause of cancer deaths in women. Metastasis in BC is caused by immunosurveillance deficiency, such NK cell maturation, low NK activity and decreasing cytotoxicity. This study was performed to improve activating receptors and cytotoxicity of NK cells using interleukins (ILs). Methods: Human recombinant IL-2, -15, and -18 were used to induce NK cells. We measured the activating and inhibiting receptors, proliferation activity of NK cells, and the cytotoxicity of NK cells on BC cells (MCF7). The effects of ILs were tested on the NK cell receptors CD314, CD158a and CD107a with flowcytometry, proliferation at various incubation times with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and concentrations of TNF-α and IFN-γ by NK cells with ELISA. Results: ILs increased NK cell receptor levels (CD314, CD158a, and CD107a) at 24 hours of incubation. ILs increased NK cell viability, which increased with longer incubation. Moreover, ILs-induced NK cells inhibited proliferation in MCF7 cells, as well as increased TNF-α, IFN-γ, PRF1 and GzmB secretion. Conclusion: IL-2, IL-15, and IL-18 improved activating receptors and proliferation of NK cells. IL-induced NK cells increased TNF-α, IFN-γ, PRF1 and GzmB secretion and cytotoxic activity on BC cells. High NK cell numbers increased BC cell growth inhibition.


Assuntos
Neoplasias da Mama/imunologia , Citotoxicidade Imunológica/imunologia , Interleucina-15/farmacologia , Interleucina-18/farmacologia , Interleucina-2/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias da Mama/patologia , Citotoxicidade Imunológica/efeitos dos fármacos , Citotoxinas , Feminino , Humanos , Interleucina-15/metabolismo , Interleucina-18/metabolismo , Interleucina-2/metabolismo , Células Matadoras Naturais/metabolismo
4.
Ann N Y Acad Sci ; 1480(1): 207-218, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32954509

RESUMO

Hydrogen sulfide gas (H2 S) is a chemical weapon and a common environmental pollutant. H2 S intoxication is lethal to humans and animals. H2 S contact to the eye can cause vision loss. However, the molecular mechanisms associated with H2 S toxicity to the cornea remain unclear, and no specific therapy exists to mitigate ocular damage from H2 S. Here, we report H2 S-induced cytotoxicity and the parameters contributing to the molecular mechanisms associated with corneal toxicity using primary human corneal stromal fibroblasts (hCSFs) in vitro. Sodium hydrosulfide (NaSH) was used as a source of H2 S, and the cytotoxicity of H2 S was determined by treating hCSF cells with varying concentrations of NaSH (0-10 mM) for 0-72 hours. Changes in cell proliferation, oxidative stress factors, and the expression of inflammatory and fibrotic genes were studied using standard commercial kits and qRT-PCR. NaSH exposure to hCSFs showed dose- and time-dependent cytotoxicity. The IC50 of NaSH was determined to be 5.35 mM. NaSH 5.35 mM exposure led to significantly decreased cytochrome c oxidase activity, increased ROS production, and increased expression of inflammatory and fibrotic genes in hCSF cells. H2 S/NaSH exposure alters normal mitochondrial function, oxidative stress, and inflammatory and fibrotic gene responses in corneal stromal fibroblasts in vitro.


Assuntos
Substância Própria/metabolismo , Citotoxinas/toxicidade , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Sulfeto de Hidrogênio/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Células Cultivadas , Substância Própria/patologia , Fibroblastos/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Espécies Reativas de Oxigênio/metabolismo
5.
mBio ; 11(5)2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948688

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8+ T cell subsets. PD-1-expressing CD8+ T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.IMPORTANCE Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.


Assuntos
Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Linfócitos T Citotóxicos/patologia , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Betacoronavirus/patogenicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Citotoxinas/metabolismo , Feminino , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Pandemias , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Linfócitos T Citotóxicos/imunologia
6.
PLoS One ; 15(9): e0239614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986753

RESUMO

Chemotherapy response remains unpredictable in most patients with cancer. In this study, we performed whole-exome sequencing of 79 cancer xenografts derived from human cancer tissues to identify genetic predictors of chemosensitivity to nine cytotoxic anticancer drugs. Xenografts were harvested from 12 organs with cancer and implanted into nude mice. The mice were exposed to one of nine cytotoxic anticancer drugs (5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C, methotrexate, vincristine, and vinblastine) to assess the correlation between chemosensitivity response and variant allele frequency. We found 162 candidate variants that were possibly associated with chemosensitivity to one or more of the nine anticancer drugs (P < 0.01). In a subgroup analysis of breast and gastric cancer xenografts, 78 and 67 variants, respectively, were possibly associated with chemosensitivity. This approach may help to contribute to the development of personalized treatments that may allow for the prescription of optimal chemotherapy regimens among patients with cancer.


Assuntos
Antineoplásicos/uso terapêutico , Citotoxinas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Variação Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Resultado do Tratamento , Sequenciamento Completo do Exoma
8.
Arch Biochem Biophys ; 692: 108546, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32818507

RESUMO

Epigallocatechin-3-gallate (EGCG), a major polyphenol component of green tea, presents anticancer efficacy. However, its exact mechanism of action is not known. In this study, we evaluated the effect of EGCG alone or in combination with current chemotherapeutics [gemcitabine, 5-flourouracil (5-FU), and doxorubicin] on pancreatic, colon, and lung cancer cell growth, as well as the mechanisms involved in the combined action. EGCG reduced pancreatic, colon, and lung cancer cell growth in a concentration and time-dependent manner. EGCG strongly induced apoptosis and blocked cell cycle progression. Moreover, EGCG enhanced the growth inhibitory effect of 5-FU and doxorubicin. Of note, EGCG enhanced 5-FU's and doxorubicin's effect on apoptosis, but not on cell cycle. Mechanistically, EGCG reduced ERK phosphorylation concentration-dependently, and sensitized gemcitabine, 5-FU, and doxorubicin to further suppress ERK phosphorylation in multiple cancer cell lines. In conclusion, EGCG presents a strong anticancer effect in pancreatic, colon, and lung cancer cells and is a robust combination partner for multiple chemotherapeutics as evidenced by reducing cancer cell growth, in part, by inhibiting the ERK pathway.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Catequina/análogos & derivados , Citotoxinas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Células A549 , Catequina/farmacologia , Células HT29 , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
9.
Chem Biol Interact ; 330: 109231, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853594

RESUMO

Hetero mononuclear rhenium(I) metal complexes (I-V) using different substituted indole-pyrazoline based ligands were synthesized and characterized by spectroscopic and analytical methods. The binding of the rhenium complexes to Herring sperm DNA was monitored by UV spectroscopy, viscosity measurements, and molecular docking studies; groove binding was suggested as the most possible mode and the DNA-binding constants of the complexes were evaluated. In vivo and in vitro cytotoxicity of compounds were evaluated against the brine shrimp and S. cerevisiae cells. An antimicrobial study was carried out by estimating MIC (Minimum Inhibitory Concentration) against two Gram-positive and three Gram-negative bacteria. All synthesized complexes are biologically more active than the corresponding ligands. The anti-proliferation activity of complexes was evaluated on MCF-7, HCT116, and A549 cancer cells by MTT assay. The toxicity profile of synthesized compounds was confirmed by H2O2 production by reactive oxygen species. The increased concentration of lipid peroxidation end products increased free radicals, which enhancing the oxidative stress level in living organisms and results in cell death.


Assuntos
Complexos de Coordenação/farmacologia , Indóis/química , Pirazóis/química , Rênio/química , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Artemia/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Citotoxinas/toxicidade , DNA/metabolismo , Humanos , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos
10.
Acta Crystallogr C Struct Chem ; 76(Pt 8): 723-733, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32756034

RESUMO

The present study examines a series of six biologically-active flavonoid and chromanone derivatives by X-ray crystal structure analysis: (E)-3-benzylidene-2-phenylchroman-4-one, C22H16O2, I, (E)-3-(4-methylbenzylidene)-2-phenylchroman-4-one, C23H18O2, II, (E)-3-(3-methylbenzylidene)-2-phenylchroman-4-one, C23H18O2, III, (E)-3-(4-methoxybenzylidene)-2-phenylchroman-4-one, C23H18O3, IV, (E)-3-benzylidenechroman-4-one, C16H12O2, V, and (E)-3-(4-methoxybenzylidene)chroman-4-one, C17H14O3, VI. The cytotoxic activities of the presented crystal structures have been determined, together with their intermolecular interaction preferences and Hirshfeld surface characteristics. An inverse relationship was found between the contribution of C...C close contacts to the Hirshfeld surface and cytotoxic activity against the WM-115 cancer line. Dependence was also observed between the logP value and the percentage contribution of C...H contacts to the Hirshfeld surface.


Assuntos
Antineoplásicos/farmacologia , Cromanos/química , Citotoxinas/farmacologia , Flavonoides/química , Antineoplásicos/química , Cristalografia por Raios X , Citotoxinas/química , Ligação de Hidrogênio
11.
Int J Nanomedicine ; 15: 5043-5060, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764935

RESUMO

Background: Hydroxyapatite (HAP) is a common component of most idiopathic calcium oxalate (CaOx) stones and is often used as a nidus to induce the formation of CaOx kidney stones. Methods: This work comparatively studies the cytotoxicity of four kinds of HAP crystals with different sizes (40 nm to 2 µm), namely, HAP-40 nm, HAP-70 nm, HAP-1 µm, and HAP-2 µm, on human renal proximal tubular epithelial cells (HK-2). Results: HAP crystals reduce the viability and membrane integrity of HK-2 cells in a concentration-dependent manner and consequently cause cytoskeleton damage, cell swelling, increased intracellular reactive oxygen species level, decreased mitochondrial membrane potential, increased intracellular calcium concentration, blocked cell cycle and stagnation in G0/G1 phase, and increased cell necrosis rate. HAP toxicity to HK-2 cells increases with a decrease in crystal size. Conclusion: Cell damage caused by HAP crystals increases the risk of kidney stone formation.


Assuntos
Citotoxinas/química , Citotoxinas/toxicidade , Durapatita/química , Durapatita/toxicidade , Células Epiteliais/efeitos dos fármacos , Rim/citologia , Oxalato de Cálcio/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
12.
PLoS One ; 15(7): e0236319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726328

RESUMO

Jacaranda mimosifolia trees are grown in frost-free regions globally. The aim of this study was to evaluate the methanol crude extract and various fractions of increasing polarity of J. mimosifolia leaves for bioactive metabolites, as well as antimicrobial, antioxidant and anticancer activities. The anti-inflammatory potential of the various fractions of J. mimosifolia leaf extract was studied via the lipoxygenase (LOX) inhibitory assay. Methanol crude extract (ME), derived fractions extracted with chloroform (CF) and ethyl acetate (EAF), and residual aqueous extract (AE) of dried J. mimosifolia leaves were assayed for polyphenolic compounds, their antioxidant, antimicrobial and lipoxygenase (LOX) inhibitory activities, and anticancer properties. Polyphenolic compounds were determined via HPLC while phytochemicals (total phenolics, flavonoids, tannins and ortho-diphenol contents), antioxidant activities (DPPH, hydrogen peroxideperoxide, hydroxyl and superoxide radical anions) and LOX were measured via spectrophotometry. Methanol extracts and various fractions were evaluated for antibacterial activities against Bacillus subtilis, Klebsiella pneumonia, Pseudomonas aeruginosa and Staphylococcus aureus. Antifungal potential of the fractions was tested against three species: Aspergillus flavus, Aspergillus fumigatus and Fusarium oxysporum. The highest values for total phenolic content (TPC), total flavonoid content (TFC), flavonols, tannins and ortho-diphenols were in the ME, followed by CF > EAF > AE. ME also had the highest antioxidant activity with EC50 values 48±1.3, 45±2.4, 42±1.3 and 46±1.3 µg/mL based on the DPPH, hydrogen peroxide, hydroxyl radical and superoxide radical assays, respectively. TPC and TFC showed a significant, strong and positive correlation with the values for each of these antioxidant activities. ME exhibited anti-inflammatory potential based on its LOX inhibitory activity (IC50 = 1.3 µg/mL). ME also had the maximum antibacterial and antifungal potential, followed by EAF > CF > AE. Furthermore, ME showed the strongest cytotoxic effect (EC50 = 10.7 and 17.3 µg/mL) against human hormone-dependent prostate carcinoma (LnCaP) and human lung carcinoma (LU-1) cell lines, respectively. Bioactive compounds present in leaf methanol extracts of J. mimosifolia were identified using gas chromatography-mass spectrometry (GC-MS). Fifteen compounds were identified including phenolic and alcoholic compounds, as well as fatty acids. Our results suggest that J. mimosifolia leaves are a good source of natural products with antioxidant, anti-inflammatory and anti-cancer properties for potential therapeutic, nutraceutical and functional food applications.


Assuntos
Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Bignoniaceae/química , Extratos Vegetais/farmacologia , Anti-Infecciosos/química , Antioxidantes/química , Aspergillus/efeitos dos fármacos , Aspergillus/patogenicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Extratos Vegetais/química , Folhas de Planta/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade
13.
Eur J Haematol ; 105(4): 476-483, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32544294

RESUMO

OBJECTIVES: We sought to characterise the outcomes of patients with haematological malignancy and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hospital in our regional network of 7 hospitals. METHODS: Consecutive hospitalised patients with haematological malignancy and SARS-CoV-2 infection were identified from 01/03/2020 to 06/05/2020. Outcomes were categorised as death, resolved or ongoing. The primary outcome was preliminary case fatality rate (pCFR), defined as the number of cases resulting in death as a proportion of all diagnosed cases. Analysis was primarily descriptive. RESULTS: 66 Patients were included, overall pCFR was 51.5%. Patients ≥ 70 years accounted for the majority of hospitalised cases (42, 63%) and fatalities (25, 74%). Mortality was similar between females (52%) and males (51%). Immunosuppressive or cytotoxic treatment within 3 months of the diagnosis of SARS-CoV-2 infection was associated with a significantly higher pCFR of 70%, compared with 28% in those not on active treatment (P = .0013, 2 proportions z test). CONCLUSIONS: Mortality rates in patients with haematological malignancy and SARS-CoV-2 infection in hospital are high supporting measures to minimise the risk of infection in this population.


Assuntos
/complicações , Neoplasias Hematológicas/complicações , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , /prevenção & controle , Citotoxinas/efeitos adversos , Feminino , Neoplasias Hematológicas/terapia , Hospitalização , Humanos , Imunossupressão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Prospectivos , Reino Unido/epidemiologia
14.
Sci Rep ; 10(1): 9456, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528137

RESUMO

A silicalite-1 film (SF) deposited on Ti-6Al-4V alloy was investigated in this study as a promising coating for metallic implants. Two forms of SFs were prepared: as-synthesized SFs (SF-RT), and SFs heated up to 500 °C (SF-500) to remove the excess of template species from the SF surface. The SFs were characterized in detail by X-ray photoelectron spectroscopy (XPS), by Fourier transform infrared spectroscopy (FTIR), by scanning electron microscopy (SEM) and water contact angle measurements (WCA). Two types of bone-derived cells (hFOB 1.19 non-tumor fetal osteoblast cell line and U-2 OS osteosarcoma cell line) were used for a biocompatibility assessment. The initial adhesion of hFOB 1.19 cells, evaluated by cell numbers and cell spreading area, was better supported by SF-500 than by SF-RT. While no increase in cell membrane damage, in ROS generation and in TNF-alpha secretion of bone-derived cells grown on both SFs was found, gamma H2AX staining revealed an elevated DNA damage response of U-2 OS cells grown on heat-treated samples (SF-500). This study also discusses differences between osteosarcoma cell lines and non-tumor osteoblastic cells, stressing the importance of choosing the right cell type model.


Assuntos
Citotoxinas/farmacologia , Osteoblastos/efeitos dos fármacos , Osteócitos/efeitos dos fármacos , Titânio/química , Materiais Biocompatíveis/química , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citotoxinas/química , Temperatura Alta , Humanos , Teste de Materiais/métodos , Microscopia Eletrônica de Varredura/métodos , Espectroscopia Fotoeletrônica/métodos , Propriedades de Superfície/efeitos dos fármacos
15.
Food Chem ; 331: 127303, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32562979

RESUMO

ß-phenylethylamine and tryptamine are biogenic amines (BA) often found in foods. In general, BA are assumed to be toxic and their accumulation in food is not recommended. However, present knowledge regarding the toxicity of ß-phenylethylamine and tryptamine is limited; more information is needed if qualitative and quantitative risk assessments of foods are to be successfully conducted. This study describes a real-time analysis of ß-phenylethylamine and tryptamine toxicity on a human intestinal epithelial cell line. Both BA caused cell necrosis and apoptosis, although the former was the main mode of action of ß-phenylethylamine, and the latter the main mode of action of tryptamine. Only tryptamine was cytotoxic at concentrations found in BA-rich foods. The results presented in this work may contribute to establish legal limits for ß-phenylethylamine and tryptamine in food.


Assuntos
Citotoxinas/toxicidade , Alimentos/efeitos adversos , Triptaminas/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Mucosa Intestinal/citologia , Legislação sobre Alimentos , Fenetilaminas/toxicidade , Medição de Risco
16.
Toxicol Appl Pharmacol ; 401: 115071, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454055

RESUMO

Prostate Cancer (PCa) is the second most common cancer among men in United States after skin cancer. Conventional chemotherapeutic drugs available for PCa treatment are limited due to toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatment for advanced PCa. In this current study, we focused on evaluating the anti-cancer efficacy of Eprinomectin (EP), a novel avermectin analog against PC3 metastatic PCa cells. EP displayed robust inhibition of cell viability of PC3 cells in addition to suppressing the colony formation and wound healing capabilities. Our study showed that EP targets PC3 cells via inducing ROS and apoptosis activation. EP treatment enforces cell cycle arrest at G0/G1 phase via targeting cyclin-dependent kinase 4 (CDK4) and subsequent induction of apoptosis in PC3 cells. At the molecular level, EP effectively inhibited the expression of various cancer stem cell markers such as ALDH1, Sox-2, Nanog, Oct3/4 and CD44. Interestingly, EP also inhibited the activity of alkaline phosphatase, a maker of pluripotent stem cells. Of note, EP treatment resulted in the translocation of ß-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/ß-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4, and c-Myc. In addition, EP inhibited the anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ivermectina/análogos & derivados , Lactonas/farmacologia , Compostos Macrocíclicos/farmacologia , Neoplasias da Próstata/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/fisiologia , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Ivermectina/química , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lactonas/uso terapêutico , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Masculino , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
17.
Ann N Y Acad Sci ; 1479(1): 223-233, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32408394

RESUMO

Nitrogen mustard (NM) is a highly toxic alkylating agent. Inhalation exposure can cause acute and chronic lung injury. This study's aims were to develop an in vitro coculture model of mustard-induced airway injury and to identify growth factors contributing to airway pathology. Primary human bronchial epithelial cells cultured with pulmonary endothelial cells were exposed to NM (25, 50, 100, 250, or 500 µM) or PBS (control) for 1 hour. Lactate dehydrogenase (LDH) and transepithelial electrical resistance (TEER) were measured before and 24 h after NM exposure. Fixed cultures were stained for hematoxylin and eosin or live/dead staining. Culture media were analyzed for 11 growth factors. A 1-h vapor exposure to greater than or equal to 50 µM NM increased supernatant LDH, decreased TEER, and caused airway epithelial cell detachment. Endothelial cell death occurred at 500 µM NM. Vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF) expression increased in 500 µM NM-exposed cultures compared with PBS-exposed control cultures. NM vapor exposure causes differential cytotoxicity to airway epithelial and endothelial injury in culture. Increased VEGF-A and PlGF expression occurred acutely in airway cocultures. Future studies are required to validate the role of VEGF signaling in mustard-induced airway pathology.


Assuntos
Citotoxinas/toxicidade , Células Endoteliais/metabolismo , Células Epiteliais/metabolismo , Pulmão/metabolismo , Mecloretamina/toxicidade , Fator A de Crescimento do Endotélio Vascular/biossíntese , Linhagem Celular , Células Endoteliais/patologia , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/patologia , Proteínas de Membrana/biossíntese
18.
Carbohydr Polym ; 239: 116106, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32414437

RESUMO

Hemorrhage remains a big threat to trauma patients, especially in combat fields. Therefore, we formulated a biocompatible and biopolymer based chitosan/carrageenan composite dressing. This dressing was fabricated using freeze-drying that will serve as a promising material to promote hemostasis and tissue growth required during hemorrhage. The efficacy of dressing was evaluated for its physiochemical analysis, surface morphology, and biodegradability. Further, human dermal fibroblast cells were seeded on dressing and demonstrated non-toxic effects on the cells by showing enhanced cell attachment and proliferation. In vitro hemostatic properties of the dressing were analyzed by human Thrombin-Antithrombin assay. The dressing formed showed steady blood coagulation implying red blood cells and platelet adhesion that helped in thrombin formation, which is responsible for enhancing wound healing. Thus, it is concluded that the composite dressing can be a potent combination to accelerate hemostatic activity against hemorrhage and promote tissue growth for effective wound healing.


Assuntos
Materiais Biocompatíveis/farmacologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Carragenina/farmacologia , Quitosana/farmacologia , Citotoxinas/farmacologia , Hemorragia/tratamento farmacológico , Hemostáticos/farmacologia , Cicatrização/efeitos dos fármacos , Bandagens , Materiais Biocompatíveis/química , Coagulação Sanguínea/efeitos dos fármacos , Lesões Encefálicas Traumáticas/patologia , Carragenina/química , Quitosana/química , Citotoxinas/química , Hemorragia/patologia , Hemostáticos/química , Humanos , Tamanho da Partícula , Propriedades de Superfície
19.
Am Soc Clin Oncol Educ Book ; 40: 485-500, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32421446

RESUMO

Over the past 2 decades, rapid advancement in systemic anticancer therapeutics has led to astounding improvement in survival rates of patients with cancer. However, this celebrated progress has brought with it an evolving spectrum of drug toxicities that limit their prodigious capabilities. Cutaneous adverse events are of the most frequent of these toxicities, with substantial impact on quality of life and commonly resulting in dose reduction or change in therapy. Thus, familiarity with the array of dermatologic manifestations caused by these drugs is prudent for patient treatment. As such, the advent of dedicated oncodermatologists, and their introduction into multidisciplinary cancer care, has been crucial in optimizing treatment through therapeutic achievement and overall well-being. This review will address the epidemiology, clinical presentations, and management strategies of the major dermatologic adverse events of systemic anticancer agents, including cytotoxic chemotherapy, targeted therapy, and immunotherapy.


Assuntos
Antineoplásicos/efeitos adversos , Citotoxinas/efeitos adversos , Imunoterapia/efeitos adversos , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/terapia , Pele/efeitos dos fármacos , Humanos
20.
J Antibiot (Tokyo) ; 73(8): 548-553, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404990

RESUMO

A new cytotoxic agent designated as 2-epi-anthracimycin (1) was isolated along with anthracimycin and anthracimycin B (2-demethylanthracimycin) from the culture broth of the marine-derived actinomycete Streptomyces sp. OPMA00631. The structure of 1 was elucidated based on spectroscopic analyses (1D and 2D NMR data and ROESY correlations). Compound 1 exhibited cytotoxicity against Jurkat cells with an IC50 value of 50.5 µM in 20 h. The effect of 1 on the cell cycle distribution of Jurkat cells was investigated. Compound 1 (7.80 µM) increased G1 phase cells from 51.1 to 62.0% and conversely, decreased G2 and M phase cells from 30.7 to 19.3 % in 20 h. At a higher concentration, 1 (250 µM) markedly increased subG1 phase cells (1.9% at 0 h to 16.5% at 20 h), while the proportion of G1 phase cells was maintained (62.3%). These results suggest that 1 exhibits cytotoxicity against Jurkat cells by arresting the cell cycle at the G1 phase.


Assuntos
Actinobacteria/química , Organismos Aquáticos/química , Citotoxinas/química , Citotoxinas/farmacologia , Policetídeos/química , Policetídeos/farmacologia , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Células Jurkat
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