RESUMEN
Numerous reports have shown that conjugated benzimidazole derivatives possess various kinds of biological activities, including anticancer properties. In this report, we designed and synthesized 24 new molecules comprising a benzimidazole ring, arene, and alkyl chain-bearing cyclic moieties. The results showed that the N-substituted benzimidazole derivatives bearing an alkyl chain and a nitrogen-containing 5- or 6-membered ring enhanced the cytotoxic effects on human breast adenocarcinoma (MCF-7) and human ovarian carcinoma (OVCAR-3) cell lines. Among the 24 synthesized compounds, (2E)-1-(1-(3-morpholinopropyl)-1H-benzimidazol-2 -yl)-3-phenyl-2-propen-1-one) (23a) reduced the proliferation of MCF-7 and OVCAR-3 cell lines demonstrating superior outcomes to those of cisplatin.
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Bencimidazoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Chalconas/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chalconas/síntesis química , Chalconas/química , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Estructura Molecular , Neoplasias Ováricas/patología , Relación Estructura-ActividadRESUMEN
We describe a novel strategy to produce vaccine antigens using a plant cell-suspension culture system in lieu of the conventional bacterial or animal cell-culture systems. We generated transgenic cell-suspension cultures from Nicotiana benthamiana leaves carrying wild-type or chimeric Bamboo mosaic virus (BaMV) expression constructs encoding the viral protein 1 (VP1) epitope of foot-and-mouth disease virus (FMDV). Antigens accumulated to high levels in BdT38 and BdT19 transgenic cell lines co-expressing silencing suppressor protein P38 or P19. BaMV chimeric virus particles (CVPs) were subsequently purified from the respective cell lines (1.5 and 2.1 mg CVPs/20 g fresh weight of suspended biomass, respectively), and the resulting CVPs displayed VP1 epitope on the surfaces. Guinea pigs vaccinated with purified CVPs produced humoral antibodies. This study represents an important advance in the large-scale production of immunopeptide vaccines in a cost-effective manner using a plant cell-suspension culture system.
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Quimera/metabolismo , Epítopos/metabolismo , Nicotiana/genética , Células Vegetales/metabolismo , Potexvirus/fisiología , Virión/metabolismo , Animales , Especificidad de Anticuerpos/inmunología , Epítopos/inmunología , Epítopos/ultraestructura , Cobayas , Inmunización , Plantas Modificadas Genéticamente , Recombinación Genética/genética , Suspensiones , Nicotiana/citología , Nicotiana/virología , Virión/ultraestructuraRESUMEN
In this study, novel aminothiazole-paeonol derivatives were synthesized and characterized using ¹H-NMR, (13)C-NMR, IR, mass spectroscopy, and high performance liquid chromatography. All the new synthesized compounds were evaluated according to their anticancer effect on seven cancer cell lines. The experimental results indicated that these compounds possess high anticancer potential regarding human gastric adenocarcinoma (AGS cells) and human colorectal adenocarcinoma (HT-29 cells). Among these compounds, N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methoxybenzenesulfonamide (13c) had the most potent inhibitory activity, with IC50 values of 4.0 µM to AGS, 4.4 µM to HT-29 cells and 5.8 µM to HeLa cells. The 4-fluoro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (13d) was the second potent compound, showing IC50 values of 7.2, 11.2 and 13.8 µM to AGS , HT-29 and HeLa cells, respectively. These compounds are superior to 5-fluorouracil (5-FU) for relatively higher potency against AGS and HT-29 human cancer cell lines along with lower cytotoxicity to fibroblasts. Novel aminothiazole-paeonol derivatives in this work might be a series of promising lead compounds to develop anticancer agents for treating gastrointestinal adenocarcinoma.
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Acetofenonas/síntesis química , Acetofenonas/farmacología , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HT29 , Células HeLa , Humanos , Estructura MolecularRESUMEN
Heat stress poses a significant challenge to egg production in layer hens. High temperatures can disrupt the physiological functions of these birds, leading to reduced egg production and lower egg quality. This study evaluated the microclimate of laying hen houses using different management systems to determine the impact of heat stress on productivity and hen health. The results showed that the ALPS system, which manages the hen feeding environment, effectively improved productivity and decreased the daily death rate. In the traditional layer house, the daily death rate decreased by 0.045%, ranging from 0.086% to 0.041%, while the daily production rate increased by 3.51%, ranging from 69.73% to 73.24%. On the other hand, in a water-pad layer house, the daily death rate decreased by 0.033%, ranging from 0.082% to 0.049%, while the daily production rate increased by 21.3%, ranging from 70.8% to 92.1%. The simplified hen model helped design the indoor microclimate of commercial layer houses. The average difference in the model was about 4.4%. The study also demonstrated that fan models lowered the house's average temperature and reduced the impact of heat stress on hen health and egg production. Findings indicate the need to control the humidity of inlet air to regulate temperature and humidity, and suggest that Model 3 is an energy-saving and intelligent solution for small-scale agriculture. The humidity of the inlet air affects the temperature experienced by the hens. The THI drops to the alert zone (70-75) when humidity is below 70%. In subtropical regions, we consider it necessary to control the humidity of the inlet air.
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Tetra-O-methyl-nordihydroguaiaretic acid (terameprocol; M4N), a global transcription inhibitor, in combination with a second anticancer drug induces strong tumoricidal activity and has the ability to suppress energy metabolism in cultured cancer cells. In this study, we showed that after continuous oral consumption of high-fat (HF) diets containing M4N, the M4N concentration in most of the organs in mice reached ~1 µM (the M4N concentration in intestines and fat pads was as high as 20-40 µM) and treatment with the combination of M4N with temozolomide (TMZ) suppressed glycolysis and the tricarboxylic acid cycle in LN229 human glioblastoma implanted in xenograft mice. Combination treatment of M4N with TMZ also reduced the levels of lactate dehydrogenase A (LDHA), a key enzyme for glycolysis; lactate, a product of LDHA-mediated enzymatic activity; nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for nicotinamide adenine dinucleotide plus hydrogen (NADH)/NAD+ salvage pathway; and NAD+, a redox electron carrier essential for energy metabolism. It was also shown that M4N suppressed oxygen consumption in cultured LN229 cells, indicating that M4N inhibited oxidative phosphorylation. Treatment with M4N and TMZ also decreased the level of hypoxia-inducible factor 1A, a major regulator of LDHA, under hypoxic conditions. The ability of M4N to suppress energy metabolism resulted in induction of the stress-related proteins activating transcription factor 4 and cation transport regulator-like protein 1, and an increase in reactive oxygen species production. In addition, the combination treatment of M4N with TMZ reduced the levels of oncometabolites such as 2-hydroxyglutarate as well as the aforementioned lactate. M4N also induced methylidenesuccinic acid (itaconate), a macrophage-specific metabolite with anti-inflammatory activity, in tumor microenvironments. Meanwhile, the ability of M4N to suppress energy metabolism prevented obesity in mice consuming HF diets, indicating that M4N has beneficial effects on normal tissues. The dual ability of combination treatment with M4N to suppress both energy metabolism and oncometabolites shows that it is potentially an effective therapy for cancer.
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Glioblastoma , Humanos , Animales , Ratones , Masoprocol/farmacología , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/prevención & control , Glioblastoma/patología , Dieta Alta en Grasa/efectos adversos , NAD , Línea Celular Tumoral , Metabolismo Energético , Microambiente TumoralRESUMEN
Skeletal muscle growth in livestock impacts meat quantity and quality. Concerns arise because certain feed additives, like beta-agonists, may affect food safety. Skeletal muscle is a specialized tissue consisting of nondividing and multinucleated muscle fibers. Myostatin (MSTN), a protein specific to skeletal muscle, is secreted and functions as a negative regulator of muscle mass by inhibiting the proliferation and differentiation of myoblasts. To enhance livestock muscle growth, phytogenic feed additives could be an alternative as they inhibit MSTN activity. The objective of this study was to establish a systematic screening platform using MSTN activity to evaluate phytogenics, providing scientific evidence of their assessment and potency. In this study, we established a screening platform to monitor myostatin promoter activity in rat L8 myoblasts. Extract of Glycyrrhiza uralensis (GUE), an oriental herbal medicine, was identified through this screening platform, and the active fractions of GUE were identified using a process-scale liquid column chromatography system. For in vivo study, GUE as a feed additive was investigated in growth-finishing pigs. The results showed that GUE significantly increased body weight, carcass weight, and lean content in pigs. Microbiota analysis indicated that GUE did not affect the composition of gut microbiota in pigs. In summary, this established rodent myoblast screening platform was used to identify a myogenesis-related phytogenic, GUE, and further demonstrated that the active fractions and compounds inhibited MSTN expression. These findings suggest a novel application for GUE in growth performance enhancement through modulation of MSTN expression. Moreover, this well-established screening platform holds significant potential for identifying and assessing a diverse range of phytogenics that contribute to the process of myogenesis.
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Gut microbiota play a key role in health maintenance and disease pathogenesis in animals. Dietary phytochemicals are crucial factors shaping gut bacteria. Here, we investigated the function and mechanism of a phytogenic formulation, EUBIO-BPSG (BP), in laying hens. We found that BP dose-dependently improved health and egg production in 54-week-old hens. Furthermore, BP was correlated with increased fecal Lactobacillus, decreased Escherichia coli and Salmonella enterica, and reduced antibiotic resistance (AR) and antibiotic resistance genes (ARG) in chicken stools. The 16S rDNA data showed that BP increased seven genera of probiotics and reduced 13 genera of pathogens in chicken feces. In vitro co-culture experiments showed that BP at 4 µg/mL and above promoted growth of L. reuteri while large 100- and 200-fold higher doses suppressed growth of E. coli and S. enterica, respectively. Mechanistic studies indicated that L. reuteri and its supernatants antagonized growth of E. coli and S. enterica but not vice-versa. Five short-chain fatty acids and derivatives (SCFA) produced from L. reuteri directly killed both pathogens via membrane destruction. Furthermore, BP inhibited conjugation and recombination of ARG via interference with conjugation machinery and integrase activity in E. coli. Collectively, this work suggests that BP promotes host health and reproductive performance in laying hens through regulation of gut microbiota through increasing probiotics and decreasing pathogens and spreading ARG.
RESUMEN
Three perglycosylated nordihydroguaiaretic acids (NDGA) were synthesized through the Huiseng 1,3-dipolar cycloaddition reaction. These sugar-NDGA conjugates containing triazole-linkages possessed good solubility in water. NDGA-(triazol-galactose)(4) (12b) and NDGA-(triazol-glucose)(4) (12c) were found to act as inhibitors against human hepatocellular carcinoma Hep3B cells in culture.
Asunto(s)
Antineoplásicos/química , Galactósidos/química , Glucósidos/química , Masoprocol/análogos & derivados , Masoprocol/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Galactósidos/síntesis química , Galactósidos/uso terapéutico , Glucósidos/síntesis química , Glucósidos/uso terapéutico , Glicosilación , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Masoprocol/síntesis química , Masoprocol/uso terapéutico , Triazoles/síntesis química , Triazoles/química , Triazoles/uso terapéuticoRESUMEN
As an essential trace element, selenium (Se) deficiency results in White Muscle Disease in livestock and Keshan disease in humans. The main objectives of this study were to clone and characterize the chicken selenoprotein W (SeW) gene and investigate SeW mRNA expression in chicken tissues. The deduced amino acid (AA) sequence of chicken SeW contains 85 AAs with UAG as the stop codon. Like all SeW genes identified in different species, chicken SeW contains one well-conserved selenocysteine (Sec) at the 13th position encoded by the UGA codon. The proposed glutathione (GSH)-binding site at the Cys(37) of SeW is not conserved in the chicken, but Cys(9) and Sec(13), with possible GSH binding, are conserved in SeWs identified from all species. There are 23-59% and 50-61% homology in cDNA and deduced AA sequences of SeW, respectively, between the chicken and other species. The predicted secondary structure of chicken SeW mRNA indicates that the selenocysteine insertion sequence element is type II with invariant adenosines within the apical bulge. The SeW mRNA expression is high in skeletal muscle followed by brain, but extremely low in other tissues from chickens fed a commercial maize-based diet. The SeW gene is ubiquitously expressed in heart, skeletal muscle, brain, testis, spleen, kidney, lung, liver, stomach and pancreas in chickens fed a commercial diet supplemented with sodium selenite. These results indicate that dietary selenium supplementation regulates SeW gene expression in the chicken and skeletal muscle is the most responsive tissue when dietary Se content is low.
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Selenoproteína W/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Pollos , ADN Complementario/genética , Perfilación de la Expresión Génica , Masculino , Datos de Secuencia Molecular , Músculo Esquelético , Conformación de Ácido Nucleico , ARN Mensajero/química , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Selenio/metabolismo , Selenoproteína W/genética , Alineación de SecuenciaRESUMEN
PURPOSE: The goal of this study was to review relevant randomized controlled trials or case-control studies to determine radical resection compared with simple cholecystectomy for gallbladder carcinoma. METHODS: Using appropriate keywords, we identified relevant studies using PubMed, the Cochrane Library, and Embase. Key pertinent sources in the literature were also reviewed, and all articles published through September 2019 were considered for inclusion. For each study, we assessed odds ratios, mean difference, and 95% confidence interval (CI) to assess and synthesize outcomes. RESULTS: We included 19 studies with a total of 1791 patients in the radical resection group and 3014 in the simple cholecystectomy group. Compared with simple cholecystectomy, radical resection significantly improved the 5-year disease-free survival rate [relative risk (RR): 1.36, 95% CI: 1.02-1.81], the 1-year overall survival (OS) rate (RR: 1.27, 95% CI: 1.04-1.54), and the 3-year OS rate (RR: 1.71, 95% CI: 1.02-2.85). However, there was no significant difference in the recurrence rate (RR: 1.04, 95% CI: 0.87-1.23), and in the 5-year OS rate (RR: 1.05, 95% CI: 0.92-1.19) between the 2 groups. CONCLUSION: Compared with simple cholecystectomy, radical resection has advantages in improving the 5-year disease-free survival rate, and the 1- and 3-year OS rate of gallbladder carcinoma patients.
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Colecistectomía , Neoplasias de la Vesícula Biliar/cirugía , Neoplasias de la Vesícula Biliar/mortalidad , Neoplasias de la Vesícula Biliar/patología , HumanosRESUMEN
Artemisia species are aromatic herbs used as food and/or ethnomedicine worldwide; however, the use of these plants is often impeded by misidentification. Here, molecular and chemotaxonomic approaches were combined to assist in the morphology-based authentication of Artemisia species, and Artemisia indica and Artemisia argyi were identified. The plant extracts and compounds obtained from these species, 1,8-cineole, carveol, α-elemene, α-farnesene, methyl linolenate, diisooctyl phthalate inhibited the growth of food-borne harmful bacteria. Mechanistic studies showed that the extract and active compounds of A. indica killed Gram-negative and -positive bacteria via destruction of the bacterial membrane. Finally, in vivo data demonstrated that A. indica protected against bacterial infection in mice as evidenced by survival rate, bacterial load in organs, gut pathology, diarrhea, body weight, food consumption, stool weight, and pathology score. A. indica and its active compounds have potential for use as food supplements for food-borne bacterial diseases and thus improve human health.
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Antibacterianos/farmacología , Artemisia/química , Fitoquímicos/análisis , Extractos Vegetales/farmacología , Animales , Antibacterianos/química , Carga Bacteriana , Diarrea/tratamiento farmacológico , Diarrea/microbiología , Femenino , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Plantas Medicinales/química , Intoxicación Alimentaria por Salmonella/tratamiento farmacológico , Intoxicación Alimentaria por Salmonella/mortalidad , TaiwánRESUMEN
Bidens pilosa (BP) is an edible Asteraceae plant found worldwide that has traditionally been used as food without noticeable side effects. BP has also been used as an herbal medicine to treat over 41 categories of disease in humans and animals. However, to date no long-term toxicity study of BP has been conducted in animals. In this study, 24-week oral toxicity of BP at doses of 0%, 0.5%, 2.5%, 5% and 10% of food was investigated in mice. Mortality, body weight, organ weight, food intake, water consumption, hematology, serum biochemistry, urinalysis, genotoxicity and organ histopathology of animals of both sexes were analyzed. No significant difference in the above parameters was observed between control and BP-fed mice except that body weight and food intake in those fed with 10% BP were significantly less than controls. In addition, similar results were seen in chickens fed with BP for 28 days. Collectively, the data demonstrate that BP has no adverse effects in mice and chickens at dose of 5% or less of food.
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Avian coccidiosis is an economically important disease in the poultry industry. In view of the disadvantages of anti-coccidial drugs in chickens, edible plants and their compounds are re-emerging as an alternative strategy to combat this disease. A previous publication reported that the edible plant B. pilosa showed promise for use against coccidiosis. Here, we first investigated into the anti-coccidial effects of B. pilosa. We found that B. pilosa at 100 ppm or more significantly suppressed E. tenella as evidenced by reduction in mortality rate, oocyst excretion and gut pathological severity in chickens and its minimum prophylactic duration was 3 days. Next, we explored the mode of action of anti-coccidial mechanism of B. pilosa. The E. tenella oocysts were not directly killed by B. pilosa; however, administration of the plant suppressed oocyst sporulation, sporozoite invasion, and schizonts in the life cycle of E. tenella. Besides, B. pilosa boosted T cell-mediated immunity. Finally, we characterized the related anti-coccidial phytochemicals and their mode of action. One of three potent polyynes present in B. pilsoa, Compound 1 (cytopiloyne), acted against coccidiosis in chickens in a similar manner to B. pilosa. These data illustrate the anti-coccidial potency and mechanism of B. pilosa and one of its active compounds, and provide a cornerstone for development of novel herbal remedies for avian coccidiosis.
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Bidens/química , Pollos/inmunología , Coccidiosis/tratamiento farmacológico , Coccidiosis/veterinaria , Eimeria tenella/efectos de los fármacos , Extractos Vegetales/farmacología , Enfermedades de las Aves de Corral/prevención & control , Animales , Pollos/crecimiento & desarrollo , Pollos/parasitología , Coccidiosis/parasitología , Eimeria tenella/inmunología , Femenino , Oocistos/efectos de los fármacos , Enfermedades de las Aves de Corral/parasitologíaRESUMEN
Angiogenesis, a morphogenic event endothelial cells (ECs) undergo in response to 3-D environmental triggers, is critical to the survival and ultimate functional capacity of engineered tissue constructs. Here we present a new collagen mimetic peptide (CMP) architecture consisting of multiple anionic charges at the peptide's N-terminus designed to attract growth factors by charge-charge interactions and bind to collagen by CMP-collagen interaction. The anionic CMPs exhibited specific binding affinity to type I collagen substrates while attracting vascular endothelial growth factors (VEGFs), which led to enhanced morphological features of ECs, indicative of tubulogenesis. The results show that these new CMPs could be used to direct proliferation and differentiation of cells in collagen scaffolds by localization and sustained delivery of growth factors and other morphogens.
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Materiales Biocompatibles/química , Colágeno/química , Células Endoteliales/citología , Péptidos/química , Células Cultivadas , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Sustancias Macromoleculares , Modelos Biológicos , Neovascularización Patológica , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Traditional serological enzyme-linked immunosorbent assay (ELISA) is routinely used to monitor pathogens during quarantine in most animal facilities to prevent possible infection. However, the ELISA platform is a single-target assay, and screening all targeted pathogens is time-consuming and laborious. In this study, to increase sensitivity and to reduce diagnosis time for high-throughput processes, multiplex PCR and DNA biochip techniques were combined to develop a multi-pathogen diagnostic method for use instead of routine ELISA. Eight primer sets were designed for multiplex PCR to detect genes from seven targeted bacterial and viral pathogens. DNA-DNA hybridization was conducted on a biochip following the multiple PCR analysis. Using this method, a total of 24 clinical samples were tested, and the result showed that not only single infection but also co-infection by multi-pathogens can be detected. In conclusion, multiplex PCR coupled with a DNA biochip is an efficient method for detecting multi-pathogens in a reaction. This platform is a useful tool for quarantine services and disease prevention in animal facilities.
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Animales de Laboratorio , Bacterias/aislamiento & purificación , Infecciones Bacterianas/diagnóstico , Reacción en Cadena de la Polimerasa Multiplex/métodos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Enfermedades de los Roedores/diagnóstico , Fosfatasa Alcalina/química , Animales , Infecciones Bacterianas/microbiología , Biotinilación , Conjugación Genética , Sondas de ADN , Mediciones Luminiscentes , Enfermedades de los Roedores/microbiología , Sensibilidad y Especificidad , Estreptavidina/químicaRESUMEN
The objectives were to investigate the roles of different calpains and protein kinase C (PKC) isoforms in muscle differentiation. Concentrations of mu- and m-calpain increased significantly whereas PKCalpha and delta declined significantly during L8 myoblast differentiation. Both mu-calpain and m-calpain antisense oligonucleotides inhibited myotube formation and creatine kinase activity during L8 myoblast differentiation. These results implied that both mu- and m-calpain were involved in L8 myoblast differentiation. To investigate the involvement of calpain in regulation of PKC concentrations, mu-calpain antisense oligonucleotides were added to L8 myoblasts. PKCalpha remained unchanged and PKCdelta declined. By adding m-calpain antisense oligonucleotides instead, PKCalpha level remained unchanged and PKCdelta concentrations increased significantly during differentiation. These results suggest that PKCalpha, but not PKCdelta, is the substrate for mu-calpain and PKCalpha and delta are the substrates for the m-calpain. In addition, more phosphorylated myogenin was found in day 2 antisense oligonucleotides treated L8 cells. It is concluded that the decline of PKCalpha mediated by m- and mu-calpain is essential for L8 myoblast differentiation. The decline of PKC during myoblast differentiation may cause hypo-phosphorylation of myogenin, which in turn activates muscle-specific genes during myogenesis.
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Calpaína/metabolismo , Diferenciación Celular/fisiología , Mioblastos/metabolismo , Proteína Quinasa C-alfa/metabolismo , Proteína Quinasa C-delta/metabolismo , Animales , Calpaína/antagonistas & inhibidores , Calpaína/genética , Diferenciación Celular/efectos de los fármacos , Línea Celular , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/fisiología , Oligodesoxirribonucleótidos Antisentido/genética , Oligodesoxirribonucleótidos Antisentido/farmacología , Proteína Quinasa C-alfa/genética , Proteína Quinasa C-delta/genética , RatasRESUMEN
PURPOSE: Multidrug resistance (MDR) continues to be a major obstacle for successful anticancer therapy. One of the principal factors implicated in MDR is the over expression of P-glycoprotein (Pgp), the product of the MDR1 gene. METHODS: Here we explore the possibility of using the transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) to inhibit Sp1-regulated MDR1 gene expression and restore doxorubicin and paclitaxel sensitivity to multidrug resistant human cancer cells in vitro and in vivo. RESULTS: We found that M4N acted synergistically with doxorubicin and paclitaxel in inhibiting the growth of the cells in culture allowing significant dose reductions of both drugs. We observed no such synergism when M4N was used in combination with cisplatin, another chemotherapeutic agent, but not a Pgp substrate, as analyzed by the combination index and isobologram methods. Analysis of MDR1 mRNA and Pgp levels revealed that at sublethal doses, M4N inhibited MDR1 gene expression in the multidrug resistant NCI/ADR-RES cells and reversed the MDR phenotype as measured by Rhodamine-123 retention. In addition, M4N was found to inhibit doxorubicin-induced MDR1 gene expression in drug sensitive MCF-7 breast cancer cells. CONCLUSIONS: M4N and maltose-tri-O-methyl nordihydroguaiaretic acid (maltose-M3N), a water-soluble derivative of NDGA, were also able to reverse the MDR phenotype of the tumor cells in a xenograft model system and combination therapy with M4N or maltose-M3N and paclitaxel was effective at inhibiting growth of these tumors in nude mice.
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Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Masoprocol/análogos & derivados , Masoprocol/farmacología , Monosacáridos/farmacología , Paclitaxel/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Masoprocol/administración & dosificación , Ratones , Ratones Desnudos , Monosacáridos/administración & dosificación , Paclitaxel/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
PURPOSE: We have previously shown that the transcriptional inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) induces growth arrest in tumor cells and exhibits tumoricidal activity when injected intratumorally into tumor cell explants in mice. The experiments reported here were designed to determine whether M(4)N can be given systemically and inhibit the growth of five different human xenograft tumors. EXPERIMENTAL DESIGN: Nude (nu/nu) mice bearing xenografts of each of five human tumor types (i.e., hepatocellular carcinoma, Hep 3B; prostate carcinoma, LNCaP; colorectal carcinoma, HT-29; breast carcinoma, MCF7; and erythroleukemia, K-562) were treated with M4N given i.v. or i.p. in a Cremophor EL-based solvent system or orally in a corn oil based diet. Tumors from the treated animals were measured weekly and analyzed for the expression of the Cdc2 and survivin genes, both previously shown to be down-regulated by M4N. RESULTS: Systemic M4N treatment suppressed the in vivo growth of xenografts in each of the five human tumor types. Four of the five tumor models were particularly sensitive to M4N with tumor growth inhibitions (T/C values) of < or = 42%, whereas the fifth, HT-29, responded to a lesser extent (48.3%). Growth arrest and apoptosis in both the xenograft tumors and in the tumor cells grown in culture were accompanied by reductions in both Cdc2 and tumor-specific survivin gene expression. Pharmacokinetic analysis following oral and i.v. administration to ICR mice indicated an absolute bioavailability for oral M4N of approximately 88%. Minimal drug-related toxicity was observed. CONCLUSION: These preclinical studies establish that when given systemically, M4N can safely and effectively inhibit the growth of human tumors in nude mice.
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Proliferación Celular/efectos de los fármacos , Masoprocol/análogos & derivados , Masoprocol/farmacología , Neoplasias Experimentales/prevención & control , Administración Oral , Animales , Área Bajo la Curva , Proteína Quinasa CDC2/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Proteínas Inhibidoras de la Apoptosis , Inyecciones Intravenosas , Células K562 , Masoprocol/administración & dosificación , Masoprocol/farmacocinética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Survivin , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Obesity and its complications are a major global health problem. In this study, we investigated the anti-obesity effect and mechanism of an edible plant, Bidens pilosa, and its active constituent. We first assessed the long-term effect of B. pilosa on body composition, body weight, blood parameters in ICR mice. We observed that it significantly decreased fat content and increased protein content in ICR mice. Next, we verified the anti-obesity effect of B. pilosa in ob/ob mice. It effectively and dose-dependently reduced fat content, adipocyte size and/or body weight in mice. Moreover, mechanistic studies showed that B. pilosa inhibited the expression of peroxisome proliferator activated receptor γ (PPARγ), CCAAT/enhancer binding proteins (C/EBPs) and Egr2 in adipose tissue. Finally, we examined the effect of 2-ß-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne (GHT) on adipogenesis in adipocytes. We found that B. pilosa significantly decreased the adipogenesis and lipid accumulation. This decrease was associated with the down-regulation of expression of Egr2, C/EBPs, PPARγ, adipocyte Protein 2 (aP2) and adiponectin. In summary, this work demonstrated that B. pilosa and GHT suppressed adipogenesis and lipid content in adipocytes and/or animals via the down-regulation of the Egr2, C/EBPs and PPARγ pathways, suggesting a novel application of B. pilosa and GHT against obesity.
Asunto(s)
Adipogénesis/efectos de los fármacos , Bidens/química , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , PPAR gamma/metabolismo , Extractos Vegetales/farmacología , Células 3T3-L1 , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Bidens/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Obesos , PPAR gamma/genética , Extractos Vegetales/química , ARN Mensajero/metabolismo , Rosiglitazona , Transducción de Señal/efectos de los fármacos , Tiazolidinedionas/farmacologíaRESUMEN
Hepatitis B virus (HBV) is a causative reagent that frequently causes progressive liver diseases, leading to the development of acute, chronic hepatitis, cirrhosis, and eventually hepatocellular carcinoma (HCC). Despite several antiviral drugs including interferon-α and nucleotide derivatives are approved for clinical treatment for HBV, critical issues remain unresolved, e.g., low-to-moderate efficacy, adverse side effects, and resistant strains. In this study, novel Paeonol-phenylsulfonyl derivatives were synthesized and their antiviral effect against HBV was evaluated. The experimental results indicated that these compounds process significant antiviral potential, including the inhibition of viral antigen expression and secretion, and the suppression of HBV viral DNA replication. Among compounds synthesized in this research, compound 2-acetyl-5-methoxyphenyl 4-methoxybenzenesulfonate (7f) had the most potent inhibitory activity with IC50 value of 0.36 µM, and high selectivity index, SI (TC50/IC50) 47.75; which exhibited an apparent inhibition effect on viral gene expression and viral propagation in cell culture model. So, we believe our compounds could serve as reservoir for antiviral drug development.