RESUMO
COVID-19 is pandemic since 2020 and further information is necessary on the risk factors associated with the infection of SARS-CoV-2. As an entry mechanism, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as receptor and transmembrane serine protease 2 (TMPRSS2) to activate fusion with host plasma membrane. Because dysgeusia is an early symptom of COVID-19, we here studied the expression of ACE2 and TMPRSS2 in the tongue and the associated tissues of mice and humans with immunohistochemistry and immunoblot analysis. ACE2 expression was low in the human tongue but was observed in the squamous epithelium, perineurium, arterial wall, salivary glands as well as taste buds. In contrast, mice showed high expression. In sharp contrast, TMPRSS2 expression was high in all the cells mentioned above in humans but relatively low in mice except for salivary glands. We then performed semi-quantitation of immunohistochemistry data of human ACE2 and TMPRSS2 and analyzed for age, sex, alcohol intake, and smoking habit with logistic regression analysis. We found that alcohol intake and female gender were the significant risk factors for increasing TMPRSS2 expression. In conclusion, TMPRSS2 is an important factor to be considered regarding SARS-CoV-2 entry and amplification in the oral cavity, which is promoted through drinking habit.
RESUMO
Maffucci syndrome, first described in 1881, is a rare, non-hereditary skeletal disorder characterized by multiple enchondromas in combination with soft tissue hemangiomas. Recent studies have implicated somatic mutations in IDH1/2 contributing to the pathogenesis of Maffucci syndrome. This study describes the first case of Maffucci syndrome harboring a mutation in IDH1, which was associated with a hemangioma in the oral mucosa. A 32-year-old man, who was diagnosed with Maffucci syndrome during childhood, was referred to our department in April 2020 due to a mass in the left buccal mucosa. The mass was soft, dome-shaped, had dark red protrusions and well-defined borders, and the dimensions were approximately 15 × 10 mm. Magnetic resonance imaging revealed a mass with a dimension of 13 × 10 mm, which appeared hyperintense on T2-weighted images. The vascular lesion was surgically resected under local anesthesia owing to hemangioma diagnosis. We then analyzed the IDH1/2 sequences using DNA extracted from the excised tumor tissue and peripheral blood. The analysis revealed the presence of a heterozygous mutation in IDH1 in the tumor tissue, corresponding to an R132C substitution. The mutation was not present in peripheral blood DNA. After over one year of resection, the patient is presently free from tumor recurrence and is under follow-up for the early detection of recurrent hemangioma.
Assuntos
Encondromatose , Hemangioma , Adulto , Encondromatose/diagnóstico por imagem , Encondromatose/genética , Hemangioma/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Mucosa Bucal/patologia , Mutação , Recidiva Local de NeoplasiaRESUMO
OBJECTIVE: Owing to variations in the exterior appearances of noncancerous diseases in the oral cavity, clinicians may have difficulty diagnosing oral squamous cell carcinoma (OSCC). Tissue biopsy is confirmatory, but invasive. Therefore, reliable tumor markers for OSCC are required. Here, exosomal Alix (exoAlix) levels were measured in serum/salivary samples from patients with OSCC and healthy controls (HCs). METHODS: Fifty-seven patients admitted to Nagoya University Hospital from 2017 through 2019 were enrolled, and serum samples (OSCC, n = 29; HC, n = 21) and/or saliva samples (OSCC, n = 23; HC, n = 20) were collected. Exosomal fractions were isolated using ultracentrifugation. ExoAlix levels were measured using enzyme-linked immunosorbent assay. RESULTS: Serum/salivary exoAlix levels were significantly higher in patients with OSCC than in HCs. Receiver operating characteristic analyses revealed that sensitivity, specificity, positive predictive value, and area under the curve were 0.345, 1.000, 1.000, and 0.685, respectively, for serum exoAlix and 0.348, 1.000, 1.000, and 0.712, respectively, for salivary exoAlix at optimal cut-off values (serum, 0.205; saliva, 0.193). All tested OSCC tissue sections (n = 21) were immuno-reactive for Alix. CONCLUSION: Serum and salivary exoAlix were identified as potential diagnostic OSCC biomarkers. Serum exoAlix was suitable for prediction of therapeutic responses.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Biomarcadores Tumorais , Carcinoma de Células Escamosas/diagnóstico , Humanos , Neoplasias Bucais/diagnóstico , Saliva , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Previous studies have shown that dissolved substances in some natural hot springs have analgesic/anti-nociceptive and anti-inflammatory actions. However, the mechanisms underlying how such dissolved substances exert these actions are not fully understood. In the present study on mice, we examined the analgesic/anti-nociceptive and anti-inflammatory properties of a mineral cream containing natural hot spring ingredients. The anti-nociceptive effects of the mineral cream were assessed by using the von Frey test. Application of the mineral cream to the hind paw of mice produced a significant anti-nociceptive effect compared to control. The anti-nociceptive effects of the mineral cream were also assessed following the injection of complete Freund's adjuvant (CFA) into the hind paws of mice after pre-treatment for one or four weeks with the mineral cream. Histological experiments with light microscopy showed that the mineral cream did not reduce inflammation caused by the CFA treatment. In addition, the mineral cream did not inhibit oxidative stress as evidenced by increased levels of oxidative metabolites (d-ROMs) and biological anti-oxidant potential (BAP). These results suggest that the mineral cream does not exert a protective effect against inflammation, and that the constituents of the mineral cream may produce their anti-nociceptive effects transdermally via different mechanisms including the nervous system.
Assuntos
Analgésicos/farmacologia , Balneologia , Minerais/farmacologia , Creme para a Pele/farmacologia , Analgésicos/farmacocinética , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Minerais/farmacocinética , Creme para a Pele/farmacocinéticaRESUMO
The 5-HT5A receptor is arguably the least understood 5-HT receptor. Despite widespread expression in human and rodent brains it lacks specific ligands. Our previous results suggest that 5-HT5A receptor antagonists may be effective against cognitive impairment in schizophrenia. In this study, using behavioral, immunohistochemical, electrophysiological and microdialysis techniques, we examined the mechanism by which ASP5736, a novel and selective 5-HT5A receptor antagonist, exerts a positive effect in animal models of cognitive impairment. We first confirmed the effect of ASP5736 on cognitive deficits in rats treated subchronically with phencyclidine hydrochloride (PCP) using an attentional set shifting task. Subsequently, we identified 5-HT5A receptors in dopaminergic (DAergic) neurons and parvalbumin (PV)-positive interneurons in the ventral tegmental area (VTA) and in PV-positive interneurons in the medial prefrontal cortex (mPFC). Burst firing of the DAergic cells in the parabrachial pigmental nucleus (PBP) in the VTA, which predominantly project to the mPFC, was significantly enhanced by treatment with ASP5736. In contrast, ASP5736 exerted no significant effect on either the firing rate or burst firing in the DA cells in the paranigral nucleus (PN), that project to the nucleus accumbens (N. Acc.). ASP5736 increased the release of DA and gamma-aminobutyric acid (GABA) in the mPFC of subchronically PCP-treated rats. These results support our hypothesis that ASP5736 might block the inhibitory 5-HT5A receptors on DAergic neurons in the VTA that project to the mPFC, and interneurons in the mPFC, and thereby improve cognitive impairment by preferentially enhancing DAergic and GABAergic neurons in the mPFC.
Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Guanidinas/farmacologia , Isoquinolinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Potenciais de Ação/fisiologia , Animais , Disfunção Cognitiva/induzido quimicamente , Discriminação Psicológica/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Interneurônios/fisiologia , Masculino , Fenciclidina , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Ratos , Psicologia do Esquizofrênico , Antagonistas da Serotonina/farmacologia , Área Tegmentar Ventral/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
OBJECTIVE: The objective of this study is to examine the effect of acarbose, an alpha-glucosidase inhibitor, on body weight in a real-life setting by pooling data from post-marketing surveillance. METHODS: Data from 10 studies were pooled (n=67,682) and the effect of acarbose on body weight was analysed taking into account baseline body weight, glycemic parameters and other baseline characteristics. RESULTS: The mean relative reduction in body weight was 1.45 ± 3.24% at the 3-month visit (n=43,510; mean baseline 73.4 kg) and 1.40 ± 3.28% at the last visit (n=54,760; mean baseline 73.6 kg) (both p<0.0001). These reductions were dependent on baseline body weight (overweight: -1.33 ± 2.98% [n=13,498; mean baseline 71.6 kg]; obese: -1.98 ± 3.40% [n=20,216; mean baseline 81.3 kg]). When analysed by baseline glycemic parameter quartiles, the reduction was independent of fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbA1c) and postprandial glucose excursion (PPGE). A bivariate analysis of covariance identified female sex, South East Asian and East Asian ethnicity, younger age, higher body mass index, short duration of diabetes, and no previous treatment as factors likely to impact positively on body weight reduction with acarbose. CONCLUSIONS: This post-hoc analysis showed that acarbose treatment reduces body weight independent of glycemic control status but dependent on baseline body weight.
Assuntos
Acarbose/uso terapêutico , Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Saúde Global , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Acarbose/efeitos adversos , Fatores Etários , Fármacos Antiobesidade/efeitos adversos , Povo Asiático , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Saúde Global/etnologia , Inibidores de Glicosídeo Hidrolases/efeitos adversos , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/etnologia , Estudos Observacionais como Assunto , Sobrepeso/complicações , Sobrepeso/etnologia , Vigilância de Produtos Comercializados , Caracteres Sexuais , Redução de Peso/efeitos dos fármacosRESUMO
Metal dental restoration materials cause dose enhancement upstream and dose disturbance downstream of the high-density inhomogeneous regions in which these materials are used. In this study, we evaluated the impact of a dental metallic crown (DMC) on intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) for head and neck cancer. Additionally, the possibility of sparing the oral mucosa from dose enhancement using an individual intraoral mouthpiece was evaluated. An experimental oral phantom was designed to verify the dosimetric impact of a DMC. We evaluated the effect on single beam, parallel opposing beam, arc beam, IMRT, and VMAT treatment plans. To evaluate the utility of a 3-mm-thick intraoral mouthpiece, the doses across the mouthpiece were measured. For single beam irradiation, the measured doses at the entrance and exit planes of the DMC were 51% higher and 21% lower than the calculated dose by the treatment planning system, respectively. The maximum dose enhancements were 22% and 46% for parallel opposing beams and the 90° arc rotation beam, respectively. For IMRT and VMAT, the measured doses adjacent to the DMC were 12.2% ± 6.3% (mean ± 1.96SD) and 12.7% ± 2.5% higher than the calculated doses, respectively. With regard to the performance of the intraoral mouthpiece for the IMRT and VMAT cases, the disagreement between measured and calculated doses at the outermost surface of the mouthpieces were -2.0%, and 2.0%, respectively. Dose enhancements caused by DMC-mediated radiation scattering occurred during IMRT and VMAT. Because it is difficult to accurately estimate the dose perturbations, careful consideration is necessary when planning head and neck cancer treatments in patients with DMCs. To spare the oral mucosa from dose enhancement, the use of an individual intraoral mouthpiece should be considered.
Assuntos
Coroas/efeitos adversos , Neoplasias de Cabeça e Pescoço/radioterapia , Imagens de Fantasmas , Planejamento da Radioterapia Assistida por Computador/normas , Radioterapia de Intensidade Modulada/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Boca/efeitos da radiação , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodosRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and chronic inflammation, which lead to the progressive destruction of cartilage and bone in the joints. Numerous studies have reported that administrations of various types of MSCs improve arthritis symptoms in animal models, by paracrine mechanisms. However, the therapeutic effects of the secreted factors alone, without the cell graft, have been uncertain. Here, we show that a single intravenous administration of serum-free conditioned medium (CM) from human deciduous dental pulp stem cells (SHED-CM) into anti-collagen type II antibody-induced arthritis (CAIA), a mouse model of rheumatoid arthritis (RA), markedly improved the arthritis symptoms and joint destruction. The therapeutic efficacy of SHED-CM was associated with an induction of anti-inflammatory M2 macrophages in the CAIA joints and the abrogation of RANKL expression. SHED-CM specifically depleted of an M2 macrophage inducer, the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9), exhibited a reduced ability to induce M2-related gene expression and attenuate CAIA. SHED-CM also inhibited the RANKL-induced osteoclastogenesis in vitro. Collectively, our findings suggest that SHED-CM provides multifaceted therapeutic effects for treating CAIA, including the ED-Siglec-9-dependent induction of M2 macrophage polarization and inhibition of osteoclastogenesis. Thus, SHED-CM may represent a novel anti-inflammatory and reparative therapy for RA.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Polpa Dentária/citologia , Células-Tronco/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anticorpos , Antígenos CD/metabolismo , Criança , Colágeno Tipo II/imunologia , Meios de Cultivo Condicionados/química , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Injeções Intravenosas , Articulações/efeitos dos fármacos , Articulações/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismoRESUMO
Exosomes are 50-100-nm-diameter membrane vesicles released from various types of cells. Exosomes retain proteins, mRNAs and miRNAs, which can be transported to surrounding cells. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, and is released from the cell surface to the culture medium in vitro. Recently, it was reported that secreted CD109 from the cell surface downregulates transforming growth factor-ß signaling in human keratinocytes. In this study, we revealed that CD109 is a component of the exosome in conditioned medium. FLAG-tagged human CD109 (FLAG-CD109) in conditioned medium secreted from HEK293 cells expressing FLAG-CD109 (293/FLAG-CD109) was immunoprecipitated with anti-FLAG affinity gel, and the co-precipitated proteins were analyzed by mass spectrometry and western blotting. Exosomal proteins were associated with CD109. We revealed the presence of CD109 in exosome fractions from conditioned medium of 293/FLAG-CD109. Moreover, the localization of CD109 in the exosome was demonstrated using immuno-electron microscopy. When we used HEK293 cells expressing FLAG-tagged truncated CD109, which does not contain the C-terminal region, the association of truncated CD109 with exosomes was not detected in conditioned medium. These findings indicate that CD109 is an exosomal protein and that the C-terminal region of CD109 is required for its presence in the exosome.
Assuntos
Antígenos CD/química , Meios de Cultura/metabolismo , Exossomos/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/metabolismo , Células HEK293 , Humanos , Relação Estrutura-AtividadeRESUMO
Stem cells from human exfoliated deciduous teeth (SHEDs) can regenerate various tissues. We investigated the impact of SHED-conditioned medium (SHED-CM) on myocardial injury in a mouse model of ischemia-reperfusion (I/R). Wild-type (WT) mice were subjected to myocardial ischemia followed by reperfusion. SHED-CM was intravenously injected at 5 min after reperfusion. Administration of SHED-CM reduced myocardial infarct size as well as decreased apoptosis and inflammatory cytokine levels, such as TNF-α, IL-6, and IL-ß, in the myocardium following I/R. In cultured cardiac myocytes, SHED-CM significantly suppressed apoptosis under hypoxia/serum-deprivation and reduced LPS-induced expression of pro-inflammatory genes. Furthermore, anti-apoptotic action of SHED-CM was stronger than bone marrow-derived stem cell (BMSC)-CM or adipose-derived stem cell (ADSC)-CM in cardiac myocytes. SHED-CM contains a higher concentration of hepatocyte growth factor (HGF) than BMSC-CM and ADSC-CM, and neutralization of HGF attenuated the inhibitory actions of SHED-CM on apoptosis in cardiac myocytes. Finally, WT mice were intravenously treated with an HGF-depleted SHED-CM, followed by myocardial I/R. HGF depletion significantly attenuated the inhibitory actions of SHED-CM on myocardial infarct size and apoptosis after I/R. SHED-CM protects the heart from acute ischemic injury because it suppresses inflammation and apoptosis. SHED-CM could be a useful treatment option for acute myocardial infarction.
Assuntos
Polpa Dentária/citologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão , Células-Tronco/citologia , Animais , Apoptose , Meios de Cultivo Condicionados , CamundongosRESUMO
Oxidative stress and the ubiquitin-proteasome system play a key role in the pathogenesis of Parkinson disease. Although the herbicide paraquat is an environmental factor that is involved in the etiology of Parkinson disease, the role of 26S proteasome in paraquat toxicity remains to be determined. Using PC12 cells overexpressing a fluorescent protein fused to the proteasome degradation signal, we report here that paraquat yielded an inhibitory effect on 26S proteasome activity without an obvious decline in 20S proteasome activity. Relative low concentrations of proteasome inhibitors caused the accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is targeted to the ubiquitin-proteasome system, and activated the antioxidant response element (ARE)-dependent transcription. Paraquat also upregulated the protein level of Nrf2 without increased expression of Nrf2 mRNA, and activated the Nrf2-ARE pathway. Consequently, paraquat induced expression of Nrf2-dependent ARE-driven genes, such as γ-glutamylcysteine synthetase, catalase, and hemeoxygenase-1. Knockdown of Nrf2 or inhibition of γ-glutamylcysteine synthetase and catalase exacerbated paraquat-induced toxicity, whereas suppression of hemeoxygenase-1 did not. These data indicate that the compensatory activation of the Nrf2-ARE pathway via inhibition of 26S proteasome serves as part of a cellular defense mechanism to protect against paraquat toxicity.
Assuntos
Elementos de Resposta Antioxidante/fisiologia , Herbicidas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Paraquat/farmacologia , Complexo de Endopeptidases do Proteassoma/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Animais , Elementos de Resposta Antioxidante/genética , Catalase/fisiologia , Glutamato-Cisteína Ligase/fisiologia , Células PC12 , Doença de Parkinson/etiologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , RatosRESUMO
BACKGROUND AIMS: Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, resulting from severe, destructive lung inflammation and irreversible lung fibrosis. We evaluated the use of stem cells derived from human exfoliated deciduous teeth (SHEDs) or SHED-derived serum-free conditioned medium (SHED-CM) as treatments for bleomycin (BLM)-induced mice acute lung injury (ALI), exhibiting several pathogenic features associated with the human disease ARDS. METHODS: Mice with BLM-induced ALI with or without SHED or SHED-CM treatment were examined for weight loss and survival. The lung tissue was characterized by histological and real-time quantitative polymerase chain reaction analysis. The effects of SHED-CM on macrophage differentiation in vitro were also assessed. RESULTS: A single intravenous administration of either SHEDs or SHED-CM attenuated the lung injury and weight loss in BLM-treated mice and improved their survival rate. Similar recovery levels were seen in the SHEDs and SHED-CM treatment groups, suggesting that SHED improves ALI by paracrine mechanisms. SHED-CM contained multiple therapeutic factors involved in lung-regenerative mechanisms. Importantly, SHED-CM attenuated the BLM-induced pro-inflammatory response and generated an anti-inflammatory/tissue-regenerating environment, accompanied by the induction of anti-inflammatory M2-like lung macrophages. Furthermore, SHED-CM promoted the in vitro differentiation of bone marrow-derived macrophages into M2-like cells, which expressed high levels of Arginase1, CD206 and Ym-1. DISCUSSION: Our results suggest that SHED-secreted factors provide multifaceted therapeutic effects, including a strong M2-inducing activity, for treating BLM-induced ALI. This work may open new avenues for research on stem cell-based ARDS therapies.
Assuntos
Lesão Pulmonar Aguda/terapia , Polpa Dentária/citologia , Síndrome do Desconforto Respiratório/terapia , Transplante de Células-Tronco , Dente Decíduo/citologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Arginase/metabolismo , Arginase/farmacologia , Bleomicina/farmacologia , Diferenciação Celular , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Polpa Dentária/metabolismo , Feminino , Humanos , Lectinas Tipo C/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Macrófagos/citologia , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Lectinas de Ligação a Manose/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Superfície Celular/metabolismo , Regeneração , Síndrome do Desconforto Respiratório/patologia , Dente Decíduo/metabolismoRESUMO
Despite the human 5-HT5A receptor being cloned in 1994, the biological function of this receptor has not been extensively characterized due to a lack of specific ligands. We recently reported that the selective 5-HT5A receptor antagonist ASP5736 ameliorated cognitive impairment in several animal models of schizophrenia. Given that areas of the brain with high levels of 5-HT5A receptor expression, such as the hippocampus and cerebral cortex, have important functions in cognition and memory, we evaluated the chemically diverse, potent and brain-penetrating 5-HT5A receptor antagonists ASP5736, AS2030680, and AS2674723 in rodent models of cognitive dysfunction associated with dementia. Each of these compounds exhibited a high affinity for recombinant 5-HT5A receptors that was comparable to that of the non-selective ligand of this receptor, lysergic acid diethylamide (LSD). Although each compound had a low affinity for other receptors, 5-HT5A was the only receptor for which all three compounds had a high affinity. Each of the three compounds ameliorated scopolamine-induced working memory deficit in mice and improved reference memory impairment in aged rats at similar doses. Further, ASP5736 decreased the binding of LSD to 5-HT5A receptors in the olfactory bulb of rats in a dose-dependent manner and occupied 15%-50% of brain 5-HT5A receptors at behaviorally effective doses. These results indicate that the 5-HT5A receptor is involved in learning and memory and that treatment with 5-HT5A receptor antagonists might be broadly effective for cognitive impairment associated with not only schizophrenia but also dementia.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/psicologia , Guanidinas/uso terapêutico , Isoquinolinas/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Receptores de Serotonina/metabolismo , Escopolamina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Envelhecimento , Animais , Encéfalo/metabolismo , Transtornos Cognitivos/induzido quimicamente , Demência/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Guanidinas/farmacologia , Isoquinolinas/farmacologia , Dietilamida do Ácido Lisérgico/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Camundongos Endogâmicos , Bulbo Olfatório/metabolismo , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/farmacologiaRESUMO
BACKGROUND: Alpha-glucosidase inhibitors are recommended in some international guidelines as first-line, second-line and third-line treatment options but are not used worldwide due to perceived greater effectiveness in Asians than Caucasians. METHODS: Data from ten post-marketing non-interventional studies using acarbose, the most widely used alpha-glucosidase inhibitor, from 21 countries, provinces and country groups were pooled. Effects on glycated hemoglobin (HbA1c ) were analysed for four major ethnicity/region groups (European Caucasians and Asians from East, Southeast and South Asia) to identify differences in the response to acarbose. RESULTS: The safety and efficacy populations included 67 682 and 62 905 patients, respectively. Mean HbA1c in the total population decreased by 1.12 ± 1.31% at the 3-month visit from 8.4% at baseline (p < 0.0001). Reductions in HbA1c , fasting plasma glucose and post-prandial plasma glucose were greater in patients with higher baseline values. Acarbose was well tolerated, with few episodes of hypoglycemia (0.03%) and gastrointestinal adverse events (2.76%). Data from 30 730 Caucasians from Europe and Asians from three major regions of Asia with non-missing gender/age information and baseline/3-month HbA1c data were analysed by multivariable analyses of covariance. After adjustment for relevant baseline confounding factors, Southeast and East Asians had slightly better responses to acarbose than South Asians and European Caucasians; however, the differences were small. CONCLUSIONS: Acarbose was effective in both European Caucasians and Asians; however, after adjustment for baseline confounding factors, significant small differences in response favoured Southeast and East Asians.
Assuntos
Acarbose/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Resistência a Medicamentos , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Hiperglicemia/prevenção & controle , Acarbose/efeitos adversos , Adulto , Povo Asiático , Glicemia/análise , Estudos de Coortes , Bases de Dados Factuais , Diabetes Mellitus/sangue , Diabetes Mellitus/etnologia , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Inibidores de Glicosídeo Hidrolases/efeitos adversos , Humanos , Masculino , Análise Multivariada , Vigilância de Produtos Comercializados , População BrancaRESUMO
We recently identified ASP5736, (N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide (2E)-but-2-enedioate), a novel antagonist of 5-HT5A receptor, and here describe the in vitro and in vivo characterization of this compound. ASP5736 exhibited a high affinity for the human 5-HT5A receptor (Ki = 3.6 ± 0.66 nM) and antagonized 5-carboxamidotryptamine (5-CT)-induced Ca(2+) influx in human cells stably expressing the 5-HT5A receptor with approximately 200-fold selectivity over other receptors, including other 5-HT receptor subtypes, enzymes, and channels except human 5-HT2c receptor (Ki = 286.8 nM) and 5-HT7 receptor (Ki = 122.9 nM). Further, ASP5736 dose-dependently antagonized the 5-CT-induced decrease in cAMP levels in HEK293 cells stably expressing the 5-HT5A receptor. We then evaluated the effects of ASP5736 on cognitive impairments in several animal models of schizophrenia. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both ameliorated by ASP5736. In addition, ASP5736 also attenuated MK-801- and methamphetamine (MAP)-induced hyperactivity in mice without causing sedation, catalepsy, or plasma prolactin increase. The addition of olanzapine did not affect ASP5736-induced cognitive enhancement, and neither the sedative nor cataleptogenic effects of olanzapine were worsened by ASP5736. These results collectively suggest that ASP5736 is a novel and potent 5-HT5A receptor antagonist that not only ameliorates positive-like symptoms but also cognitive impairments in animal models of schizophrenia, without adverse effects. Present studies also indicate that ASP5736 holds potential to satisfy currently unmet medical needs for the treatment of schizophrenia by either mono-therapy or co-administered with commercially available antipsychotics.
Assuntos
Antipsicóticos/farmacologia , Guanidinas/farmacologia , Isoquinolinas/farmacologia , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Cálcio/metabolismo , Catalepsia/tratamento farmacológico , Catalepsia/fisiopatologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Guanidinas/química , Guanidinas/farmacocinética , Células HEK293 , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Receptor 5-HT2C de Serotonina/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Esquizofrenia/fisiopatologia , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacocinéticaRESUMO
CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is expressed at high levels in some human tumors including squamous cell carcinomas. As CD109 is reportedly cleaved by furin and its soluble form is secreted into culture medium in vitro, we hypothesized that CD109 could serve as a tumor marker in vivo. In this study, we investigated CD109 as a novel serum tumor marker using transgenic mice that overexpress mouse CD109 (mCD109-TG mice) and tumor xenografted mice inoculated with human CD109 (hCD109)-overexpressing HEK293 cells. In sera and urine of mCD109-TG mice, mCD109 was detected using western blotting. In xenografted mice, hCD109 secreted from inoculated tumors was detected in sera, using western blotting and CD109 ELISA. Concentrations of tumor-secreted CD109 increased proportionally as tumors enlarged. Concentrations of secreted CD109 decreased notably by 17 h after tumor resection, and became undetectable 48 h after resection. The half-life of tumor-secreted CD109 was about 5.86±0.17 h. These results indicate that CD109 is present in serum as a soluble form, and suggest its potential as a novel tumor marker in patients with cancers that express CD109.
Assuntos
Antígenos CD/sangue , Proteínas de Neoplasias/sangue , Neoplasias/sangue , Animais , Antígenos CD/genética , Antígenos CD/urina , Modelos Animais de Doenças , Feminino , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/urina , Neoplasias/genética , Neoplasias/patologia , Carga TumoralRESUMO
PURPOSE: Recently, it has been revealed that bone marrow-derived mesenchymal stem cells (MSCs) accelerate the healing of skin wounds. Although the proliferative capacity of MSCs decreases with age, MSCs secrete many growth factors. The present study examined the effect of mesenchymal stem cell-conditioned medium (MSC-CM) on wound healing. MATERIALS AND METHODS: The wound-healing process was observed macroscopically and histologically using an excisional wound-splinting mouse model, and the expression level of hyaluronic acid related to the wound healing process was observed to evaluate the wound-healing effects of MSC, MSC-CM, and control (phosphate-buffered saline). RESULTS: The MSC and MSC-CM treatments accelerated wound healing versus the control group. At 7 days after administration, epithelialization was accelerated, thick connective tissue had formed in the skin defect area, and the wound area was reduced in the MSC and MSC-CM groups versus the control group. At 14 days, infiltration of inflammatory cells was decreased versus 7 days, and the wounds were closed in the MSC and MSC-CM groups, while a portion of epithelium was observed in the control group. At 7 and 14 days, the MSC and MSC-CM groups expressed significantly higher levels of hyaluronic acid versus the control group (P < .05). The expression level of hyaluronic acid was lower at 14 days than at 7 days in all three groups. CONCLUSIONS: Both the MSC and MSC-CM groups accelerated wound healing versus the control group to a similar degree. Accordingly, it is suggested that the MSC-CM contains growth factor derived from stem cells, is able to accelerate wound healing as well as stem cell transplantation, and may become a new therapeutic method for wound healing in the future.
Assuntos
Meios de Cultivo Condicionados , Ácido Hialurônico/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Células-Tronco Mesenquimais/metabolismo , Pele/lesões , Cicatrização/fisiologia , Animais , Meios de Cultivo Condicionados/química , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Nus , Distribuição Aleatória , Fatores de TempoRESUMO
Expression and implication of carbohydrate antigens in squamous cell carcinomas (SCCs) in oral cavity was examined. In the cell lines, type 2H and Lewis y antigens were markedly expressed. In the tissues from SCC patients and benign disorders, type 2H was highly expressed in hyperplasia (96.4 %), displasia (92.9 %) and SCC (100 %). Lewis y was, in turn, expressed mainly in cancer tissues (91.3 %), suggesting that Lewis y is a cancer-associated antigen. Normal oral mucosa showed no expression of these blood group antigens. Surprisingly, Lewis y antigen disappeared in the invasion sites where Ki-67 was definitely stained. Over-expression of Lewis y with manipulation of a fucosyltransferase cDNA resulted in suppression of cell growth and invasion, and knockdown of Lewis y also brought about increased cell growth and invasion. In either situations, no changes in the expression of sialyl-Lewis x could be found. Lowered tumor growth and invasion into surrounding tissues were also shown in Lewis y-positive SCC grafts in nu/nu mice. All these results together with alternative staining between Lewis y and Ki-67 in cancer tissues and FUT1 transfectants suggested that loss of Lewis y is a crucial event for the late stage of SCCs.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Antígenos do Grupo Sanguíneo de Lewis/metabolismo , Neoplasias Bucais/metabolismo , Oligossacarídeos/metabolismo , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Linhagem Celular Tumoral , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Antígenos do Grupo Sanguíneo de Lewis/genética , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Neoplasias Bucais/genética , Neoplasias Bucais/imunologia , Invasividade Neoplásica , Transplante de Neoplasias , Oligossacarídeos/genética , Especificidade de Órgãos , Antígeno Sialil Lewis X , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
BACKGROUND: The efficacy of concurrent intra-arterial infusion chemoradiotherapy for adenoid cystic carcinoma (ACC) has been described in only a few reports. Herein, we report on 2 patients with unresectable ACC of the maxillary sinus treated with this approach. METHODS: Patients received concurrent chemoradiotherapy. External beam radiation was administered 5 times a week at 2 Gray (Gy) per fraction for a total of 60 Gy. Chemotherapy consisting of docetaxel and cisplatin was administered by superselective intra-arterial infusion via a superficial temporal artery. RESULTS: After the completion of all treatments in both patients, biopsy specimens of the primary lesions showed complete disappearance of all viable and nonviable tumor cells and new bone formation at the bony walls of the maxillary sinus. Although complications such as mucositis, neutropenia, and anorexia were observed, they were well-tolerated and manageable. CONCLUSION: Concurrent chemoradiotherapy using superselective intra-arterial infusion is a potential option for patients with unresectable maxillary ACC.