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Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide. A substantial body of literature supports the crucial role of vitamin D (VD) in the etiology, progression, prognosis, and treatment of cancer. Recent clinical studies have found an inverse correlation between CRC incidence and serum VD levels. However, the low water solubility of VD and its anticarcinogenic activity at supraphysiological plasma levels, which causes hypercalcemia, required carrier systems. Carbon-based nanomaterials are excellent eco-friendly candidates, with exceptional chemical resistance, efficient mechanical properties, and negligible weight. Furthermore, composite aerogels manufactured from these nanomaterials have gained interest due to their extensive surface areas and porous structures, which make them suitable for delivering drugs. Our research aimed to study the development of composite aerogels loaded with VD by utilizing carbon nanofibers (CNFs) in an aerogel matrix provided to colon cancer cells. For this purpose, Aero1 as a drug delivery system was first prepared and characterized using XRD, FTIR, and SEM methods. Biochemical methods were employed to evaluate the antiproliferative, apoptotic, and anti-migratory effects on colon cancer cells. FTIR and XRD measurements confirmed the production of aerogels. SEM analysis revealed that aerogels have a non-uniform surface. The findings showed that aerogels can effectively deliver VD to the colon cancer cells, while also inhibiting cancer cell proliferation and migration. This research suggests that the Aero1 drug delivery system could be a valuable tool in the fight against colon cancer and other health issues.
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BACKGROUND: The aim of this study was to evaluate the possible protective effects of dapagliflozin in an experimental sepsis model in rats. METHODS: Saline (1 mL/kg, p.o.) or dapagliflozin (10 mg/kg, p.o.) was administered to Sprague-Dawley rats for 5 days prior to the surgical procedures. Under anesthesia, sepsis was induced by cecal ligation puncture, while sham control groups underwent laparotomy only. Blood urea nitrogen, creatinine, and glucose levels were measured in serum samples and the levels of malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), tumor necrosis factor alpha, interleukin 1 beta, caspase 8, and caspase 9 were determined in tissue samples (kidney, liver, and lung). Histological evaluation was also performed. RESULTS: The administration of dapagliflozin in a sepsis model reduced oxidative stress (MDA), increased antioxidant levels (GSH), and reduced inflammation (MPO) in the kidney (p<0.05). Dapagliflozin also decreased oxidative stress (MDA) in lung tissue and decreased inflammation (MPO) in lung and liver tissue (p<0.05). Caspase 8 and 9 levels in kidney, lung, and liver tissue were increased (p<0.05) in the dapagliflozin group compared with the sepsis group. According to the histopathological results, sepsis was moderately improved in renal tissue and slightly attenuated in lung and liver tissue with the administration of dapagliflozin. CONCLUSION: Dapagliflozin had a preventive effect on sepsis-induced kidney damage, but the protective effect was mild in lung and liver tissue in the present study.
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Compuestos de Bencidrilo , Glucósidos , Sepsis , Animales , Compuestos de Bencidrilo/farmacocinética , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Modelos Animales de Enfermedad , Glucósidos/farmacocinética , Glucósidos/farmacología , Glucósidos/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Ratas , Sepsis/sangre , Sepsis/tratamiento farmacológico , Sepsis/fisiopatología , Distribución TisularRESUMEN
BACKGROUND & AIM: Alpha lipoic acid (LA) was shown to exert neuroprotection in trauma-induced spinal cord injury (SCI), which is frequently associated with urinary bladder complaints in patients with SCI. Accordingly, the protective effects of LA on biochemical and histological changes in bladder as well as functional studies were assessed. METHODS: Wistar albino rats were divided as control, SCI, and LA (50 mg/kg/day, ip) treated SCI groups (SCI+LA). The standard weight-drop (100 g/cm force at T10) method was used to induce a moderately severe SCI. One week after the injury, neurological examination was performed and the rats were decapitated. Bladder samples were taken for histological examination, functional (isolated tissue bath) studies, and for the measurement of biochemical parameters (malondialdehyde, MDA; gluthathione, GSH; nerve growth factor, NGF; caspase-3, luminol and lucigenin chemiluminescences). RESULTS: SCI caused a significant (P < 0.001) increase in the detrusor muscle thickness. It increased the contractility responses to carbachol and relaxation responses to papaverine (P < 0.05-0.001). There were also significant alterations in MDA, caspase-3, luminol, and lucigenin chemiluminescences with concomitant decreases in NGF and GSH (P < 0.05). LA treatment reversed histological and functional (contraction and relaxation responses) changes induced by SCI (P < 0.05-0.001), but no significant recovery was observed in the impaired neurological functions. CONCLUSION: These results indicate that LA have a beneficial effect in improving the bladder tonus via its antioxidant and anti-inflammatory actions following SCI.
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Antioxidantes/administración & dosificación , Traumatismos de la Médula Espinal/complicaciones , Ácido Tióctico/administración & dosificación , Enfermedades de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Vejiga Urinaria/inervación , Vejiga Urinaria/patología , Vejiga Urinaria/fisiopatología , Enfermedades de la Vejiga Urinaria/etiologíaRESUMEN
In this study, a series of thiosemicarbazide derivatives 12-14, 1,2,4-triazol-3-thione derivatives 15-17 and compounds bearing 2-(4H-1,2,4-triazole-3-ylthio)acetamide structure 18-32 have been synthesized starting from phenolic compounds such as 2-naphthol, paracetamol and thymol. Structures and purity of the target compounds were confirmed by the use of their chromatographic and spectral data besides microanalysis. All of the synthesized new compounds 12-32 were evaluated for their anti-HIV activity. Among these compounds, three representatives 18, 19 and 25 were selected and evaluated by the National Cancer Institute (NCI) against the full panel of 60 human cancer cell lines derived from nine different cancer types. Antiproliferative effects of the selected compounds were demonstrated in human tumor cell lines K-562, A549 and PC-3. These compounds inhibited cell growth assessed by MTT assay. Compound 18, 19 and 25 exhibited anti-cancer activity with IC50 values of 5.96 µM (PC-3 cells), 7.90 µM (A549/ATCC cells) and 7.71 µM (K-562 cells), respectively. After the cell viability assay, caspase activation and Bcl-2 activity of the selected compounds were measured and the loss of mitochondrial membrane potential (MMP) was detected. Compounds 18, 19 and 25 showed a significant increase in caspase-3 activity in a dose-dependent manner. This was not observed for caspase-8 activity with compound 18 and 25, while compound 19 was significantly elevated only at the dose of 50 µM. In addition, all three compounds significantly decreased the mitochondrial membrane potential and expression of Bcl-2.
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Acetamidas/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Acetamidas/síntesis química , Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Relación Estructura-Actividad , TriazolesRESUMEN
Hyperglycemia is one of the major causes of suppressed angiogenesis and impaired wound healing leading to chronic wounds. Nesfatin-1 a novel peptide was reported to have antioxidant and anti-apoptotic properties. This study is aimed to investigate the potential healing-promoting effects of nesfatin-1 in non-diabetic or diabetic rats with surgical wounds. In male Sprague-Dawley rats, hyperglycemia was induced by intraperitoneal (ip) injection of streptozotocin (55 mg/kg). Under anesthesia, dorsum skin tissues of normoglycemic (n=16) and hyperglycemic rats were excised (2 × 2 cm, full-thickness), while control rats (n=16) had neither hyperglycemia nor wounds. Half of the rats in each group were treated ip with saline, while the others were treated with nesfatin-1 (2 µg/kg/day) for 3 days until they were decapitated. Plasma interleukin-1-beta (IL-1ß), transforming growth factor-beta (TGF-ß-1), IL-6 levels, and dermal tissue malondialdehyde (MDA), glutathione (GSH) levels, myeloperoxidase (MPO) and caspase-3 activity were measured. For histological examination, paraffin sections were stained with hematoxylin-eosin or Masson's trichrome and immunohistochemistry for vascular endothelial growth factor (VEGF) was applied. ANOVA and Student's t-tests were used for statistical analysis. Compared to control rats, skin MPO activity, MDA and caspase-3 levels were increased similarly in saline-treated normo- and hyperglycemic rats. Nesfatin-1 depressed MDA, caspase-3, MPO activity and IL-1ß with concomitant elevations in dermal GSH and plasma TGF-ß-1 levels. Histopathological examination revealed regeneration of epidermis, regular arrangement of collagen fibers in the dermis and a decrease in VEGF immunoreactivity in the epidermal keratinocytes of nesfatin-1-treated groups. Nesfatin-1 improved surgical wound healing in both normo- and hyperglycemic rats via the suppression of neutrophil recruitment, apoptosis and VEGF activation.
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Antioxidantes/farmacología , Proteínas de Unión al Calcio/farmacología , Proteínas de Unión al ADN/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Proteínas del Tejido Nervioso/farmacología , Piel/efectos de los fármacos , Herida Quirúrgica/tratamiento farmacológico , Animales , Caspasa 3/genética , Caspasa 3/inmunología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/inmunología , Glutatión/inmunología , Glutatión/metabolismo , Hiperglucemia/inducido químicamente , Hiperglucemia/complicaciones , Hiperglucemia/inmunología , Inyecciones Intraperitoneales , Interleucina-1beta/sangre , Interleucina-1beta/inmunología , Interleucina-6/sangre , Interleucina-6/inmunología , Masculino , Malondialdehído/inmunología , Malondialdehído/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Infiltración Neutrófila/efectos de los fármacos , Nucleobindinas , Oxidación-Reducción , Peroxidasa/genética , Peroxidasa/inmunología , Ratas , Ratas Sprague-Dawley , Piel/inmunología , Piel/lesiones , Estreptozocina , Herida Quirúrgica/complicaciones , Herida Quirúrgica/inmunología , Herida Quirúrgica/patología , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/inmunología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/inmunología , Cicatrización de Heridas/efectos de los fármacosRESUMEN
A series of diflunisal 4-thiazolidinones were synthesized. Some selected compounds were determined at one dose towards the full panel of 60 human cancer cell lines by National Cancer Institute. 2',4'-Difluoro-4-hydroxy-N-[4-oxo-2-(thiophen-2-yl)-1,3-thiazolidin-3-yl]biphenyl- 3-carboxamide (4a) demonstrated the most marked effect on K-562 cancer cell line with 58.59 % growth inhibition at 10 µM. Compound 4a was evaluated in vitro using the MTT colorimetric method against human leukemia cell line K-562 and mouse embryonic fibroblasts cell line NIH- 3T3 at different doses for cell viability and growth inhibition. Compound 4a exhibited anticancer activity with IC50 value of 5.2 µM against K-562 cells and did not display cytotoxicity towards NIH-3T3 cells compared with diflunisal. In addition, this compound could be an interesting prototype as an antiproliferative agent.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diflunisal/química , Animales , Antineoplásicos/química , Línea Celular Tumoral , Técnicas de Química Sintética , Diflunisal/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células K562/efectos de los fármacos , Ratones , Células 3T3 NIHRESUMEN
Tolmetin hydrazide and a novel series of tolmetin hydrazide-hydrazones 4a-l were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR) methods. N'-[(2,6-Dichlorophenyl)methylidene]-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetohydrazide (4g) was evaluated in vitro using the MTT colorimetric method against the colon cancer cell lines HCT-116 (ATCC, CCL-247) and HT-29 (ATCC, HTB-38) to determine growth inhibition and cell viability at different doses. Compound 4g exhibited anti-cancer activity with an IC50 value of 76 µM against colon cancer line HT-29 (ATCC, HTB-38) and did not display cytotoxicity toward control NIH3T3 mouse embryonic fibroblast cells compared to tolmetin. In addition, this compound was evaluated for caspase-3, caspase-8, caspase-9, and annexin-V activation in the apoptotic pathway, which plays a key role in the treatment of cancer. We demonstrated that the anti-cancer activity of this compound was due to the activation of caspase-8 and caspase-9 involved in the apoptotic pathway. In addition, in this study, we investigated the catalytical effect of COX on the HT-29 cancer line, the apoptotic mechanism, and the moleculer binding of tolmetin and compound 4g on the COX enzyme active site.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Hidrazonas/síntesis química , Hidrazonas/farmacología , Tolmetina/síntesis química , Tolmetina/farmacología , Antineoplásicos/metabolismo , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Ciclooxigenasa 1/química , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Activación Enzimática , Células HCT116 , Células HT29 , Humanos , Hidrazonas/metabolismo , Células MCF-7 , Simulación del Acoplamiento Molecular , Conformación Proteica , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Tolmetina/análogos & derivados , Tolmetina/metabolismoRESUMEN
The field of reproductive biology has undergone significant developments in the last decade. The notion that there is a fixed reserve pool of oocytes before birth was established by Zuckerman in 1951. However, in 2004, an article published in nature challenged this central dogma of mammalian reproductive biology. Tilly's group reported the existence of ovarian germline stem cells (GSCs) in postnatal ovaries of mice and suggested that the bone marrow could be an extragonadal source of ovarian GSCs. These findings were strongly criticized; however, several independent groups have since successfully isolated and characterized ovarian GSCs in postnatal mice. The ovarian GSCs are located in the ovarian surface epithelium and express markers of undifferentiated GSCs. When transplanted into mouse ovaries, mouse ovarian GSCs could differentiate and produce embryos and offspring. Similarly, in a recent study, ovarian GSCs were found to be present in the ovaries of women of reproductive age. Conversely, there is increasing evidence that stem cells responsible for maintaining a healthy state in normal tissue may be a source of some cancers, including ovarian cancer. Cancer stem cells (CSCs) have been found in many tissues, including ovaries. Some researchers have suggested that ovarian cancer may be a result of the transformation and dysfunction of ovarian GSCs with self-renewal properties. Drug resistant and metastasis-generating CSCs are responsible for many important problems affecting ovarian cancer patients. Therefore, the identification of CSCs will provide opportunities for the development of new therapeutic strategies for treatments for infertility and ovarian cancer. In this article, we summarize the current understanding of ovarian GSCs in adult mammals, and we also discuss whether there is a relationship between GSCs and CSCs.
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BACKGROUND: This study was designed to determine the possible protective effect of captopril treatment against oxidative damage in heart and lung tissues induced by burn injury. METHODS: Under ether anesthesia, the shaved dorsum of Wistar albino rats was exposed to 90°C water bath for 10 seconds. Captopril was administered intraperitoneally (10 mg/kg) after the burn injury and repeated twice daily. In the sham group, the dorsum was dipped in a 25°C water bath for 10 seconds. At the end of the 24 hours, echocardiographic recordings were performed, then animals were decapitated and heart and lung tissue samples were taken for the determination of tumor necrosis factor-α (TNF-α) as a pro-inflammatory cytokine, malondialdehyde and glutathione levels and myeloperoxidase, caspase-3, and Na+,K+-ATPase activity in addition to the histological analysis. RESULTS: Burn injury caused significant alterations in left ventricular function. In heart and lung tissues, TNF-α and malondialdehyde levels and myeloperoxidase and caspase-3 activities were found to be increased, while glutathione levels and Na+, K+-ATPase activity were decreased due to burn injury. Captopril treatment significantly elevated the reduced glutathione level and Na+, K+-ATPase activity, and decreased cytokine and malondialdehyde levels and myeloperoxidase and caspase-3 activities. CONCLUSION: Captopril prevents burn-induced damage in heart and lung tissues and protects against oxidative organ damage.
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Quemaduras/metabolismo , Captopril/farmacología , Corazón/efectos de los fármacos , Pulmón/efectos de los fármacos , Sustancias Protectoras/farmacología , Traumatismos Torácicos/metabolismo , Animales , Caspasa 3/metabolismo , Electrocardiografía , Femenino , Glutatión/metabolismo , Pulmón/química , Pulmón/patología , Masculino , Miocardio/química , Miocardio/patología , Ratas , Ratas Wistar , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: The aim was to investigate the putative anti-inflammatory and anti-apoptotic effect of obestatin in a rat model of subarachnoidal haemorrhage (SAH). METHODS: To induce SAH, rats were injected with 0.3 mL blood into their cisterna magna. At 48 hours rats were decapitated after neurological examination. Blood-brain barrier (BBB) permeability, brain water content, oxidative stress markers and histological analysis were done in brain tissue. RESULTS: The results showed that neurological examination scores were increased in the SAH group and, moreover, BBB permeability was impaired and oedema formed. SAH resulted in increased levels of plasma tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 levels and caspase-3 activity. Lipid peroxidation and protein oxidation levels and myeloperoxidase activity were all increased in the brain tissue, with concomitant decreases in antioxidant enzymes. On the other hand, SAH-induced neurological impairment and oxidative brain injury were ameliorated in the obestatin-treated group. CONCLUSION: The present study provides the first evidence that peripheral administration of obestatin exerts potent anti-inflammatory and neuroprotective effects in SAH-induced oxidative damage by maintaining a balance in oxidant-antioxidant status through the augmentation of endogenous antioxidants and the inhibition of pro-inflammatory mediators.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Edema Encefálico/patología , Lesiones Encefálicas/patología , Encéfalo/patología , Estrés Oxidativo , Hormonas Peptídicas/farmacología , Hemorragia Subaracnoidea/patología , Vasoespasmo Intracraneal/patología , Animales , Antiinflamatorios/administración & dosificación , Antioxidantes/administración & dosificación , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Edema Encefálico/tratamiento farmacológico , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/tratamiento farmacológico , Inmunohistoquímica , Masculino , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Hormonas Peptídicas/administración & dosificación , Ratas , Ratas Wistar , Hemorragia Subaracnoidea/tratamiento farmacológico , Vasoespasmo Intracraneal/tratamiento farmacológicoRESUMEN
Ischemic injury, which occurs as a result of sympathetic hyperactivity, plays an important role in heart failure. Melatonin is thought to have antiatherogenic, antioxidant, and vasodilatory effects. In this study, we investigated whether melatonin protects against ischemic heart failure (HF). In Wistar albino rats, HF was induced by left anterior descending (LAD) coronary artery ligation and rats were treated with either vehicle or melatonin (10 mg/kg) for 4 weeks. At the end of this period, echocardiographic measurements were recorded and the rats were decapitated to obtain plasma and cardiac tissue samples. Lactate dehydrogenase, creatine kinase, aspartate aminotransferase, alanine aminotransferase, and lysosomal enzymes (ß-D-glucuronidase, ß-galactosidase, ß-D-N-acetyl-glucosaminidase, acid phosphatase, and cathepsin-D) were studied in plasma samples, while malondialdehyde and glutathione levels and Na+, K+-ATPase, caspase-3 and myeloperoxidase activities were determined in the cardiac samples. Sarco/endoplasmic reticulum calcium ATPase (SERCA) and caveolin-3 levels in cardiac tissues were evaluated using Western blot analyses. Furthermore, caveolin-3 levels were also determined by histological analyses. In the vehicle-treated HF group, cardiotoxicity resulted in decreased cardiac Na+, K+-ATPase and SERCA activities, GSH contents and caveolin-3 levels, while plasma LDH, CK, and lysosomal enzyme activities and cardiac MDA and Myeloperoxidase (MPO) activities were found to be increased. On the other hand, melatonin treatment reversed all the functional and biochemical changes. The present results demonstrate that Mel ameliorates ischemic heart failure in rats. These observations highlight that melatonin is a promising supplement for improving defense mechanisms in the heart against oxidative stress caused by heart failure.
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Antioxidantes/uso terapéutico , Insuficiencia Cardíaca/prevención & control , Corazón/efectos de los fármacos , Melatonina/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Insuficiencia Cardíaca/etiología , Masculino , Melatonina/farmacología , Isquemia Miocárdica/complicaciones , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Etodolac hydrazide and a novel series of etodolac hydrazide-hydrazones 3-15 and etodolac 4-thiazolidinones 16-26 were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR, (13)C NMR, HREI-MS) methods. Some selected compounds were determined at one dose toward the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI, Bethesda, USA). 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetic acid[(4-chlorophenyl)methylene]hydrazide 9 demonstrated the most marked effect on the prostate cancer cell line PC-3, with 58.24% growth inhibition at 10(-5) M (10 µM). Using the MTT colorimetric method, compound 9 was evaluated in vitro against the prostate cell line PC-3 and the rat fibroblast cell line L-929, for cell viability and growth inhibition at different doses. Compound 9 exhibited anticancer activity with an IC(50) value of 54 µM (22.842 µg/mL) against the PC-3 cells and did not display any cytotoxicity toward the L-929 rat fibroblasts, compared to etodolac. In addition, this compound was evaluated for caspase-3 and Bcl-2 activation in the apoptosis pathway, which plays a key role in the treatment of cancer.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Etodolaco/análogos & derivados , Etodolaco/farmacología , Hidrazonas/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Caspasa 3/metabolismo , Línea Celular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Etodolaco/síntesis química , Etodolaco/química , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Concentración 50 Inhibidora , Masculino , Neoplasias/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Análisis EspectralRESUMEN
A series of novel N-(3-substituted aryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamides 2a-e were synthesized by the addition of ethyl a-bromoacetate and anhydrous sodium acetate in dry ethanol to N-(substituted aryl/alkylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzene sulfonamides 1a-e, which were synthesized by the reaction of alkyl/aryl isothiocyanates with celecoxib. The structures of the isolated products were determined by spectral methods and their anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV NS5B RNA-dependent RNA polymerase (RdRp) activities evaluated. The compounds were also tested for gastric toxicity and selected compound 1a was screened for its anticancer activity against 60 human tumor cell lines. These investigations revealed that compound 1a exhibited anti-inflammatory and analgesic activities and further did not cause tissue damage in liver, kidney, colon and brain compared to untreated controls or celecoxib. Compounds 1c and 1d displayed modest inhibition of HCV NS5B RdRp activity. In conclusion, N-(ethylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (1a) may have the potential to be developed into a therapeutic agent.
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Antineoplásicos/farmacología , Antivirales/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Pirazoles/farmacología , Sulfonamidas/farmacología , Compuestos de Sulfonilurea/farmacología , Tiazolidinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Antioxidantes , Antivirales/síntesis química , Antivirales/toxicidad , Dominio Catalítico , Celecoxib , Línea Celular Tumoral , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/toxicidad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Femenino , Hepacivirus/enzimología , Miembro Posterior/efectos de los fármacos , Miembro Posterior/patología , Humanos , Isotiocianatos/química , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Unión Proteica , Pirazoles/síntesis química , Pirazoles/toxicidad , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Sulfonamidas/síntesis química , Sulfonamidas/toxicidad , Compuestos de Sulfonilurea/síntesis química , Compuestos de Sulfonilurea/toxicidad , Tiazolidinas/síntesis química , Tiazolidinas/toxicidad , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/químicaRESUMEN
Oxidative stress induced by spinal cord injury (SCI) has deleterious effects on the function of several organ systems including the urinary bladder. In this study, we investigated the possible protective actions of melatonin on SCI-induced oxidative damage and urinary bladder dysfunction. Wistar albino rats (n = 24) were divided randomly as control, vehicle- or melatonin (10 mg/kg, ip)-treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury at T10 was used. Injured animals were given either vehicle or melatonin 15 min postinjury. One week postinjury, each rat was neurologically examined and then decapitated; blood samples were taken to evaluate neuron-specific enolase (NSE) and soluble protein 100ß (S-100ß). Spinal cord (SC) and urinary bladder samples were taken for functional studies and histological examination or stored for the measurement of malondialdehyde (MDA), glutathione (GSH) and nerve growth factor (NGF) levels and caspase-3 activity. Isometric contractions in bladder strips were induced by carbachol. In the SCI rats, decreased contractile responses of the bladder strips were found to be restored by melatonin treatment. Serum S-100ß levels and NSE activities and tissue MDA levels and caspase-3 activities, all of which were elevated in the vehicle-treated SCI animals as compared to the control values, were reversed by melatonin treatment. On the other hand, reduced GSH and NGF levels due to SCI were restored by melatonin treatment. Furthermore, melatonin treatment improved histological findings. These findings suggest that melatonin reduces SCI-induced tissue injury and improves bladder functions through its effects on oxidative stress and NGF.
Asunto(s)
Melatonina/uso terapéutico , Traumatismos de la Médula Espinal/terapia , Vejiga Urinaria/metabolismo , Vejiga Urinaria/fisiopatología , Animales , Caspasa 3/metabolismo , Glutatión/metabolismo , Malondialdehído/metabolismo , Ratas , Ratas Wistar , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
BACKGROUND: There is substantial evidence to suggest that oxidative stress plays a significant role in the development of acute brain injury after subarachnoid hemorrhage (SAH). OBJECTIVE: To investigate the putative neuroprotective effect of nesfatin-1, a novel peptide with anorexigenic properties, in a rat model of SAH. METHODS: Male Wistar albino rats were randomly divided into control, saline-treated SAH, and nesfatin-1 (10 µg/kg IP)-treated SAH groups. To induce SAH, rats were injected with 0.3 mL blood into their cisterna magna. Forty-eight hours after SAH induction, neurological examination scores were recorded and the rats were decapitated. Brain tissue samples were taken for the determination of blood-brain barrier (BBB) permeability, brain water content, and oxidative stress markers and for histological analysis. RESULTS: The neurological examination scores were increased on the second day of SAH induction. SAH resulted in impaired blood-brain barrier and edema, along with increased levels of brain tumor necrosis factor-α, interleukin-1ß, interleukin-6, lipid peroxidation, protein carbonylation, and myeloperoxidase activity with concomitant decreases in antioxidant enzymes. Conversely, in the nesfatin-1-treated SAH group, SAH-induced neurological impairment and oxidative brain injury were ameliorated by nesfatin treatment. Furthermore, SAH-induced morphological changes in the basilar arteries were improved by nesfatin-1 treatment, whereas caspase-3 activity and SAH-induced elevations in the plasma levels of proinflammatory cytokines were also depressed by nesfatin-1 treatment. CONCLUSION: These findings suggest that nesfatin-1, which appears to have antiapoptotic and anti-inflammatory properties, exerts neuroprotection in SAH-induced injury in rats by inhibiting neutrophil infiltration and subsequent release of inflammatory mediators.
Asunto(s)
Antiinflamatorios/farmacología , Hipoxia Encefálica/tratamiento farmacológico , Proteínas del Tejido Nervioso/farmacología , Estrés Oxidativo/fisiología , Hemorragia Subaracnoidea/tratamiento farmacológico , Animales , Barrera Hematoencefálica/efectos de los fármacos , Proteínas de Unión al Calcio , Proteínas de Unión al ADN , Hipoxia Encefálica/etiología , Hipoxia Encefálica/patología , Masculino , Fármacos Neuroprotectores/farmacología , Nucleobindinas , Ratas , Ratas Wistar , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/patologíaRESUMEN
The aim of this study is to investigate the effects of exogenous L-arginine and HDL on LDL and oxidized LDL (ox-LDL)-mediated platelet activation. Adenosine diphosphate (ADP)-activated platelets have been incubated with lipoproteins with or without L-arginine. P-selectin receptor numbers per platelet have been measured by flow cytometry. After incubation with only L-arginine (without lipoproteins), platelet nitric oxide (NO) levels and P-selectin receptor numbers significantly increased compared to the controls (P < .05). After incubation with LDL or ox-LDL, receptor numbers of P-selectin significantly increased (P < .001). However, P-selectin receptor numbers in platelets treated with L-arginine + LDL or L-arginine + ox-LDL decreased compared to the levels in platelets treated with only LDL or ox-LDL (P < .01, P < .001, respectively). Addition of HDL to L-arginine + ox-LDL caused significant reduction in P-selectin receptor numbers as in the control values (P < .001).We have concluded that L-arginine causes enhanced platelet NO levels and blocks the effects of LDL or ox-LDL on platelet P-selectin receptor numbers and HDL also strengthens this effect of L-arginine.
Asunto(s)
Arginina/farmacología , Plaquetas/metabolismo , Lipoproteínas HDL/farmacología , Lipoproteínas LDL/farmacología , Lipoproteínas/farmacología , Selectina-P/sangre , Activación Plaquetaria/efectos de los fármacos , Adulto , Plaquetas/efectos de los fármacos , Células Cultivadas , LDL-Colesterol/sangre , LDL-Colesterol/farmacología , Interacciones Farmacológicas , Humanos , Lipoproteínas/sangre , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Óxido Nítrico/sangre , Adulto JovenRESUMEN
OBJECTIVE: We aimed to detect novel in vitro effects of clopidogrel on platelets by assessment of the following parameters: malondialdehyde, glutathione, nitrite, aggregation response, and expressions of P-selectin, fibrinogen, apolipoprotein A1, apolipoprotein B, and phosphatidylserine. METHODS: Platelets were obtained from healthy (n: 9) and hyperlipidemic (n: 9) volunteers. Expressions of P-selectin, fibrinogen, apolipoproteins A1/B and phosphatidylserine with and without clopidogrel were assayed by flow cytometry. Malondialdehyde, glutathione, aggregation and nitrite levels were also assayed. RESULTS: Without clopidogrel, the baseline values of platelet aggregation, malondialdehyde, and expressions of P-selectin, fibrinogen and phosphatidylserine were significantly higher, whereas nitrite and expression of apolipoproteins A1/B were significantly lower in hyperlipidemics than in the healthy group. In both groups, clopidogrel significantly reduced aggregation and expression of fibrinogen, but it elevated nitrite levels. Clopidogrel significantly decreased P-selectin and phosphatidylserine expression and malondialdehyde but increased expressions of apolipoproteins A1/B only in hyperlipidemics. CONCLUSION: It seems that clopidogrel has some new in vitro antiplatelet effects. The present study is a basic in vitro study to suggest new insights into the effects of clopidogrel on platelet functions.
RESUMEN
OBJECTIVES: The circulating lipoproteins may cause some abnormalities in platelet composition and function in hypercholesterolemia. The aim of this study was to investigate whether platelet apoptosis, platelet activation, platelet aggregation, platelet-leukocyte aggregate (PLA) formation and lipid peroxidation occur simultaneously in hyperlipidemia. DESIGN AND METHODS: Expression of GpIIb/IIIa (CD41a), P-selectin (CD62-P), platelet-bound fibrinogen (antifibrinogen), platelet membrane phosphatidylserine (PS), platelet-monocyte aggregates (mono-PLA) and platelet-neutrophil aggregates (neut-PLA) was measured in eight hyperlipidemic and eight normal subjects using flow cytometry. ADP (10 microM) was used to activate platelets. Furthermore, ADP induced platelet aggregation responses, platelet malondialdehyde (MDA) and glutathione (GSH) levels were determined. RESULTS: Before platelet activation, platelet CD62-P, antifibrinogen, annexin-V, mono-PLA, neut-PLA and platelet MDA levels as well as platelet aggregation responses in the hyperlipidemics were significantly higher than those in the controls (P<0.01, P<0.01, P<0.01, P<0.001, P<0.001, P<0.01, P<0.001, respectively), whereas GpIIb/IIIa expression and GSH levels were not different significantly (P > 0.05). In the control group, CD62-P, antifibrinogen and annexin-V levels increased significantly after ADP activation (P<0.05, P<0.05, P<0.01, respectively). In hyperlipidemic subjects, annexin-V expression increased significantly after activation (P<0.01), whereas expression of GpIIb/IIIa, CD62-P and antifibrinogen remained unchanged (P>0.05). The levels of total cholesterol (T-CHO), low density lipoprotein cholesterol (LDL-C), serum fibrinogen (S-FGN) and high density lipoprotein cholesterol (HDL-C) in patients were found to be correlated with platelet CD62-P, antifibrinogen, annexin-V, mono-PLA and MDA. CONCLUSIONS: In conclusion, it seems that in hyperlipidemia, some platelets are in an activated state in circulation, and that increased lipid peroxidation, early apoptosis, platelet-leukocytes aggregate formation and platelet aggregation altogether accompany this process.
Asunto(s)
Apoptosis , Plaquetas/metabolismo , Hiperlipidemias/fisiopatología , Leucocitos/metabolismo , Peroxidación de Lípido , Agregación Plaquetaria , Adulto , Apoptosis/fisiología , Adhesión Celular/fisiología , Femenino , Fibrinógeno/metabolismo , Glutatión/metabolismo , Humanos , Peroxidación de Lípido/fisiología , Masculino , Selectina-P/biosíntesis , Fosfatidilserinas/metabolismo , Agregación Plaquetaria/fisiología , Complejo GPIb-IX de Glicoproteína Plaquetaria/biosíntesis , Valores de ReferenciaRESUMEN
In this study, platelet glycoprotein (Gp) receptor numbers were measured by a flow cytometric assay using Cytoquant Gp in seven hypercholesterolemic and five normal subjects. Thrombin receptor agonist peptide (TRAP) was used to activate platelets. In hypercholesterolemia the Gp receptor numbers per resting platelet were found to be: 38,629 +/- 8,538 (GpIIb/IIIa), 22,269 +/- 5,628 (GpIb), 37,037 +/- 9,810 (GpIIIa), 224 +/- 504 (CD62-P). After activation, receptor numbers were determined to be: 56,399 +/- 9,003 (GpIIb/IIIa), 10,970 +/- 5,319 (GpIb), 50,715 +/- 7,904 (GpIIIa), 1,222 +/- 687 (P-selectin). In the normal group before the activation, receptor numbers were: 43,828 +/- 8,862 (GpIIb/IIIa), 22,166 +/- 3,847 (GpIb), 42,351 +/- 1,049 (GpIIIa), 62 +/- 139 (CD62-P), After activation, receptor numbers were determined to be: 60,573 +/- 4,294 (GpIIb/IIIa), 13,003 +/- 4,118 (GpIb), 52, 067 +/- 1,039 (GpIIIa), 3,608 +/- 1,508 (CD62-P). In hypercholesterolemic subjects, GpIIb/IIIa and GpIIIa receptor numbers on activated platelets increased significantly, whereas P-selectin numbers remained unchanged. However, the GpIb levels decreased significantly. In the control group, after activation, GpIIb/IIIa and P-selectin receptors increased significantly, GpIIIa receptor numbers did not change significantly, whereas GpIb receptor numbers decreased significantly. When the GpIIb/IIIa, GpIb, GpIIIa receptor numbers of the control group and hypercholesterolemic group were compared before and after activation, no significant changes were observed (P > 0.05). But P-selectin receptor numbers were significantly decreased in hypercholesterolemic patients compared to normals following TRAP activation (P < 0.05). In this study, the effect of hypercholesterolemia on platelet function was observed. The striking observation about present study was the marked decrease in P-selectin expression after activation in the hypercholesterolemics compared to normals. This finding suggests some sort of platelet dysfunction in these individuals.