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1.
Poult Sci ; 98(11): 5809-5819, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31347673

RESUMO

The effect of essential total sulfur amino acids (TSAA) like methionine and cysteine on the cecal microbiome of broilers was investigated at 2 different time points (days 21 and 42) of broiler rearing. A total of 360-day-old Cobb male broiler chicks were randomly distributed to 6 dietary treatments in a 2 × 3 factorial arrangement, with 2 levels of antibiotic growth promoters (AGP: 0 and 0.05%) and 3 levels of TSAA (DL-methionine) either for starter (0.7, 0.8, and 0.9%) or finisher chicks (0.52, 0.62, and 0.72%), labeled as diets 1 to 6. Cecal digesta from each replicate (n = 10) were sampled on days 21 and 42. DNA was extracted for the amplification of the V4 region of bacterial 16S rRNA genes and subjected to Illumina sequencing. Bioinformatic analyses were performed using QIIME, Mothur, and ad hoc tools and functional profiles of the inferred metagenome were analyzed using PICRUST. Statistical difference was determined by 2-way ANOVA and PERMANOVA. Clustering of cecal communities using PCoA showed clear separation of microbial communities based on age (P < 0.05) of birds and between low and medium/ high levels of TSAA (DL-methionine). At day 21, bacterial richness and diversity were higher than at day 42 where Clostridium cluster XI and Lactobacillus were found most abundant. No variability in taxonomic richness at the genus level was observed with AGP and DL-methionine supplementation. Interbird variation for richness was greater at day 42 compared to day 21. The mean fold difference of richness was greater (1.5 mean fold) with diets 1 and 6, suggesting interactive effects of AGP and TSAA (DL-methionine) in the diet. KEGG function profiles calculated by PICRUST suggest that the cecal microbiome increased glycolysis and energy generation correlated with increased dietary TSAA (DL-methionine) supplementation levels during the late broiler growth period (day 42). This study increases our knowledge of microbial dynamics and functions that are relevant to host nutrition and performance that may help us tailoring alternative strategies for raising poultry birds under antibiotic-free conditions.


Assuntos
Aminoácidos Sulfúricos/metabolismo , Antibacterianos/farmacologia , Bacitracina/farmacologia , Ceco/microbiologia , Galinhas/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Racemetionina/metabolismo , Salicilatos/farmacologia , Aminoácidos Sulfúricos/administração & dosagem , Ração Animal/análise , Animais , Antibacterianos/administração & dosagem , Bacitracina/administração & dosagem , Galinhas/fisiologia , Dieta/veterinária , Suplementos Nutricionais/análise , Masculino , Racemetionina/administração & dosagem , Distribuição Aleatória , Salicilatos/administração & dosagem
2.
Environ Sci Pollut Res Int ; 26(18): 18440-18450, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31049858

RESUMO

In view of the suspected negative impact of synthetic fungicides to the human health, nutritional quality, and non-targeted organisms, the use of plant-based antifungal agents has gained considerable interest to the agri-food industries. The aim of this study was to explore the antifungal and aflatoxin B1 (AFB1) inhibitory activity of chitosan (low molecular weight) encapsulated methyl salicylate. The nanoencapsulation of methyl salicylate (Ne-MS) has been characterized by SEM, FTIR, and XRD analysis. The encapsulation efficiency and loading capacity of Ne-MS ranged between 32-34% and 5-7% respectively. The minimum inhibitory concentration of Ne-MS (1.00 µL/mL) against the growth and aflatoxin B1 production by Aspergillus flavus was found to be lower than the free MS (1.50 µL/mL). Mode of action studies demonstrated that the Ne-MS cause a significant decrease in the ergosterol content, leakage of vital ions (Ca2+, Mg2+, and K+), utilization of different carbon source by the A. flavus. Further, the docking result showed ver1 and omt A gene of AFB1 biosynthesis are the possible molecular site of action of methyl salicylate. The in situ study revealed that Ne-MS had no significant negative impact on the organoleptic properties of the food system (maize) which strengthen its potential as a biorational alternative of synthetic fungicides.


Assuntos
Aflatoxina B1/análise , Aspergillus flavus/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Nanopartículas/química , Salicilatos/farmacologia , Aflatoxina B1/biossíntese , Aspergillus flavus/metabolismo , Fungicidas Industriais/administração & dosagem , Humanos , Testes de Sensibilidade Microbiana , Salicilatos/administração & dosagem , Zea mays/efeitos dos fármacos
3.
Mol Nutr Food Res ; 63(8): e1801097, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30680927

RESUMO

SCOPE: High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways. METHODS AND RESULTS: A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways. CONCLUSION: These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.


Assuntos
Anticarcinógenos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/prevenção & controle , Obesidade/complicações , Adiposidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colite/tratamento farmacológico , Colite/etiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Curcumina/administração & dosagem , Curcumina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos Endogâmicos , Obesidade/etiologia , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/metabolismo , Salicilatos/administração & dosagem , Salicilatos/farmacologia , Transdução de Sinais/efeitos dos fármacos
4.
Anal Bioanal Chem ; 411(1): 147-156, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30377739

RESUMO

A high-throughput matrix-assisted laser desorption/ionization mass spectrometry (MALDI)-MS-based metabolomics platform was developed using a pre-fabricated microarray of nanoparticles and organic matrices. Selected organic matrices, inorganic nanoparticle (NP) suspensions, and sputter coated metal NPs, as well as various additives, were tested for metabolomics analysis of the turkey gut microbiome. Four NPs and one organic matrix were selected as the optimal matrix set: α-cyano-4-hydroycinnamic acid, Fe3O4 and Au NPs in positive ion mode with 10 mM sodium acetate, and Cu and Ag NPs in negative ion mode with no additive. Using this set of five matrices, over two thousand unique metabolite features were reproducibly detected across intestinal samples from turkeys fed a diet amended with therapeutic or sub-therapeutic antibiotics (200 g/ton or 50 g/ton bacitracin methylene disalicylate (BMD), respectively), or non-amended feed. Among the thousands of unique features, 56 of them were chemically identified using MALDI-MS/MS, with the help of in-parallel liquid chromatography (LC)-MS/MS analysis. Lastly, as a proof of concept application, this protocol was applied to 52 turkey cecal samples at three different time points from the antibiotic feed trial. Statistical analysis indicated variations in the metabolome of turkeys with different ages or treatments. Graphical abstract ᅟ.


Assuntos
Antibacterianos/administração & dosagem , Bacitracina/administração & dosagem , Ensaios de Triagem em Larga Escala/métodos , Intestinos/microbiologia , Metabolômica , Microbiota , Nanopartículas/química , Salicilatos/administração & dosagem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Perus/microbiologia , Animais , Cromatografia Líquida/métodos , Cobre/química , Ácidos Cumáricos/química , Relação Dose-Resposta a Droga , Óxido Ferroso-Férrico/química , Ouro/química , Estruturas Metalorgânicas , Estudo de Prova de Conceito , Reprodutibilidade dos Testes , Prata/química , Espectrometria de Massas em Tandem/métodos
6.
Poult Sci ; 98(2): 904-911, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30285253

RESUMO

Antibiotic growth promoters have been widely used in poultry to improve overall performance. The emergence of antibiotic resistance has resulted in sanctions imposed on the use of antibiotics in poultry diets, and alternatives such as herbal extracts are being considered to improve growth performance. The aim of this study was to compare the performance and feed digestibility of the feed supplement Novacid, which contains organic acids, glucomannan, and phytochemicals, with that of the antibiotic growth promoter bacitracin methylene disalicylate (BMD) in commercial broiler chickens. Six hundred 1-d-old Ross × Ross 308 male broiler chicks were randomly and equally assigned to six treatment groups with five replicates each (20 chicks per replicate). The chicks were fed a corn-soybean meal basal diet, and divided into two groups: unchallenged and challenged with E. coli (400 mg/kg Escherichia coli inoculation). Each of these groups was divided into three study groups: untreated, treated with 0.05% Novacid, and treated with 400 mg/kg BMD. At day 42, inclusion of Novacid or BMD significantly (P < 0.05) improved the performance in the unchallenged groups relative to the control group. However, in E. coli-challenged groups, Novacid and BMD did not improve performance. Ileal digestibility of crude fat, crude protein, and gross energy were reduced in the Novacid group (P < 0.05). BMD and Novacid were equally effective in controlling ileal nutrient digestibility and feed coliform count (P < 0.05). Novacid reduced cecal E. coli and Salmonella count compared to BMD and control. Thus, a phytochemical feed supplement with organic acids and glucomannan could be an effective substitute for antibiotic growth promoters in broiler diets, but cannot replace antibiotics to counter potent infectious agents such as E. coli.


Assuntos
Bacitracina/metabolismo , Galinhas/fisiologia , Suplementos Nutricionais , Digestão/efeitos dos fármacos , Substâncias de Crescimento/metabolismo , Salicilatos/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/metabolismo , Bacitracina/administração & dosagem , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Escherichia coli/fisiologia , Substâncias de Crescimento/administração & dosagem , Masculino , Nutrientes/fisiologia , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Salicilatos/administração & dosagem
7.
Oncol Rep ; 41(1): 369-376, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30320342

RESUMO

Liver cancer is one of the most devastating types of cancer worldwide. Despite years of improvements in treatment, the prognosis of patients with this type of malignancy remains poor due to frequent recurrence and metastasis after surgical resection. Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo biloba L. that possesses a wide range of bioactive properties. However, to the best of our knowledge, whether GA can inhibit the invasion of liver cancer cells and the underlying mechanisms remains unknown. The aim of the present study was to investigate the effects of GA on the migration and invasion abilities of liver cancer cells and the underlying molecular mechanism. The results revealed that GA suppressed the migration and invasion abilities of HepG2 cells. In addition, GA treatment inhibited the expression of invasion­related molecules (MMP­2 and MMP­9) and prevented the epithelial­mesenchymal transition (EMT) of HepG2 cells. Further experiments revealed that GA­reduced hepatocyte growth factor (HGF) production and suppressed c­Met phosphorylation may be the underlying mechanisms. Exogenous recombinant HGF supplementation improved the cell invasion ability impaired by GA. Moreover, the in vivo experiment revealed that GA inhibited the tumor growth of liver cancer and prevented EMT. Collectively, these data indicated that GA effectively suppressed the invasion and EMT of HepG2 cells via downregulation of HGF/c­Met signaling, thus GA may serve as a novel chemotherapeutic agent for the treatment of HCC.


Assuntos
Regulação para Baixo , Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/metabolismo , Salicilatos/administração & dosagem , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Salicilatos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Chemother Pharmacol ; 82(3): 511-519, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29992354

RESUMO

PURPOSE: Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. METHODS: Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. RESULTS: A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1-13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79-373). CONCLUSION: Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. CLINICAL TRIAL REGISTRATION: JAPIC Clinical Trials Information; JapicCTI-121751.


Assuntos
Farneseno Álcool/análogos & derivados , Neoplasias/tratamento farmacológico , Salicilatos/administração & dosagem , Proteínas ras/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Farneseno Álcool/administração & dosagem , Farneseno Álcool/efeitos adversos , Farneseno Álcool/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/patologia , Salicilatos/efeitos adversos , Salicilatos/farmacocinética
9.
Biochim Biophys Acta Mol Basis Dis ; 1864(10): 3109-3121, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29908908

RESUMO

A host of pathogenic factors induce acute kidney injury (AKI) leading to insufficiencies of renal function. In the present study we evaluated the role of myocardin-related transcription factor A (MRTF-A) in the pathogenesis of AKI. We report that systemic deletion of MRTF-A or inhibition of MRTF-A activity with CCG-1423 significantly attenuated AKI in mice induced by either ischemia-reperfusion or LPS injection. Of note, MRTF-A deficiency or suppression resulted in diminished renal ROS production in AKI models with down-regulation of NAPDH oxdiase 1 (NOX1) and NOX4 expression. In cultured macrophages, MRTF-A promoted NOX1 transcription in response to either hypoxia-reoxygenation or LPS treatment. Interestingly, macrophage-specific MRTF-A deletion ameliorated AKI in mice. Mechanistic analyses revealed that MRTF-A played a role in regulating histone H4K16 acetylation surrounding the NOX gene promoters by interacting with the acetyltransferase MYST1. MYST1 depletion repressed NOX transcription in macrophages. Finally, administration of a MYST1 inhibitor MG149 alleviated AKI in mice. Therefore, we data illustrate a novel epigenetic pathway that controls ROS production in macrophages contributing to AKI. Targeting the MRTF-A-MYST1-NOX axis may yield novel therapeutic strategies to combat AKI.


Assuntos
Lesão Renal Aguda/genética , Histona Acetiltransferases/metabolismo , Macrófagos/metabolismo , NADPH Oxidase 1/genética , NADPH Oxidase 4/genética , Transativadores/genética , Acetilação , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Anilidas/farmacologia , Animais , Benzamidas/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Deleção de Genes , Histona Acetiltransferases/antagonistas & inibidores , Histonas/metabolismo , Lipopolissacarídeos/efeitos adversos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , NADPH Oxidase 1/metabolismo , NADPH Oxidase 4/metabolismo , Regiões Promotoras Genéticas , Espécies Reativas de Oxigênio/metabolismo , Salicilatos/administração & dosagem , Salicilatos/farmacologia
10.
Int J Oncol ; 53(2): 725-736, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901113

RESUMO

The active form of the small GTPase RAS binds to downstream effectors to promote cell growth and proliferation. RAS signal enhancement contributes to tumorigenesis, invasion, and metastasis in various different cancers. HRAS proto-oncogene GTPase (HRAS), one of the RAS isoforms, was the first human oncogene for which mutations were reported in T24 bladder cancer (BC) cells in 1982, and HRAS mutation or upregulation has been reported in several cancers. According to data from The Cancer Genome Atlas, HRAS expression was significantly upregulated in clinical BC samples compared to healthy samples (P=0.0024). HRAS expression was also significantly upregulated in BC with HRAS mutation compared to patients without HRAS mutation (P<0.0001). The tumor suppressive effect of salirasib, a RAS inhibitor, has been reported in several cancer types, but only at relatively high concentrations. As such, RAS inhibitors have not been used for clinical applications. The aim of the current study was to investigate the therapeutic potential of targeting HRAS using salirasib and small interfering RNA (siRNA) and to characterize the mechanism by which HRAS functions using recently developed quantitative in vitro proteome-assisted multiple reaction monitoring for protein absolute quantification (iMPAQT), in BC cells. iMPAQT allows measurement of the absolute abundance of any human protein with the high quantitative accuracy. Salirasib and siRNA targeting of HRAS inhibited cell proliferation, migration and invasion in HRAS wild type and HRAS-mutated cell lines. Proteomic analyses revealed that several metabolic pathways, including the oxidative phosphorylation pathway and glycolysis, were significantly downregulated in salirasib-treated BC cells. However, the expression levels of hexokinase 2, phosphoglycerate kinase 1, pyruvate kinase, muscle (PKM)1, PKM2 and lactate dehydrogenase A, which are downstream of RAS and target genes of hypoxia inducible factor-1α, were not notably downregulated, which may explain the high concentration of salirasib required to inhibit cell viability. These findings provide insight into the mechanisms of salirasib, and suggest the need for novel therapeutic strategies to treat cancers such as BC.


Assuntos
Antineoplásicos/administração & dosagem , Farneseno Álcool/análogos & derivados , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Salicilatos/administração & dosagem , Regulação para Cima/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Farneseno Álcool/administração & dosagem , Farneseno Álcool/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Glicólise/efeitos dos fármacos , Humanos , Camundongos , Mutação , Fosforilação Oxidativa/efeitos dos fármacos , Proteômica , Salicilatos/farmacologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Niger J Clin Pract ; 21(1): 54-58, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29411724

RESUMO

OBJECTIVE: Standard triple therapy for Helicobacter pylori has a low eradication rate in Turkey. The aim of this study was to evaluate and compare the effectiveness of 7-day and 14-day lansoprazole, amoxicillin, clarithromycin, and bismuth subsalicylate (LACB) treatment regimens as first-line H. pylori eradication therapies. MATERIALS AND METHODS: This study included 70 patients with symptoms of dyspepsia and a positive H. pylori stool antigen test (SAT). Thirty-five patients received the modified quadruple therapy regimen for 7 days (LACB-7) whereas the remaining 35 patients received the treatment for 14 days (LACB-14). Eradication was assessed by SAT 1 month after the end of therapy. RESULTS: A total of 64 patients completed the therapy. The cumulative per-protocol (PP) and intention-to-treat (ITT) eradication rates were 89% (n = 57/64) and 81.4% (n = 57/70), respectively. Both the PP and ITT eradication rates were superior in the LACB-14 group, compared with the LACB-7 group (PP: 90.6% vs. 87.5%; ITT: 81.4% vs. 80%, respectively), but these differences were not statistically significant (P = 0.689). CONCLUSIONS: Both the 7-day and 14-day first-line LACB therapies provided a high cure rate, were well tolerated, and were equally effective against H. pylori infection in Turkey.


Assuntos
Antibacterianos/administração & dosagem , Antidiarreicos/administração & dosagem , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Inibidores da Bomba de Prótons/administração & dosagem , Adulto , Amoxicilina/administração & dosagem , Bismuto/administração & dosagem , Claritromicina/administração & dosagem , Esquema de Medicação , Quimioterapia Combinada , Dispepsia/microbiologia , Feminino , Infecções por Helicobacter/complicações , Humanos , Lansoprazol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Estudos Prospectivos , Salicilatos/administração & dosagem
13.
J Cancer Res Clin Oncol ; 144(4): 685-695, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29374786

RESUMO

PURPOSE: We report on our preclinical findings of a simple salicylic diamine compound (THG 1213) which has yielded exceptional results as a potential chemotherapeutic drug. THG 1213 is an easy to synthesize chiral and metal-free salan compound. METHODS: THG 1213 was tested on several leukemia, lymphoma and solid tumor cell lines in vitro. The effects have been studied by LDH release essay, FACS flow cytometry, photometric cell count, immunoblotting, and NMR spectroscopy. RESULTS: THG 1213 selectively inhibits proliferation and induces apoptosis in leukemia, lymphoma and solid tumor cell lines. Necrosis or effects on healthy leucocytes could not be detected. Apoptosis is induced via the intrinsic and extrinsic pathways. The salan THG 1213 overcomes multidrug resistance in tumor cells and acts synergistically with vincristine and daunorubicin. CONCLUSIONS: THG 1213 displays remarkable antitumor properties. In particular, the lack of metallic components of THG 1213 could prove to be beneficial in future clinical trials, as metal-containing drugs are known to show severe side effects.


Assuntos
Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Fenilenodiaminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Daunorrubicina/administração & dosagem , Daunorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Leucemia/patologia , Linfoma/patologia , Neoplasias/tratamento farmacológico , Fenilenodiaminas/administração & dosagem , Salicilatos/administração & dosagem , Salicilatos/farmacologia , Vincristina/administração & dosagem , Vincristina/farmacologia
14.
Am J Med Sci ; 355(1): 6-12, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29289264

RESUMO

This article reviews topical management strategies for degenerative osteoarthritis (OA) of the knee. A search of Pubmed, Embase and the Cochrane library using MeSH terms including "topical," "treatment," "knee" and "osteoarthritis" was carried out. Original research and review articles on the effectiveness and safety, recommendations from international published guidelines and acceptability studies of topical preparations were included. Current topical treatments included for the management of knee OA include topical nonsteroidal anti-inflammatory drugs, capsaicin, salicylates and physical treatments such as hot or cold therapy. Current treatment guidelines recommend topical nonsteroidal anti-inflammatory drugs as an alternative and even first-line therapy for OA management, especially among elderly patients. Guidelines on other topical treatments vary, from recommendations against their use, to in favor as alternative or simultaneous therapy, especially for patients with contraindications to other analgesics. Although often well-tolerated and preferred by many patients, clinical care still lags in the adoption of topical treatments. Aspects of efficacy, safety and patient quality of life data require further research.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Capsaicina/administração & dosagem , Osteoartrite do Joelho/tratamento farmacológico , Guias de Prática Clínica como Assunto/normas , Salicilatos/administração & dosagem , Administração Tópica , Analgésicos/administração & dosagem , Humanos , Osteoartrite do Joelho/diagnóstico , Resultado do Tratamento
15.
Int Clin Psychopharmacol ; 33(2): 88-91, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29084087

RESUMO

This pilot study examined the effect of adjunctive salsalate on psychopathology and cognition in patients with schizophrenia. This was a 12-week, open-label trial of salsalate (1.5 g, twice per day) in patients with schizophrenia. Psychopathology, cognition, and daily function were assessed at baseline and week 12 using various rating scales. Blood levels of inflammatory markers including white blood cell count, high-sensitivity C-reactive protein, and interleukin-6 levels were also measured. Eight patients completed the study. There was no significant change in any of the rating scales at week 12. However, there was a trend decrease in the Positive and Negative Syndrome Scale total score, and a trend improvement in the Brief University of California San Diego Performance-based Skills Assessment total score (58.3±11.4 vs. 53.5±11.9, P=0.072; 69.7±18.2 vs. 79.1±15.9, P=0.084, respectively). There was a trend improvement in quality of life as measured by the Quality of Life Scale total score (74.0±20.8 vs. 76.9±22.7, P=0.080). There was a significant decrease in white blood cell count (6.8±1.3 vs. 6.0±1.2 k/mm, P=0.022). There was no change in the levels of high-sensitivity C-reactive protein or interleukin-6 over 12 weeks (P's>0.1). Salsalate may have positive therapeutic effect in patients with schizophrenia. Future studies to examine potential benefits of salsalate as an adjunctive treatment to improve clinical symptoms and daily function in patients with schizophrenia are warranted.


Assuntos
Inflamação , Qualidade de Vida , Salicilatos , Esquizofrenia , Psicologia do Esquizofrênico , Atividades Cotidianas/psicologia , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Biomarcadores/análise , Proteína C-Reativa/análise , Cognição/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Interleucina-6/análise , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Projetos Piloto , Escalas de Graduação Psiquiátrica , Psicopatologia , Salicilatos/administração & dosagem , Salicilatos/efeitos adversos , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento
17.
Med Princ Pract ; 26(6): 523-529, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29131124

RESUMO

OBJECTIVE: The aim of this study was to compare the efficacy and safety of 2-week levofloxacin-containing triple therapy, levofloxacin-containing bismuth quadruple therapy, and standard bismuth-containing quadruple therapy as a first-line regimen for the eradication of Helicobacter pylori. METHODS: A total of 329 patients with H. pylori infection were randomly divided into 3 groups to receive one of the following regimens: (a) levofloxacin-containing bismuth quadruple therapy, RBAL (rabeprazole 20 mg, b.i.d., bismuth subsalicylate 562 mg, b.i.d., amoxicillin 1 g, b.i.d, levofloxacin 500 mg, once daily), (b) standard bismuth quadruple therapy, RBMT (rabeprazole 20 mg, b.i.d, subsalicylate 562 mg, b.i.d., metronidazole 500 mg, t.i.d, tetracycline 500 mg, q.i.d), or (c) levofloxacin-containing triple therapy, RAL (rabeprazole 20 mg, b.i.d., amoxicillin 1 g, b.i.d, levofloxacin 500 mg, once daily). The primary outcome was the eradication rate in the intention-to-treat (ITT) and per protocol (PP) analysis. RESULTS: The eradication rates of the above 3 groups using ITT analysis were RBAL 83.8%, RBMT 88.3%, and RAL 74.8% compared with 91.2, 92.5, and 79.2%, respectively, using PP analysis. The eradication rate using RBMT was significantly higher than that of RAL (p = 0.029 in ITT analysis and p = 0.017 in PP analysis). Several side effects occurred in 156 patients (54.1%) in the RBAL group, 215 (52.3%) in the RBMT group, and 56 (26.2%) in the RAL group (p > 0.05, RBAL vs. RBMT; p < 0.001, RBMT vs. RAL; p < 0.001, RBAL vs. RAL). CONCLUSION: All bismuth-containing quadruple therapies had acceptable eradication rates, but levofloxacin-containing triple therapy was not as good as quadruple therapies. Hence, quadruple therapies should be considered the preferred first-line therapy for H. pylori infections.


Assuntos
Antibacterianos/uso terapêutico , Bismuto/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Levofloxacino/uso terapêutico , Compostos Organometálicos/uso terapêutico , Salicilatos/uso terapêutico , Adolescente , Adulto , Idoso , Amoxicilina/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Bismuto/administração & dosagem , Bismuto/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Levofloxacino/administração & dosagem , Levofloxacino/efeitos adversos , Masculino , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/efeitos adversos , Salicilatos/administração & dosagem , Salicilatos/efeitos adversos , Tetraciclina/uso terapêutico , Adulto Jovem
18.
BMC Res Notes ; 10(1): 470, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28886731

RESUMO

OBJECTIVE: To determine the effect of bacitracin methylene disalicylate (BMD) and feed changes on gastrointestinal integrity, endotoxin permeability, and morphometric parameters in the duodenum of broilers. RESULTS: Birds were raised on a starter diet without growth promoting antibiotics for 31 days then switched to a grower diet. Four of the pens including 50 g/ton of BMD while 4 pens remained antibiotic free. Eight birds per treatment were sampled prior to the feed change and at 3 and 7 days following the feed change. Gastrointestinal integrity and endotoxin permeability in the duodenum were determined using a modified Ussing Chamber and an adjacent section fixed in 10% formalin for morphometric analysis. Data were analyzed using Proc Glimmix of SAS with the model fitting BMD treatment, time, and the interaction of BMD treatment and time as fixed effects. Intestinal integrity increased at d 3 and 7 compared to prior to the feed change and addition of BMD (P > 0.001) and villus height was decreased with BMD supplementation (P = 0.049). All other tested effects similar (P > 0.1). In conclusion, the practice of changing feed had a greater effect on intestinal health than addition of BMD. However, the factors driving these differences 42 are unclear.


Assuntos
Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Antibacterianos/farmacologia , Bacitracina/farmacologia , Galinhas , Dieta , Duodeno/efeitos dos fármacos , Endotoxinas , Salicilatos/farmacologia , Animais , Antibacterianos/administração & dosagem , Bacitracina/administração & dosagem , Salicilatos/administração & dosagem
19.
Biomed Pharmacother ; 95: 513-519, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28866418

RESUMO

Through a simple PEG-conjugation of the natural product Amorfrutin B, we enhanced its pharmacokinetic profile. The PEGylated molecule displayed significantly improved gastrointestinal absorption (p<0.05) and had a longer systemic circulation life (p<0.05). Oral glucose tolerance study showed PEGylated Amorfrutin B displayed longer protection against oral glucose load compared to Amorfrutin B (p<0.05). It also showed significant improvement in glucose uptake in-vitro by T3T-L1 adipocytes (p<0.05). The PEGylated molecule also showed reduced propensity of crossing the blood brain barrier and accumulating in the brain (p<0.05). It also showed reduced accumulation in the adipose tissue. Preliminary liver and kidney toxicity screening showed no significant alteration in liver or kidney function of Amorfrutin B or its PEGylated form. In conclusion, PEG modification can be an attractive strategy to reduce lipophilicity and enhance pharmacokinetic properties of natural products, derived from traditional medicine.


Assuntos
Adipócitos/metabolismo , Fabaceae/química , Absorção Gástrica/efeitos dos fármacos , Glucose/metabolismo , Polietilenoglicóis/química , Salicilatos/sangue , Salicilatos/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Teste de Tolerância a Glucose , Meia-Vida , Insulina/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Salicilatos/administração & dosagem , Salicilatos/química , Distribuição Tecidual/efeitos dos fármacos , Trítio
20.
J Exp Clin Cancer Res ; 36(1): 112, 2017 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-28830537

RESUMO

BACKGROUND: Although major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. Therefore, the identification of new molecular targets in cancer progression and development of novel therapeutic strategies to target them are very necessary for achieving better survival for patients with prostate cancer. Activation of small GTPases such as Ras and Arf1 is a critical component of the signaling pathways for most of the receptors shown to be upregulated in advanced prostate cancer. METHODS: The drug effects on cell proliferation were measured by CellTiter 96® AQueous One Solution Cell Proliferation Assay. The drug effects on cell migration and invasion were determined by Radius™ 24-well and Matrigel-coated Boyden chambers. The drug effects on apoptosis were assessed by FITC Annexin V Apoptosis Detection Kit with 7-AAD and Western blot with antibodies against cleaved PARP and Caspase 3. A NOD/SCID mouse model generated by subcutaneous injection was used to assess the in vivo drug efficacy in tumor growth. ERK activation and tumor cell proliferation in xenografts were examined by immunohistochemistry. RESULTS: We show that Exo2, a small-molecule inhibitor that reduces Arf1 activation, effectively suppresses prostate cancer cell proliferation by blocking ERK1/2 activation. Exo2 also has other effects, inhibiting migration and invasion of PCa cells and inducing apoptosis. The Ras inhibitor salirasib augments Exo2-induced cytotoxicity in prostate cancer cells partially by enhancing the suppression of ERK1/2 phosphorylation. In a xenograft mouse model of prostate cancer, Exo2 reduces prostate tumor burden and inhibits ERK1/2 activation at a dose of 20 mg/kg. Synergistic treatment of salirasib and Exo2 exhibits a superior inhibitory effect on prostate tumor growth compared with either drug alone, which may be attributed to the more efficient inhibition of ERK1/2 phosphorylation. CONCLUSION: This study suggests that simultaneous blockade of Arf1 and Ras activation in prostate cancer cells is a potential targeted therapeutic strategy for preventing prostate cancer development.


Assuntos
Fator 1 de Ribosilação do ADP/genética , Sinergismo Farmacológico , Neoplasias da Próstata/tratamento farmacológico , Proteínas ras/genética , Fator 1 de Ribosilação do ADP/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Benzaldeídos/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Farneseno Álcool/administração & dosagem , Farneseno Álcool/análogos & derivados , Humanos , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Pirimidinas/administração & dosagem , Salicilatos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/antagonistas & inibidores
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