RESUMO
This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Edema/tratamento farmacológico , Peritonite/tratamento farmacológico , Inibidores da Agregação Plaquetária/farmacologia , Úlcera/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Carragenina , Celecoxib/química , Celecoxib/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Lignanas/química , Lignanas/farmacologia , Masculino , Camundongos , Estrutura Molecular , Peritonite/induzido quimicamente , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Úlcera/induzido quimicamenteRESUMO
OBJECTIVES: Warfarin is the most widely used anticoagulant in the world, but it has several limitations including its narrow therapeutic range, need for dose adjustment and high potential for interactions. The simultaneous use of other drugs or even medicinal plants and certain foods could interfere with its therapeutic activity. In this context, this study aims to investigate the in vitro anticoagulant potential and phytochemical constitution of 17 plants selected from a previous clinical cross-sectional study (2014), that investigated the habits of plant utilization among patients taking warfarin. METHODS: Ethanol extracts and essential oils were evaluated, in vitro, as to their effect in the prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests. Four species that presented aPTT >50 s were selected for phytochemical evaluation. RESULTS: Thirteen of the 17 plants selected demonstrated a significant anticoagulant effect in at least one of the evaluated parameters. Citrus sinensis (PT=14.75 and aPTT=53.15), Mentha crispa (aPTT=51.25), Mikania laevigata (PT=14.90 and aPTT=52.10), and Nasturtium officinale (aPTT=50.55) showed greater anticoagulant potential compared to normal plasma pool (PT=12.25 and aPTT=37.73). Chemical profiles of these four species were obtained, and certain compounds were identified: rosmarinic acid from M. crispa and isoorientin from N. officinale. CONCLUSIONS: Thus, the results of this study could be a useful indicator for clinical practice towards the possibility of interaction between these plants and anticoagulants, although further clinical research is needed taking into consideration the limitations of in vitro studies. These findings also suggest that further research into the action of these plants could be of real clinical value in identifying potential alternative anticoagulant therapies.
Assuntos
Plantas Medicinais , Varfarina , Anticoagulantes , Estudos Transversais , Tempo de ProtrombinaRESUMO
In Brazil, snakes from the Bothrops genus are responsible for thousands of accidents, and their venoms are mainly composed of proteolytic enzymes. Although the antibothropic serum produced by the Brazilian Institutes is remarkably efficient, more studies are necessary, especially in veterinary medicine. The venom contain enzymes and non-enzymatic proteins that interfere with hemostasis leading to hemorrhage or even thrombosis. Possible treatment associations with known bothropic antivenom were the reason for the development of the present study. The aim of this study was to evaluate hemostasis alterations caused by Bothrops alternatus venom in rabbits followed by treatments with anti-bothropic serum, tranexamic acid and desmopressin. Twenty New Zealand rabbits were distributed into five groups (n=4) that were experimentally envenomed with 150mcg/kg of B. alternatus venom via intramuscular injection and treated as follow: Group 1 (G1) was the positive control and received venom and PBS/BSA; Group 2 (G2) was treated with tranexamic acid; Group 3 (G3) with desmopressin; Group 4 (G4) with tranexamic acid and anti-bothropic serum; and Group 5 (G5) with anti-bothropic serum and desmopressin. Blood samples were collected before venom administration, and one, four, eight and 12 hours after, for Partial activated partial thromboplastin time, Prothrombin Time, Thrombin Time and fibrinogen evaluation. Thrombin generation (TG) test was carried out with a pool of samples from final times (8 and 12h). At the end of 12h, all animals were euthanized and necropsy was conducted. Samples from muscle tissue, heart, lungs and kidney were analyzed. Classic coagulation tests showed no significant differences amongst groups and times. However, TG indicated that the venom causes a hypocoagulability state, which was not reversed by proposed treatments. Histology showed muscle inflammation, hemorrhage and necrosis, as well as hemorrhage in other tissues with no differences amongst groups. B. alternatus envenomation causes hypocoagulability detected by TG assay, but not through classical coagulation tests. The use of tranexamic acid and desmopressin for hemostasis stabilization after inoculation of the venom did not show advantage in coagulation restoration.(AU)
No Brasil, as serpentes do gênero Bothrops são responsáveis por milhares de acidentes, e seus venenos são compostos principalmente de enzimas proteolíticas. Embora o soro antiofídico produzido pelos institutos brasileiros seja notavelmente eficiente, mais estudos são necessários, especialmente na medicina veterinária. O veneno contem enzimas e proteínas não-enzimáticas que interferem com a hemostasia levando a hemorragias ou trombose. A associação de outros tratamentos ao soro antibotrópico foi a razão para o desenvolvimento do presente estudo. O objetivo deste estudo foi avaliar as alterações da hemostasia causadas pelo veneno de Bothrops alternatus em coelhos, após tratamento com soro antibotrópico, ácido tranexâmico e desmopressina. Vinte coelhos da Nova Zelândia foram distribuídos em cinco grupos (n = 4) que foram submetidos a experimentos com 150mcg/kg de veneno de B. alternatus por injeção intramuscular. O Grupo 1 (G1) foi o controle positivo e recebeu veneno e PBS / BSA, enquanto o Grupo 2 (G2) foi tratado com ácido tranexâmico, o Grupo 3 (G3) com desmopressina, o Grupo 4 (G4) com ácido tranexâmico e soro antibotrópico, e o Grupo 5 (G5) com soro antibotrópico e desmopressina. As amostras de sangue foram coletadas antes da administração do veneno, e uma, quatro, oito e 12 horas após os tratamentos para realização de tempo de tromboplastina parcial ativada parcial (TTPa), tempo de protrombina (TP), tempo de trombina (TT) e mensuração de fibrinogênio. Para o ensaio de geração de trombina (TG) foi realizado com um pool de amostras nos tempos finais (8 e 12h). Ao final das 12h, todos os animais foram sacrificados e a necropsia foi realizada. Amostras de tecido muscular, coração, pulmões e rins foram analisadas. Os testes TTPa, TP, TT e fibrinogênio não mostraram diferenças significativas entre os grupos e os tempos. No entanto, o TG indicou que o veneno causa um estado de hipocoagulabilidade, que não foi revertido pelos tratamentos propostos. Na histologia, foram observadas inflamação muscular, hemorragia e necrose, além de hemorragia em outros tecidos, sem diferenças entre os grupos. O envenenamento por B. alternatus causa hipocoagulabilidade detectada mais precocemente pelo teste de geração de trombina. O uso de ácido tranexâmico e desmopressina para estabilização da hemostasia após a inoculação do veneno não mostrou vantagem na restauração da coagulação.(AU)
Assuntos
Animais , Coelhos , Serpentes , Bothrops , Hemostasia , Técnicas HemostáticasRESUMO
In Brazil, snakes from the Bothrops genus are responsible for thousands of accidents, and their venoms are mainly composed of proteolytic enzymes. Although the antibothropic serum produced by the Brazilian Institutes is remarkably efficient, more studies are necessary, especially in veterinary medicine. The venom contain enzymes and non-enzymatic proteins that interfere with hemostasis leading to hemorrhage or even thrombosis. Possible treatment associations with known bothropic antivenom were the reason for the development of the present study. The aim of this study was to evaluate hemostasis alterations caused by Bothrops alternatus venom in rabbits followed by treatments with anti-bothropic serum, tranexamic acid and desmopressin. Twenty New Zealand rabbits were distributed into five groups (n=4) that were experimentally envenomed with 150mcg/kg of B. alternatus venom via intramuscular injection and treated as follow: Group 1 (G1) was the positive control and received venom and PBS/BSA; Group 2 (G2) was treated with tranexamic acid; Group 3 (G3) with desmopressin; Group 4 (G4) with tranexamic acid and anti-bothropic serum; and Group 5 (G5) with anti-bothropic serum and desmopressin. Blood samples were collected before venom administration, and one, four, eight and 12 hours after, for Partial activated partial thromboplastin time, Prothrombin Time, Thrombin Time and fibrinogen evaluation. Thrombin generation (TG) test was carried out with a pool of samples from final times (8 and 12h). At the end of 12h, all animals were euthanized and necropsy was conducted. Samples from muscle tissue, heart, lungs and kidney were analyzed. Classic coagulation tests showed no significant differences amongst groups and times. However, TG indicated that the venom causes a hypocoagulability state, which was not reversed by proposed treatments. Histology showed muscle inflammation, hemorrhage and necrosis, as well as hemorrhage in other tissues with no differences amongst groups. B. alternatus envenomation causes hypocoagulability detected by TG assay, but not through classical coagulation tests. The use of tranexamic acid and desmopressin for hemostasis stabilization after inoculation of the venom did not show advantage in coagulation restoration.(AU)
No Brasil, as serpentes do gênero Bothrops são responsáveis por milhares de acidentes, e seus venenos são compostos principalmente de enzimas proteolíticas. Embora o soro antiofídico produzido pelos institutos brasileiros seja notavelmente eficiente, mais estudos são necessários, especialmente na medicina veterinária. O veneno contem enzimas e proteínas não-enzimáticas que interferem com a hemostasia levando a hemorragias ou trombose. A associação de outros tratamentos ao soro antibotrópico foi a razão para o desenvolvimento do presente estudo. O objetivo deste estudo foi avaliar as alterações da hemostasia causadas pelo veneno de Bothrops alternatus em coelhos, após tratamento com soro antibotrópico, ácido tranexâmico e desmopressina. Vinte coelhos da Nova Zelândia foram distribuídos em cinco grupos (n = 4) que foram submetidos a experimentos com 150mcg/kg de veneno de B. alternatus por injeção intramuscular. O Grupo 1 (G1) foi o controle positivo e recebeu veneno e PBS / BSA, enquanto o Grupo 2 (G2) foi tratado com ácido tranexâmico, o Grupo 3 (G3) com desmopressina, o Grupo 4 (G4) com ácido tranexâmico e soro antibotrópico, e o Grupo 5 (G5) com soro antibotrópico e desmopressina. As amostras de sangue foram coletadas antes da administração do veneno, e uma, quatro, oito e 12 horas após os tratamentos para realização de tempo de tromboplastina parcial ativada parcial (TTPa), tempo de protrombina (TP), tempo de trombina (TT) e mensuração de fibrinogênio. Para o ensaio de geração de trombina (TG) foi realizado com um pool de amostras nos tempos finais (8 e 12h). Ao final das 12h, todos os animais foram sacrificados e a necropsia foi realizada. Amostras de tecido muscular, coração, pulmões e rins foram analisadas. Os testes TTPa, TP, TT e fibrinogênio não mostraram diferenças significativas entre os grupos e os tempos. No entanto, o TG indicou que o veneno causa um estado de hipocoagulabilidade, que não foi revertido pelos tratamentos propostos. Na histologia, foram observadas inflamação muscular, hemorragia e necrose, além de hemorragia em outros tecidos, sem diferenças entre os grupos. O envenenamento por B. alternatus causa hipocoagulabilidade detectada mais precocemente pelo teste de geração de trombina. O uso de ácido tranexâmico e desmopressina para estabilização da hemostasia após a inoculação do veneno não mostrou vantagem na restauração da coagulação.(AU)
Assuntos
Animais , Coelhos , Serpentes , Bothrops , Hemostasia , Técnicas HemostáticasRESUMO
AIMS: The hallmarks of type 2 diabetes (T2D) are hyperglycaemia and insulin resistance. These factors, at the cellular level, are associated with mitochondrial dysfunction and increased glucose uptake. Such events are poorly explored in the context of the salivary glands. In this study, we present a series of eight cases of a distinct salivary gland lesion characterised by multiple oncocytic cysts, and we provide new pathological insights regarding its pathogenesis. METHODS AND RESULTS: Seven patients (87.5%) had confirmed T2D, and obesity was identified in five (62.5%) patients. Clinically, the patients showed bilateral parotid gland swelling with recurrent episodes of pain and enlargement. Imaging examination revealed multiple cystic lesions in both parotid glands. Microscopically, the parotid glands showed multiple cysts of different sizes, lined by oncocytic epithelial cells. Intraluminally, strongly eosinophilic glass-like crystalloid material was observed. Immunohistochemical studies were performed, and the most notable finding was glucose transporter 1 (GLUT1) overexpression in the oncocytic cysts which is not observed in any other oncocytic lesion of patients without T2D. In addition, high expressions of mitochondrial antigen, fission 1 protein and mitofusin-2 were observed in the oncocytic epithelium of the cysts. Furthermore, most of the oncocytic cysts showed a pattern of cytokeratin expression consistent with striated ducts. CONCLUSIONS: These results strongly suggest that T2D is associated with alterations in GLUT1 expression in the cells of striated ducts with mitochondrial dysfunction, causing a hyperplastic process characterised by multiple oncocytic cysts. For this lesion, the designation of 'diabetes-associated-bilateral multiple oncocytic cysts of the parotid gland' is proposed.
Assuntos
Cistos/patologia , Diabetes Mellitus Tipo 2/complicações , Transportador de Glucose Tipo 1/metabolismo , Células Oxífilas/patologia , Doenças Parotídeas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cistos/etiologia , Cistos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Oxífilas/metabolismo , Doenças Parotídeas/etiologia , Doenças Parotídeas/metabolismo , Glândula Parótida/metabolismo , Glândula Parótida/patologiaRESUMO
AIMS: Fibroblast growth factor (FGF)-2 and fibroblast growth factor receptor (FGFR)-1 are associated with tumour invasiveness, cell proliferation, angiogenesis, and metastasis. The aims of this study were to investigate FGF-2 expression and FGFR-1 expression in oral epithelial dysplasia (OED) and oral tongue squamous cell carcinoma (OTSCC), and their correlation with OTSCC patients' prognosis. METHODS AND RESULTS: One hundred and sixty-seven cases were retrospectively selected, including 85 surgical specimens of patients with OTSCC, 46 incisional biopsies of OTSCC, and 36 incisional biopsies of OED. Tissue sections were subjected to immunohistochemical staining for FGF-2 and FGFR-1, and digitally scored. Elevated scores of FGF-2 and FGFR-1 immunostaining were associated with high-grade OEDs. FGF-2 positivity in the stroma was associated with vascular invasion and a worse prognosis, in both overall survival (OS) and disease-free survival (DFS) analyses, in univariate and multivariate models. FGFR-1 positivity in the stroma was correlated with lymph node metastasis and distant metastasis. FGFR-1 expression in either the malignant cells or the stroma was strongly correlated with shorter OS and DFS. CONCLUSIONS: Taken together, our findings suggest that increased FGF-2 expression and increased FGFR-1 expression are associated with high-grade OEDs, and are correlated with the presence of metastasis and adverse outcomes in OTSCC patients.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias da Língua/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Língua/mortalidade , Neoplasias da Língua/patologia , Adulto JovemRESUMO
OBJECTIVE: Elderly people are at a high risk of developing vitamin D (VitD) deficiency due to both decreased intake and cutaneous synthesis. Most of the biological actions of VitD are mediated by the vitamin D receptor (VDR), which is present in neurons and glial cells of the hippocampus, and in the cortex and subcortical nuclei, essential areas for cognition. It is known that VDR gene polymorphisms may decrease the VDR affinity for VitD. Objective: The present study aimed to investigate the influence of VitD levels on cognitive decline in patients with dementia due to Alzheimer's disease (AD, n = 32) and mild cognitive impairment (MCI, n = 15) compared to cognitively healthy elderly (n = 24). METHODS: We also evaluated the association of VDR gene polymorphisms with cognitive disturbance. Methods: Four polymorphisms on the VDR gene were studied, namely, BsmI, ApaI, FokI and TaqI, by polymerase chain reaction-restriction fragment length polymorphism. Serum levels of 25-hydroxy vitamin D (25(OH)D) were determined by high performance liquid chromatography. RESULTS: Results: No significant difference in 25(OH)D levels or genotypic/allelic frequencies was observed between the groups. Deficiency of 25(OH)D was more frequently observed in women. The AA/AG genotypes of the BsmI polymorphism was associated with sufficient 25(OH)D levels, while the GG genotype of this same polymorphism was associated to insufficient levels in the cognitively-impaired group (individuals with AD or MCI). CONCLUSIONS: Conclusions: The data obtained do not confirm the relationship between reductions of VitD levels, polymorphisms in the VDR gene, and altered cognitive function in this sample. However, the data indicate that BsmI polymorphism in the VDR gene is associated with the VitD levels in individuals with cognitive decline.
Assuntos
Disfunção Cognitiva/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Disfunção Cognitiva/fisiopatologia , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição por Sexo , Vitamina D/sangueRESUMO
ABSTRACT Elderly people are at a high risk of developing vitamin D (VitD) deficiency due to both decreased intake and cutaneous synthesis. Most of the biological actions of VitD are mediated by the vitamin D receptor (VDR), which is present in neurons and glial cells of the hippocampus, and in the cortex and subcortical nuclei, essential areas for cognition. It is known that VDR gene polymorphisms may decrease the VDR affinity for VitD. Objective: The present study aimed to investigate the influence of VitD levels on cognitive decline in patients with dementia due to Alzheimer's disease (AD, n = 32) and mild cognitive impairment (MCI, n = 15) compared to cognitively healthy elderly (n = 24). We also evaluated the association of VDR gene polymorphisms with cognitive disturbance. Methods: Four polymorphisms on the VDR gene were studied, namely, BsmI, ApaI, FokI and TaqI, by polymerase chain reaction-restriction fragment length polymorphism. Serum levels of 25-hydroxy vitamin D (25(OH)D) were determined by high performance liquid chromatography. Results: No significant difference in 25(OH)D levels or genotypic/allelic frequencies was observed between the groups. Deficiency of 25(OH)D was more frequently observed in women. The AA/AG genotypes of the BsmI polymorphism was associated with sufficient 25(OH)D levels, while the GG genotype of this same polymorphism was associated to insufficient levels in the cognitively-impaired group (individuals with AD or MCI). Conclusions: The data obtained do not confirm the relationship between reductions of VitD levels, polymorphisms in the VDR gene, and altered cognitive function in this sample. However, the data indicate that BsmI polymorphism in the VDR gene is associated with the VitD levels in individuals with cognitive decline.
RESUMO Idosos apresentam risco elevado de desenvolverem deficiência de Vitamina D (VitD) devido à diminuição da ingestão e da síntese na pele. A maioria das ações biológicas da VitD é mediada pelo receptor da vitamina D (VDR), que está presente nos neurônios e células gliais do hipocampo, e no córtex e em núcleos subcorticais, áreas essenciais para a cognição. Sabe-se que polimorfismos do gene VDR podem diminuir a afinidade do VDR pela VitD. Objetivo: O presente estudo teve como objetivo investigar a influência dos níveis de VitD no declínio cognitivo em pacientes com demência devida à doença de Alzheimer (DA, n = 32) e comprometimento cognitivo leve (CCL, n = 15) em comparação a um grupo de idosos cognitivamente saudáveis (n = 24). Nós também avaliamos a associação entre polimorfimos no gene do receptor de VitD e as alterações cognitivas. Métodos: Quatro polimorfismos no gene VDR foram estudados, sendo BsmI, ApaI, FokI e TaqI, por PCR-RFLP. Os níveis séricos de 25-hidroxi vitamina D (25(OH)D) foram determinados por HPLC. Resultados: Não houve diferença significativa nos níveis de 25(OH)D ou nas frequências genotípicas / alélicas entre os grupos. Níveis deficientes de 25(OH)D foram mais frequentes nas mulheres. Os genótipos AA / AG do polimorfismo BsmI foram associados a níveis suficientes de 25(OH)D, enquanto o genótipo GG deste mesmo polimorfismo foi associado a níveis insuficientes no grupo com comprometimento cognitivo (em indivíduos com DA ou CCL). Conclusões: Os resultados obtidos não confirmam a relação entre redução dos níveis de VitD, polimorfismos no gene VDR e função cognitiva alterada nesta amostra. No entanto, os dados indicam que o polimorfismo BsmI no gene VDR está associado aos níveis de VitD em indivíduos com declínio cognitivo.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Vitamina D/análogos & derivados , Receptores de Calcitriol/genética , Polimorfismo de Nucleotídeo Único/genética , Disfunção Cognitiva/genética , Vitamina D/sangue , Estudos de Casos e Controles , Expressão Gênica , Distribuição por Sexo , Distribuição por Idade , Disfunção Cognitiva/fisiopatologiaRESUMO
Fibroblast growth factor 2 (FGF-2) is a multifunctional cytokine expressed in several tissues and involved in a wide variety of biologic activities, with one low molecular weight (LMW) protein present in the cytosol, which is secreted, acting via its receptors (FGFRs), and four high molecular weight (HMW) proteins located in the nucleus. Fibroblast growth factor receptor (FGFR) family has four (FGFR1-4) transmembrane tyrosine kinase receptors expressed on several cell types, and FGFR-1 has been indicated as a potential molecular target in several types of cancer, including oral squamous cell carcinoma (OSCC). The FGF-2/FGFR-1 expression has been studied in the oral cavity, and it was associated with the wound repair process, the development of benign and malignant salivary gland tumors, besides being related to oral potentially malignant disorders (OPMDs) and OSCC. Hence, we critically review the currently available data on FGF-2/FGFR-1 expression in the normal mucosa and lesions of the oral cavity.
Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Expressão Gênica , Mucosa Bucal/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Boca , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Glândulas Salivares/metabolismo , Humanos , Mucosa Bucal/fisiologia , Cicatrização/genéticaRESUMO
Cognitive impairment, including mild cognitive impairment (MCI) and dementia, compromises the patients' cognitive abilities and, to different extents, to carry out daily activities, accompanied by personality and behavioral changes. Studies suggest that leptin, an adipokine, has a neuroprotective role against Alzheimer's disease (AD) and that cytokines are associated with inflammatory processes and dementia. This study aimed to evaluate serum leptin, hsCRP, IL-6 and TNF-α levels in a cognitive continuum group from normal to demential status, and to assess whether they correlates to Mini-Mental State Examination (MMSE) and Functional Assessment Staging (FAST) scores. Forty-three participants were included, of whom 12 with probable AD, 18 with MCI and 13 with no objective cognitive decline. Serum leptin and hsCRP levels were evaluated by immunoturbidimetric method, and IL-6 and TNF-α by ELISA. Higher TNF-α levels were found in individuals with FAST stages 1/2 and normal scores evaluated by MMSE. hsCRP levels were inversely correlated with FAST stages. No association with function or global cognition was observed for leptin and IL-6 levels. However, women presented higher leptin serum levels than men while lower leptin and IL-6 levels were observed in individuals aged ≥59â¯years. Our results suggest that TNF-α is associated with cognitive and functional decline and that inflammation could be a substrate of cognitive impairment at early clinical stages of dementia.
Assuntos
Envelhecimento/sangue , Doença de Alzheimer/sangue , Proteína C-Reativa/metabolismo , Disfunção Cognitiva/sangue , Interleucina-6/sangue , Leptina/sangue , Fator de Necrose Tumoral alfa/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: Sebaceous carcinomas are uncommon malignant cutaneous tumours originating from the pilosebaceous unit. Although its occurrence is mostly common in peri-ocular glands, other anatomical regions of the head and neck may be affected, including major and minor salivary glands. METHODS AND RESULTS: We describe a series of sebaceous adenocarcinomas of the parotid and submandibular glands. The mean age was 62.1 (range = 31-90) years. Two patients (20%) presented regional or distant metastasis to mandible and lungs. All cases were positive for cytokeratins (AE1AE3 and CK-5), epithelial membrane antigen and adipophilin and negative for androgen receptor, Factor XIIIa, S-100, vimentin and perforin. MLH1 and MSH2 were expressed in the nuclei of most tumour cells, and one case showed loss of MSH2 expression. Proliferative index (assessed by Ki-67 expression) and microvessel density (CD34-positive vessels) were higher in metastasis-associated cases. P63 expression was noted in the periphery of the tumour nests, in the basaloid cells, with a mean of 69.2% nuclear positivity. CONCLUSIONS: The sebaceous adenocarcinoma of salivary glands is rare and may show an unfavourable outcome; therefore, its correct diagnosis may be challenging. For this reason, immunohistochemical studies, including adipophilin in particular, constitute an important diagnostic tool.
Assuntos
Adenocarcinoma Sebáceo/patologia , Neoplasias Parotídeas/patologia , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias da Glândula Submandibular/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: To investigate the frequency of the cytokine single nucleotide polymorphisms (SNPs) tumor necrosis factor (TNF)-α -308G > A, tumor growth factor (TGF)-ß1 codon +10C > T, TGF-ß1 codon +25G > C, interleukin (IL)-10 -1082A > G, IL-10 -819C > T, IL-10 -592C > A, IL-6 -174G > C, and IFN-γ +874T > A in a sample of healthy and cognitively impaired elderlies and to verify the probable association between these SNPs and cognitive and functional performance of subjects aged 75 years and above. METHODS: 259 Brazilian subjects were included, comprising 81 with cognitive impairment no dementia (CIND) and 54 demented seniors (together made up the cognitively impaired group, CI) and 124 age-matched and gender-matched cognitively healthy controls (CHS). The genotyping was performed by multiplex polymerase chain reaction. The cognitive performance was evaluated by Mini-Mental State Examination Brief Cognitive Screening Battery. The functional performance was accessed by Functional Activities Questionnaire. RESULTS: The CClower genotype of TGF-ß1 codon +25G > C was frequent in both patient groups. The TThigher genotype of INF-γ +874T > A was less frequent in the dementia group. IL-10 haplotypes of lower expression were more frequent among CIND and demented patients. In CI, individuals with genetic variants that produce higher expression of TGF-ß1, INF-γ, and IL-10 showed better normalized cognitive performance. Additionally, the Alower allele of INF-γ +874T > A was related to worse functional performance in CI, while the Alower allele of TNF-α -308G > A was associated with better cognitive and functional scores in the CIND group. CONCLUSIONS: Our findings suggest a potential role for certain cytokine SNPs in the development of CIND and dementia, which may influence the functional and cognitive performance of these patients. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Disfunção Cognitiva/genética , Citocinas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Alelos , Brasil , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Interferon gama/genética , Interleucina-10/genética , Interleucina-6/genética , Masculino , Fator de Crescimento Transformador beta1/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Population aging is a global phenomenon whose main consequence is the increase of chronic degenerative diseases, including dementia. The aim of this case-control study was to evaluate the laboratorial parameters lipid profile, cortisol, and apolipoprotein E (APOE) gene genotype, comparing cognitively healthy controls and subjects with cognitive impairment no dementia (CIND) and dementia in a group of elderly people. METHODS: Three hundred and nine individuals enrolled in the Pietà Study (Brazil) were divided into three groups: control (n = 158), CIND (n = 92), and dementia (n = 59). Participants were interviewed, went through examination, and had blood samples taken. RESULTS: Age and APOE showed significant differences among the groups, while sex and lipid profile did not. According to multivariate regression logistic analyses, higher cortisol levels, lower high-density lipoprotein (HDL-c) and very low-density lipoprotein (VLDL-c), presence of ε4 allele of APOE, and aging were associated with CIND and dementia. CONCLUSION: These laboratorial parameters are risk factors associated to CIND and dementia in the elderly people and should be investigated in order to develop strategies to prevent or delay the onset of dementia in the oldest-old populations.
Assuntos
Apolipoproteínas E/genética , Transtornos Cognitivos , Demência/complicações , Hidrocortisona/sangue , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Brasil , Estudos de Casos e Controles , Transtornos Cognitivos/sangue , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genótipo , Avaliação Geriátrica , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Estudos Retrospectivos , Fatores de Risco , Estatísticas não ParamétricasRESUMO
Interleukin 6 (IL-6) is a pro-inflammatory cytokine upregulated in neurodegenerative contexts. The polymorphism IL-6 -174 G > C influences release levels of this cytokine. We aimed to evaluate the influence of IL-6 -174 G > C on global cognitive score of a group with cognitive impairment no dementia in one year of follow-up.Methods The subjects were categorized in two groups: short-term decline in global cognitive score and those with short-term stability or improvement. IL-6 174 G > C information were compared among these groups.Results We observed that individuals with cognitive impairment no dementia with GGlowergenotype were more frequent among global cognitive score non-decliners while carriers of at least one Chigherallele were more frequent in the group with global cognitive score decliners (p = 0.012; RR = 3.095 IC95%= 1.087-8.812).Conclusion These results suggest that the higher expression of IL-6 gene may be an independent risk factor for cognitive decline among individuals with cognitive impairment no dementia.
Interleucina 6 (IL-6) é uma citocina pró-inflamatória cuja produção acentua-se em contextos neurodegenerativos. O polimorfismo IL-6 -174 G > C influencia os níveis secretados deste mediador inflamatório. Nós objetivamos avaliar a influência de IL-6 -174 G > C sobre o escore cognitivo global de um grupo com comprometimento cognitivo não demência em um ano de seguimento.Métodos Os participantes foram categorizados em dois grupos: com declínio em escore cognitivo global em curto prazo e aqueles com melhora ou estabilidade do escore cognitivo global.Resultados Nós observamos que indivíduos com comprometimento cognitivo não demência carreadores do genótipo GGbaixa foram mais frequentes entre pacientes com escore cognitivo global não declinante, enquanto carreadores de no mínimo um alelo Caltaforam mais frequentes no grupo que apresentou declínio no escore cognitivo global (p = 0,012; RR = 3,095 IC95%= 1,087-8,812).Conclusão Estes resultados sugerem que a alta expressão do gene IL-6 pode ser um fator de risco independente para declínio cognitivo entre pacientes com comprometimento cognitivo não demência.
Assuntos
Idoso , Feminino , Humanos , Masculino , Transtornos Cognitivos/genética , Predisposição Genética para Doença , /biossíntese , /genética , Polimorfismo de Nucleotídeo Único , Fatores Etários , Transtornos Cognitivos/metabolismo , Estudos de Associação Genética , Técnicas de Genotipagem , /sangue , Testes Neuropsicológicos , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Interleukin 6 (IL-6) is a pro-inflammatory cytokine upregulated in neurodegenerative contexts. The polymorphism IL-6 -174 G > C influences release levels of this cytokine. We aimed to evaluate the influence of IL-6 -174 G > C on global cognitive score of a group with cognitive impairment no dementia in one year of follow-up.Methods The subjects were categorized in two groups: short-term decline in global cognitive score and those with short-term stability or improvement. IL-6 174 G > C information were compared among these groups.Results We observed that individuals with cognitive impairment no dementia with GGlowergenotype were more frequent among global cognitive score non-decliners while carriers of at least one Chigherallele were more frequent in the group with global cognitive score decliners (p = 0.012; RR = 3.095 IC95%= 1.087-8.812).Conclusion These results suggest that the higher expression of IL-6 gene may be an independent risk factor for cognitive decline among individuals with cognitive impairment no dementia.
Assuntos
Transtornos Cognitivos/genética , Predisposição Genética para Doença , Interleucina-6/biossíntese , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Fatores Etários , Idoso , Transtornos Cognitivos/metabolismo , Feminino , Estudos de Associação Genética , Técnicas de Genotipagem , Humanos , Interleucina-6/sangue , Masculino , Testes Neuropsicológicos , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Inflammation and cytokine production are a common finding in aging, which probably exert influence on cognitive and functional abilities in elderly people. Transforming-growth-factor beta 1 (TGF-ß1) is an important multifunctional anti-inflammatory cytokine that displays immunomodulatory activities. OBJECTIVE: This prospective investigation aimed to evaluate the TGF-ß1 codon 10 T>C on functional and cognitive decline in subjects aged 75+ years. METHODS: The Functional Activities Questionnaire evaluated the functional performance and the cognitive assessment was evaluated through brief cognitive tests, consisting of: the Mini-Mental State Examination, animal category fluency test, and picture drawings memory test. All tests were administered twice, with a one-year interval. RESULTS: Carriers of Tlower allele showed significant short-term decline in cognitive and functional performance, while individuals with CChigher genotype of TGF-ß1 codon 10 T>C remained stable or showed improvement. CONCLUSION: Our findings indicate that the lower production of TGF-ß1 could predict a longitudinal functional and cognitive decline in oldest-old individuals.
Assuntos
Envelhecimento/genética , Envelhecimento/psicologia , Cognição , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fator de Crescimento Transformador beta1/genética , Idoso , Brasil/epidemiologia , Códon , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/genética , Progressão da Doença , Seguimentos , Heterozigoto , Humanos , Estudos Longitudinais , Entrevista Psiquiátrica Padronizada , Estudos Prospectivos , Testes PsicológicosRESUMO
Type 2 diabetes mellitus (DM2) is a metabolic disorder associated with hyperactivation of platelets, increased formation of platelet microparticles (PMPs) and oxidative stress that are related to cardiovascular complications. Acetylsalicylic acid (ASA) is an antiplatelet agent used in the prevention of atherothrombosis. The aim of this study was to evaluate the effect of ASA by means of platelet activation and oxidative profile. We collected blood samples of 81 patients with DM2 before and during ASA treatment. These samples were analyzed to determine the levels of 2,3-dinor thromboxane-B2 (2,3-dinor-TXB2), PMPs, thiobarbituric acid reactive species (TBARS) and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT). Moreover, the relationship between the levels of 2,3-dinor-TXB2 with some clinical and laboratory variables such as glycated hemoglobin, platelet count, D dimer, low-density lipoprotein cholesterol and glycoprotein IIb/IIIa and cyclooxygenase-1 polymorphisms was evaluated. ASA intake did not change the levels of PMP, TBARS and MTT. Although a significant decrease in the levels of 2,3 dinorTXB2 (Pâ<â0.001) in patients under ASA has been observed, an equal and satisfactory response to this drug was not found. However, the presence of PIA2 allele in GPIIIa gene may be associated with a better response to ASA intake in these patients, whereas other clinical and laboratory variables showed no association with this drug use. These findings are consistent with previous reports in the literature that patients with DM2 do not benefit in an equal way from the use of ASA for primary prevention of atherothrombotic events.
Assuntos
Aspirina/farmacologia , Diabetes Mellitus Tipo 2/sangue , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Tromboxanos/metabolismo , Brasil , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacosRESUMO
Apolipoprotein gene polymorphism has an important role in lipid metabolism and in the development of cerebro- and cardio-vascular disease (CCVD), including dementia. Dyslipidemia and hemostatic abnormalities are key risk factors associated with athero-sclerotic events preceding CCVD. The aim of this study was to evaluate the possible relationships of various apolipoprotein-species with hemostatic parameters and cognitive function. Lipid profile, gene polymorphism, coagulation markers, and mini-mental state examination (MMSE) scores were assessed in 109 dys-lipidemic subjects and in 107 healthy control volunteers. Thrombin-activatable fibrinolysis inhibitor (TAFI) plasma levels were significantly higher in apolipoprotein-E2 (apoE2) patients when compared to other apoE forms. The apoA5 -1131T>C polymorphism was associated with elevated D-dimer concentration in dyslipidemic TT homozygous individuals. MMSE did not correlate with lipid or coagulation profile. These data suggest that apoE and apoA5 variants have an effect on hemostatic parameters, but they neither influence nor predict cognitive performance in non-demented individuals.
Assuntos
Apolipoproteínas A/genética , Apolipoproteínas E/genética , Dislipidemias/complicações , Predisposição Genética para Doença , Polimorfismo Genético , Trombose/epidemiologia , Trombose/genética , Adulto , Apolipoproteína A-V , Demência/epidemiologia , Demência/genética , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Dyslipidemia, a metabolic alteration that affects lipoprotein levels, is considered a major risk factor for atherosclerosis and its complications. Dyslipidemia also affects the hemostatic system, especially impairing fibrinolysis, and increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) have been associated with cardiovascular events. OBJECTIVES AND METHODS: This study evaluated the association of acquired risk factors (hypertension, body mass index - BMI, smoking, sedentary lifestyle, use or not of oral contraceptives and hormone replacement therapy, and post-menopause status), the polymorphisms Thr325Ile (rs1926447), Ala147Thr (rs3742264) and +1542C/G (rs940) in the TAFI gene, and TAFI plasma levels in 109 dyslipidemic and 105 normolipemic individuals. Biochemical analyses and TAFI levels were evaluated by colorimetric/turbidimetric assays and ELISA, respectively. Genotypic and allelic frequencies were determined by polymerase chain reaction (PCR). RESULTS: Hypertension, increased BMI, and menopause were more common in dyslipidemic individuals, who had higher TAFI levels. The alleles 325Ile, Ala147, and C showed association with lower TAFI levels. The rs3742264 polymorphism was associated with dyslipidemia in males. CONCLUSIONS: The results suggest that TAFI levels are independently associated to dyslipidemia and that the polymorphism rs3742264 may be related to cardiovascular risk in male subjects.