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1.
Expert Opin Biol Ther ; 20(8): 829-830, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32510244

RESUMO

INTRODUCTION: In light of the current Covid-19 pandemic and the ongoing, extensive debate about the use of biological agents in psoriatic patients, we felt compelled to relate our experience in the use of secukinumab in the same cohort before and during the lockdown in Italy. Areas covered: Secukinumab was not discontinued, and there were no cases of confirmed infection with SARS-CoV-2 in this cohort. Expert opinion: In our practice, there is no evidence favoring the discontinuation of secukinumab in these patients. We also present a brief commentary on the use of biological agents in patients with moderate-to-severe plaque psoriasis.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Fatores Biológicos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Fatores Biológicos/farmacologia , Terapia Biológica/métodos , Estudos de Coortes , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Feminino , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Itália , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Psoríase/complicações , Psoríase/imunologia , Resultado do Tratamento
2.
Biol Pharm Bull ; 43(3): 569-573, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115516

RESUMO

Although substantial evidence suggests that an increase in the level of trimethylamine-N-oxide (TMAO) is associated with the risk of cardiovascular diseases, including atherosclerosis, chronic kidney diseases, and hypertension, the direct effect of TMAO on vascular endothelial function remains unclear. Therefore, we investigated the acute effects of TMAO on endothelium-dependent relaxation induced by acetylcholine (ACh) in the superior mesenteric arteries and femoral arteries of rat. In endothelium-intact preparations, it was observed that TMAO (300 µmol/L for 60 min) did not affect ACh-induced relaxation in either of the two arteries. In endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation under nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibitions by Nω-nitro-L-arginine (L-NNA) and indomethacin, respectively, TMAO specifically impairs the relaxation in femoral arteries but not in the superior mesenteric arteries. Under the inhibitory actions of NOS and as well as blockade of intermediate-conductance calcium-activated potassium channel (IKCa) (by TRAM-34) and small-conductance calcium-activated potassium channel (SKCa) (by apamin), which are putative sources of EDHF, ACh-induced relaxation was low, and there were no differences between the control and TMAO-treated groups with respect to both arteries. In femoral arteries, TMAO slightly reduces ACh-induced relaxation in the presence of indomethacin (preserved NO and EDHF signals) but does not affect ACh-induced NO-mediated relaxation under the combined presence of indomethacin, TRAM-34, and apamin. These results suggest that acute treatment with TMAO specifically impairs EDHF-mediated relaxation in the femoral arteries but not in the superior mesenteric arteries. These novel observations show that TMAO is a causative factor in the development of peripheral arterial disease.


Assuntos
Fatores Biológicos/farmacologia , Artéria Femoral/efeitos dos fármacos , Metilaminas/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar
3.
Sci Rep ; 10(1): 1614, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005941

RESUMO

The biological function of non-thermal atmospheric pressure plasma has been widely accepted in several types of cancer. We previously developed plasma-activated medium (PAM) for clinical use, and demonstrated that PAM exhibits a metastasis-inhibitory effect on ovarian cancer through reduced MMP-9 secretion. However, the anti-tumor effects of PAM on endometrial cancer remain unknown. In this study, we investigated the inhibitory effect of PAM on endometrial cancer cell viability in vitro. Our results demonstrated that AMEC and HEC50 cell viabilities were reduced by PAM at a certain PAM ratio, and PAM treatment effectively increased autophagic cell death in a concentration dependent manner. In addition, we evaluated the molecular mechanism of PAM activity and found that the mTOR pathway was inactivated by PAM. Moreover, our results demonstrated that the autophagy inhibitor MHY1485 partially inhibited the autophagic cell death induced by PAM treatment. These findings indicate that PAM decreases the viability of endometrial cancer cells along with alteration of the mTOR pathway, which is critical for cancer cell viability. Collectively, our data suggest that PAM inhibits cell viability while inducing autophagic cell death in endometrial cancer cells, representing a potential novel treatment for endometrial cancer.


Assuntos
Morte Celular Autofágica/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fatores Biológicos/farmacologia , Plasma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Morfolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Triazinas/farmacologia
4.
Oncol Rep ; 43(2): 625-634, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894333

RESUMO

While exploring new angiogenesis inhibitors from microbial metabolites, we recently isolated ahpatinins C, E, and G from a soil­derived Streptomyces sp. 15JA150. Ahpatinins C, E and G are known to have pepsin and renin inhibitory activities; however, their antiangiogenic activities and underlying molecular mechanisms have not been fully elucidated. In the present study, the antiangiogenic properties of ahpatinins C, E and G were investigated. The results revealed that the natural compounds significantly inhibited the vascular endothelial growth factor (VEGF)­induced proliferation, invasion, adhesion, and tube formation of human umbilical vein endothelial cells (HUVECs) without exhibiting any cytotoxicity. It was also revealed that ahpatinin E effectively suppressed the neovascularization of the chorioallantoic membranes in growing chick embryos. Notably, ahpatinins C, E, and G led to the downregulation of VEGF­induced activation of VEGF receptor 2 (VEGFR2) and its downstream signaling mediators, including AKT, ERK1/2, JNK, p38, and NF­κB, in HUVECs. Moreover, they reduced the expression of matrix metalloproteinase (MMP)­2 and MMP­9 in the HUVECs following stimulation with VEGF. Furthermore, ahpatinins C, E, and G reduced the tumor cell­induced invasion and tube forming abilities of HUVECs, as well as the expression of VEGF, by suppressing hypoxia­inducible factor­1α (HIF­1α) activity in U87MG glioblastoma cells. Collectively, the present findings indicated that ahpatinins C, E, and G may be used in anticancer therapy by targeting tumor angiogenesis through the inhibition of both VEGFR2 and HIF­1α pathways.


Assuntos
Inibidores da Angiogênese/farmacologia , Fatores Biológicos/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Streptomyces/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Adesão Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pepstatinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
Mar Drugs ; 18(1)2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31963775

RESUMO

From the origin of our planet, about 4 [...].


Assuntos
Fatores Biológicos/farmacologia , Feófitas/química , Animais , Alimentos , Humanos , Fotossíntese/fisiologia
6.
Invest Ophthalmol Vis Sci ; 60(12): 3718-3726, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479112

RESUMO

Purpose: To evaluate the effects of human amniotic membrane-derived fibroblast (AMF) cell supernatant (AMF-sup) on corneal epithelium. Methods: The phenotype of AMF cells was analyzed by flow cytometry using cell-surface markers. AMF cells were also induced to form osteoblasts and neural cells, and cell phenotypes were observed by staining and RT-PCR. Cultivated human corneal limbal epithelial sheets generated using AMF-sup were analyzed using immunohistochemistry and colony-forming efficiency, and the wound healing of epithelial defects was observed using a tissue-punch method. The effects of instillation of each supernatant in a rabbit corneal epithelial wound healing model were compared. Results: Mesenchymal stem cell (CD29, CD44, CD73, and CD90) and neural crest (CD49d and CD56) markers were expressed on the AMF cell surface. Following induction of differentiation, isolated AMF cells showed characteristics of osteoblasts and neural cells. Application of AMF-sup resulted in maintenance of the limbal epithelial phenotype and immature state, and significantly promoted wound healing in cultivated human corneal limbal epithelial sheets (P < 0.05) and rabbit corneal epithelium (P < 0.05) compared with the control. Conclusions: These data suggest that AMF cells have multi-differentiation potential, and that AMF-sup is effective in maintaining the limbal epithelial phenotype and promoting corneal epithelial wound healing, which may be of value in ocular surface reconstruction.


Assuntos
Âmnio/citologia , Fatores Biológicos/farmacologia , Lesões da Córnea/tratamento farmacológico , Epitélio Anterior/efeitos dos fármacos , Fibroblastos/fisiologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Lesões da Córnea/metabolismo , Lesões da Córnea/patologia , Epitélio Anterior/metabolismo , Epitélio Anterior/patologia , Feminino , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Limbo da Córnea/citologia , Camundongos , Células NIH 3T3 , Fenótipo , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Cicatrização/fisiologia
7.
Mar Drugs ; 17(8)2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405226

RESUMO

Marine invertebrates and their associated microorganisms are rich sources of bioactive compounds. Among them, coral and its associated microorganisms are promising providers of marine bioactive compounds. The present review provides an overview of bioactive compounds that are produced by corals and coral-associated microorganisms, covering the literature from 2010 to March 2019. Accordingly, 245 natural products that possess a wide range of potent bioactivities, such as anti-inflammatory, cytotoxic, antimicrobial, antivirus, and antifouling activities, among others, are described in this review.


Assuntos
Antozoários/química , Antozoários/microbiologia , Organismos Aquáticos/química , Fatores Biológicos/química , Fatores Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Animais , Humanos
8.
Pediatr Clin North Am ; 66(5): 1007-1020, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31466676

RESUMO

Biologics are protein-based pharmaceuticals derived from living organisms or their proteins. We discuss the mechanism of action for currently approved biologics and a give summary of the studies on immune suppression from biologics. Most of these studies have been conducted with rheumatology patients, and many in adults. Their relevance for children is explored and existing gaps in data for children are highlighted.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Fatores Biológicos/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Síndromes de Imunodeficiência/induzido quimicamente , Criança , Ensaios Clínicos como Assunto , Humanos
9.
Mar Drugs ; 17(8)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394844

RESUMO

Two new capnosane-based diterpenoids, flaccidenol A (1) and 7-epi-pavidolide D (2), two new cembranoids, flaccidodioxide (3) and flaccidodiol (4), and three known compounds 5 to 7 were characterized from the marine soft coral Klyxum flaccidum, collected off the coast of the island of Pratas. The structures of the new compounds were determined by extensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, and spectroscopic data comparison with related structures. The rare capnosane diterpenoids were isolated herein from the genus Klyxum for the first time. The cytotoxicity of compounds 1 to 7 against the proliferation of a limited panel of cancer cell lines was assayed. The isolated diterpenoids also exhibited anti-inflammatory activity through suppression of superoxide anion generation and elastase release in the N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLF/CB)-stimulated human neutrophils. Furthermore, 1 and 7 also exhibited cytotoxicity toward the tested cancer cells, and 7 could effectively inhibit elastase release. It is worth noting that the biological activities of 7 are reported for the first time in this paper.


Assuntos
Antozoários/química , Fatores Biológicos/farmacologia , Diterpenos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocalasina B/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Espectroscopia de Ressonância Magnética/métodos , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Elastase Pancreática/metabolismo , Superóxidos/metabolismo
10.
Mar Drugs ; 17(6)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216636

RESUMO

The marine biosphere is a treasure trove of natural bioactive secondary metabolites and the richest source of structurally diverse and unique compounds, such as phlorotannins and halo-compounds, with high therapeutic potential. Eckol is a precursor compound representing the dibenzo-1,4-dioxin class of phlorotannins abundant in the Ecklonia species, which are marine brown algae having a ubiquitous distribution. In search of compounds having biological activity from macro algae during the past three decades, this particular compound has attracted massive attention for its multiple therapeutic properties and health benefits. Although several varieties of marine algae, seaweed, and phlorotannins have already been well scrutinized, eckol deserves a place of its own because of the therapeutic properties it possesses. The relevant information about this particular compound has not yet been collected in one place; therefore, this review focuses on its biological applications, including its potential health benefits and possible applications to restrain diseases leading to good health. The facts compiled in this review could contribute to novel insights into the functions of eckol and potentially enable its use in different uninvestigated fields.


Assuntos
Dioxinas/farmacologia , Dioxinas/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Fatores Biológicos/farmacologia , Fatores Biológicos/uso terapêutico , Humanos , Feófitas/química , Alga Marinha/química
11.
Am J Clin Dermatol ; 20(4): 539-564, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30997665

RESUMO

The autoinflammatory diseases comprise a broad spectrum of disorders characterized by unchecked activation of the innate immune system. Whereas aberrations in adaptive immunity have long been identified in 'autoimmune' disorders, the concept of 'autoinflammation' emerged relatively recently, first describing a group of clinical disorders characterized by spontaneous episodes of systemic inflammation without manifestations typical of autoimmune disorders. Improved knowledge of innate immune mechanisms, coupled with remarkable progress in genomics and an expanding number of clinical cases, has since led to an increasing number of disorders classified as autoinflammatory or containing an autoinflammatory component. Biologic therapies targeting specific components of the innate immune system have provided immense clinical benefit, and have further elucidated the role of innate immunity in autoinflammatory disorders. This article reviews the basic mechanisms of autoinflammation, followed by an update on the pathophysiology and treatment of the monogenic and multifactorial autoinflammatory diseases, and the common dermatologic conditions in which autoinflammation plays a major role.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Inflamação/tratamento farmacológico , Doenças Autoimunes/etiologia , Fatores Biológicos/farmacologia , Doenças Hereditárias Autoinflamatórias/etiologia , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/etiologia , Pele/efeitos dos fármacos , Pele/imunologia , Resultado do Tratamento
12.
Mar Drugs ; 17(4)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974812

RESUMO

Chitosanase has attracted great attention due to its potential applications in medicine, agriculture, and nutraceuticals. In this study, P. mucilaginosus TKU032, a bacterial strain isolated from Taiwanese soil, exhibited the highest chitosanase activity (0.53 U/mL) on medium containing shrimp heads as the sole carbon and nitrogen (C/N) source. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, a chitosanase isolated from P. mucilaginosus TKU032 cultured on shrimp head medium was determined at approximately 59 kDa. The characterized chitosanase showed interesting properties with optimal temperature and thermal stability up to 70 °C. Three chitosan oligosaccharide (COS) fractions were isolated from hydrolyzed colloidal chitosan that was catalyzed by TKU032 chitosanase. Of these, fraction I showed the highest α-glucosidase inhibitor (aGI) activity (65.86% at 20 mg/mL); its inhibitory mechanism followed the mixed noncompetitive inhibition model. Fractions II and III exhibited strong 2,2-diphenyl1-picrylhydrazyl (DPPH) radical scavenging activity (79.00% at 12 mg/mL and 73.29% at 16 mg/mL, respectively). In summary, the COS fractions obtained by hydrolyzing colloidal chitosan with TKU032 chitosanase may have potential use in medical or nutraceutical fields due to their aGI and antioxidant activities.


Assuntos
Proteínas de Bactérias/isolamento & purificação , Fatores Biológicos/biossíntese , Glicosídeo Hidrolases/isolamento & purificação , Oligossacarídeos/biossíntese , Paenibacillus/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Biocatálise , Fatores Biológicos/farmacologia , Quitosana/metabolismo , Crustáceos/química , Ensaios Enzimáticos/métodos , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Proteínas Fúngicas/metabolismo , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/metabolismo , Temperatura Alta , Oligossacarídeos/farmacologia , Paenibacillus/isolamento & purificação , Estabilidade Proteica , Microbiologia do Solo , Especificidade por Substrato , alfa-Glucosidases/metabolismo
13.
Mar Drugs ; 17(4)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978965

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons, leading to the motor dysfunctions of patients. Although the etiology of PD is still unclear, the death of dopaminergic neurons during PD progress was revealed to be associated with the abnormal aggregation of α-synuclein, the elevation of oxidative stress, the dysfunction of mitochondrial functions, and the increase of neuroinflammation. However, current anti-PD therapies could only produce symptom-relieving effects, because they could not provide neuroprotective effects, stop or delay the degeneration of dopaminergic neurons. Marine-derived natural compounds, with their novel chemical structures and unique biological activities, may provide anti-PD neuroprotective effects. In this study, we have summarized anti-PD marine-derived natural products which have shown pharmacological activities by acting on various PD targets, such as α-synuclein, monoamine oxidase B, and reactive oxygen species. Moreover, marine-derived natural compounds currently evaluated in the clinical trials for the treatment of PD are also discussed.


Assuntos
Organismos Aquáticos , Fatores Biológicos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Fatores Biológicos/isolamento & purificação , Fatores Biológicos/uso terapêutico , Ensaios Clínicos como Assunto , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/patologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/patologia
14.
Sci Transl Med ; 11(482)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842312

RESUMO

There is a major unmet clinical need to identify pathways in inflammatory bowel disease (IBD) to classify patient disease activity, stratify patients that will benefit from targeted therapies such as anti-tumor necrosis factor (TNF), and identify new therapeutic targets. In this study, we conducted global transcriptome analysis to identify IBD-related pathways using colon biopsies, which highlighted the coagulation gene pathway as one of the most enriched gene sets in patients with IBD. Using this gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that, among the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy and that PAI-1 is a key link between the epithelium and inflammation. Functionally, PAI-1 and its direct target, the fibrinolytic protease tissue plasminogen activator (tPA), played an important role in regulating intestinal inflammation. Intestinal epithelial cells produced tPA, which was protective against chemical and mechanical-mediated colonic injury in mice. In contrast, PAI-1 exacerbated mucosal damage by blocking tPA-mediated cleavage and activation of anti-inflammatory TGF-ß, whereas the inhibition of PAI-1 reduced both mucosal damage and inflammation. This study identifies an immune-coagulation gene axis in IBD where elevated PAI-1 may contribute to more aggressive disease.


Assuntos
Colite/metabolismo , Colite/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Animais , Fatores Biológicos/farmacologia , Fatores Biológicos/uso terapêutico , Coagulação Sanguínea , Proliferação de Células/efeitos dos fármacos , Citrobacter/efeitos dos fármacos , Colite/imunologia , Colite/microbiologia , Colo/patologia , Citocinas/metabolismo , Inflamação/patologia , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Interleucina-17/metabolismo , Camundongos , Índice de Gravidade de Doença , Bibliotecas de Moléculas Pequenas/farmacologia , Células Th17/imunologia , Ativador de Plasminogênio Tecidual/metabolismo , Transcrição Genética , Fator de Crescimento Transformador beta/metabolismo
15.
J Cancer Res Ther ; 15(1): 176-184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880776

RESUMO

Context: Tilorone dihydrochloride is a therapeutic agent with a different mechanism in cancer. The species of Lactobacillus have an important role in cytotoxic effect. Aims: Because of unknown effects of tilorone and culture supernatants from Lactobacillus reuteri on hepatoma, the aim of this study is to evaluate apoptotic, cytotoxic, and therapeutic effects of tilorone on mouse hepatoma cell line with and without culture supernatants from L. reuteri. Materials and Methods: To do so, after cell line culture, cells were divided into different groups such as negative control, treatment with four doses of tilorone, positive control of supernatant (single dose), and combination therapy groups of different doses of tilorone with supernatant (constant doses), for 48 h. All groups were studied with pathologic tests, biochemical study, tetrazolium dye (3-(4, 5- dimethylthiazol -2-yl)-2, 5-diphenyltetrazolium bromide [MTT]) assay, and absolute real-time-polymerase chain reaction (RT-PCR) were done to assess Bax and Bcl-2 genes expression, as molecular studies. Results: MTT assay results revealed that the tilorone tissue culture IC50 (TCIC50) on the Hepa1-6 cell line was 50 µg/ml. RT-PCR analysis showed that tilorone dihydrochloride induced upregulation and downregulation in expression of Bax and Bcl-2, respectively. Simultaneous, antioxidant effect has also seen in a way that prevented necrosis, in biochemical analysis. These results were dose dependent and statistically significant compared to the control group. Conclusions: Based on these results, it appeared that this agent could be a good candidate for further evaluation as effective chemotherapy acting through the induction of apoptosis in hepatoma. The cell death caused through bacterial supernatant was rather necrosis than apoptosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Lactobacillus reuteri/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Tilorona/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Fatores Biológicos/farmacologia , Fatores Biológicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Meios de Cultura/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Tilorona/uso terapêutico
16.
Phytomedicine ; 57: 364-376, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831485

RESUMO

BACKGROUND: Rice callus suspension culture (RCSC) has been shown to exhibit potent antiproliferative activity in multiple cancer cell lines. RCSC and its bioactive compounds can fill the need for drugs with no side effects. HYPOTHESIS/PURPOSE: The anti-inflammatory potential of RCSC and its bioactive fractions on normal colon epithelial cell lines, was investigated. STUDY DESIGN: Three cell lines, InEpC, NCM356 and CCD841-CoN were treated with proinflammatory cytokines followed by RCSC. Cytoplasmic and nuclear ROS were assayed with fluorescent microscopy and flow cytometer. Expression analysis of immune-related genes was performed in RCSC-treated cell lines. RCSC was fractionated using column chromatography and HPLC. Pooled fractions 10-18 was used to test for antiproliferative activity using colon adenocarcinoma cell line, SW620 and anti-inflammatory activity using CCD841-CoN. Mass spectrometric analysis was performed to identify candidate compounds in four fractions. RESULTS: RCSC treatment showed differential effects with higher cytoplasmic ROS levels in NCM356 and CCD841-CoN and lower ROS levels in InEpC. Nuclear generated ROS levels increased in all three treated cell lines. Flow cytometry analysis of propidium iodide stained cells indicated mitigation of cell death caused by inflammation in RCSC treated groups in both NCM356 and CCD841-CoN. Genes encoding transcription factors and cytokines were differentially regulated in NCM356 and CCD841-CoN cell lines treated with RCSC which provided insights into possible pathways. Analysis of pooled fractions 10-18 by HPLC identified 8 peaks. Cell viability assay with fractions 10-18 using SW620 showed that the number of viable cells were greatly reduced which was similar to 6X and 33X RCSC with very little effect on normal cells which similar to 1X RCSC. RCSC fractions increased nuclear and cytoplasmic ROS vs. both untreated and inflammatory control. Analysis of four fractions by mass spectrometry identified 4-deoxyphloridzin, 5'-methoxycurcumin, piceid and lupeol as candidate compounds which are likely to be responsible for the antiproliferative, anti-inflammatory and immune-regulating properties of RCSC. CONCLUSION: RCSC and its fractions showed anti-inflammatory activity on inflamed colon epithelial cells. Downstream target candidate genes which are likely to mediate RCSC effects were identified. Candidate compounds responsible for the antiproliferative and anti-inflammatory activity of RCSC and its fractions provide possible drug targets.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Fatores Biológicos/farmacologia , Fatores Imunológicos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Oryza/citologia , Técnicas de Cultura de Tecidos/métodos , Adenocarcinoma , Anti-Inflamatórios/imunologia , Antineoplásicos/química , Fatores Biológicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Neoplasias Colorretais , Citocinas/genética , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/química , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Oryza/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética
17.
Ann Endocrinol (Paris) ; 80(2): 128-133, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30833018

RESUMO

In the modern world, type-2 diabetes mellitus has become a leading public healthcare problem, due to major risks of morbidity and mortality. Prevalence has increased significantly in recent decades. Treatment involves oral hypoglycemic agents or insulin replacement therapy. Development is ongoing for cell-based diabetes therapies using stem cells with the potential to differentiate into insulin-producing cells (IPCs): embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and stem cells from adult pancreas, liver, central nervous system, bone marrow and adipose tissue. Successful induction of iPSCs, however, depends on the quantity and quality of available stem cells and the development of adapted protocols determining the environment of extrinsic factors and involvement of small molecules. Validating such new cell therapies must be founded on this experimental rationale.


Assuntos
Fatores Biológicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células-Tronco Pluripotentes/efeitos dos fármacos , Animais , Fatores Biológicos/análise , Fatores Biológicos/isolamento & purificação , Técnicas de Cultura de Células , Reprogramação Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Pâncreas/citologia , Pâncreas/efeitos dos fármacos , Pâncreas/fisiologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/fisiologia , Bibliotecas de Moléculas Pequenas/análise
19.
Sci Transl Med ; 11(475)2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651319

RESUMO

A key aspect underlying the severity of infections caused by Staphylococcus aureus is the abundance of virulence factors that the pathogen uses to thwart critical components of the human immune response. One such mechanism involves the destruction of host immune cells by cytolytic toxins secreted by S. aureus, including five bicomponent leukocidins: PVL, HlgAB, HlgCB, LukED, and LukAB. Purified leukocidins can lyse immune cells ex vivo, and systemic injections of purified LukED or HlgAB can acutely kill mice. Here, we describe the generation and characterization of centyrins that bind S. aureus leukocidins with high affinity and protect primary human immune cells from toxin-mediated cytolysis. Centyrins are small protein scaffolds derived from the fibronectin type III-binding domain of the human protein tenascin-C. Although centyrins are potent in tissue culture assays, their short serum half-lives limit their efficacies in vivo. By extending the serum half-lives of centyrins through their fusion to an albumin-binding consensus domain, we demonstrate the in vivo efficacy of these biologics in a murine intoxication model and in models of both prophylactic and therapeutic treatment of live S. aureus systemic infections. These biologics that target S. aureus virulence factors have potential for treating and preventing serious staphylococcal infections.


Assuntos
Fatores Biológicos/farmacologia , Leucocidinas/metabolismo , Testes de Neutralização , Staphylococcus aureus/metabolismo , Sequência de Aminoácidos , Animais , Citoproteção/efeitos dos fármacos , Citotoxicidade Imunológica , Hemólise/efeitos dos fármacos , Humanos , Leucocidinas/química , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fagócitos/efeitos dos fármacos , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/efeitos dos fármacos
20.
Molecules ; 24(2)2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30654598

RESUMO

Mangifera odorata fruit, the hybrid forms between M. indica (mango) and M. foetida (bacang), has been shown to exhibit potential antioxidant activity, and the fruit waste could demonstrate functional and nutritional potential. In the present study, the nutritional composition (proximate, sugars, vitamins and minerals analyses), the anti-diabetic activities and phytochemical profile of M. odorata peel and seed kernel were investigated for the first time. The results indicated that seed kernel rich in fat, protein, carbohydrate, and ash while peel contained significantly greater amount of fiber, minerals, ß-Carotene and ascorbic acid compared to seed kernel. The samples were then extracted using different solvents (acetone, ethanol, methanol at 60%, v/v and pure deionized water) and their anti-diabetic activities (α-amylase and α-glucosidase inhibition assay) were determined. Seed kernel had the lowest IC50 values for α-amylase and α-glucosidase inhibition assay in 60% ethanol and 60% acetone, respectively. Due to the toxic effect and high volatility of acetone, the ethanolic extracts of samples were further analyses for their phytochemical profile using high performance liquid chromatography-mass spectrometry (LC-MS) and ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry (UHPLC-ESI-Orbitrap-MS/MS). The most abundant compounds identified were phenolic acid, ellagic acid, and flavonoid. These findings suggest that M. odorata fruit wastes, especially the seed kernel possesses promising ability to be used as functional ingredient in the food industry.


Assuntos
Inibidores Enzimáticos/isolamento & purificação , Hipoglicemiantes/isolamento & purificação , Mangifera/química , Extratos Vegetais/análise , Sementes/química , Fatores Biológicos/isolamento & purificação , Fatores Biológicos/farmacologia , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/farmacologia , Indústria de Processamento de Alimentos , Frutas/química , Alimento Funcional , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Valor Nutritivo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Espectrometria de Massas em Tandem , alfa-Amilases/antagonistas & inibidores
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