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1.
Mol Pharmacol ; 103(3): 166-175, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36804202

RESUMO

Mucin 1 (MUC1) is aberrantly expressed in various cancers and implicated in cancer progression and chemoresistance. Although the C-terminal cytoplasmic tail of MUC1 is involved in signal transduction, promoting chemoresistance, the role of the extracellular MUC1 domain [N-terminal glycosylated domain (NG)-MUC1] remains unclear. In this study, we generated stable MCF7 cell lines expressing MUC1 and cytoplasmic tail-deficient MUC1 (MUC1ΔCT) and show that NG-MUC1 is involved in drug resistance by modulating the transmembrane permeation of various compounds without cytoplasmic tail signaling. Heterologous expression of MUC1ΔCT increased cell survival in treating anticancer drugs (such as 5-fluorouracil, cisplatin, doxorubicin, and paclitaxel), in particular by causing an approximately 150-fold increase in the IC50 of paclitaxel, a lipophilic drug, compared with the control [5-fluorouracil (7-fold), cisplatin (3-fold), and doxorubicin (18-fold)]. The uptake studies revealed that accumulations of paclitaxel and Hoechst 33342, a membrane-permeable nuclear staining dye, were reduced to 51% and 45%, respectively, in cells expressing MUC1ΔCT via ABCB1/P-gp-independent mechanisms. Such alterations in chemoresistance and cellular accumulation were not observed in MUC13-expressing cells. Furthermore, we found that MUC1 and MUC1ΔCT increased the cell-adhered water volume by 2.6- and 2.7-fold, respectively, suggesting the presence of a water layer on the cell surface created by NG-MUC1. Taken together, these results suggest that NG-MUC1 acts as a hydrophilic barrier element against anticancer drugs and contributes to chemoresistance by limiting the membrane permeation of lipophilic drugs. Our findings could help better the understanding of the molecular basis of drug resistance in cancer chemotherapy. SIGNIFICANCE STATEMENT: Membrane-bound mucin (MUC1), aberrantly expressed in various cancers, is implicated in cancer progression and chemoresistance. Although the MUC1 cytoplasmic tail is involved in proliferation-promoting signal transduction thereby leading to chemoresistance, the significance of the extracellular domain remains unclear. This study clarifies the role of the glycosylated extracellular domain as a hydrophilic barrier element to limit the cellular uptake of lipophilic anticancer drugs. These findings could help better the understanding of the molecular basis of MUC1 and drug resistance in cancer chemotherapy.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Mucina-1/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Membrana Celular/metabolismo , Paclitaxel/farmacologia , Fluoruracila/farmacologia
2.
Chem Res Toxicol ; 32(8): 1638-1645, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31273983

RESUMO

DiethoxyP(V)tetrakis(p-methoxyphenyl)porphyrin (EtP(V)TMPP) and its fluorinated derivative (FEtP(V)TMPP) were synthesized to examine their photodynamic action. These P(V)porphyrins were aggregated in an aqueous solution, resulting in the suppression of their photodynamic activity. In the presence of human serum albumin (HSA), a water-soluble protein, the aggregation states were resolved and formed a binding complex between P(V)porphyrin and HSA. These P(V)porphyrins photosensitized the oxidation of the tryptophan residue of HSA under the irradiation of long-wavelength visible light (>630 nm). This protein photodamage was explained by the electron transfer from tryptophan to the photoexcited state of P(V)porphyrins and singlet oxygen generation. The axial fluorination reduced the redox potential of the one-electron reduction of P(V)porphyrin and increased the electron transfer rate constant. However, this axial fluorination decreased the binding constant with HSA, and the quantum yield of photosensitized HSA damage through electron transfer was decreased. The photocytotoxicity of these P(V)porphyrins to HaCaT cells was also confirmed, and FEtP(V)TMPP demonstrated stronger phototoxicity than EtP(V)TMPP. In summary, a self-aggregation of porphyrin photosensitizers and resolving by targeting biomacromolecules may be used to target selective photodynamic action. The redox potential and an association with a targeting biomolecule are the important factors of the electron transfer-mediated mechanism, which is advantageous under hypoxic tumor conditions.


Assuntos
Compostos Organofosforados/química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Albumina Sérica Humana/química , Linhagem Celular , Transporte de Elétrons , Halogenação , Humanos , Luz , Modelos Moleculares , Estrutura Molecular , Oxirredução , Agregados Proteicos
3.
Bull Environ Contam Toxicol ; 103(3): 411-415, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203410

RESUMO

To clarify whether Oryzias congeners, including freshwater, brackish water, and marine medaka, would be useful models for evaluating environmental chemical effects in various aquatic ecosystems, we examined the influence of salinity on their embryo development. We also compared the toxicity values of the organotin compounds triphenyltin and tributyltin, which remain pollutants of marine and freshwater ecosystems, between Oryzias latipes (freshwater), Oryzias melastigma (brackish water), and Oryzias javanicus (saltwater). Hatching and survival rates of O. latipes were significantly decreased at a salinity of 34, whereas O. melastigma and O. javanicus were adaptable to various salinities from freshwater to seawater. The lowest observed effect concentrations of organotin compounds for survival and embryo development were the similar in the three species. The similarity of the species' responses to organotin compounds indicated that Oryzias congeners are useful for ecological risk assessment of chemicals in a range of aquatic ecosystems, from freshwater to marine.


Assuntos
Ecossistema , Desenvolvimento Embrionário/efeitos dos fármacos , Compostos Orgânicos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Água Doce , Compostos Orgânicos de Estanho/toxicidade , Oryzias/embriologia , Salinidade , Água do Mar , Compostos de Trialquitina/toxicidade
4.
Biosci Biotechnol Biochem ; 82(2): 334-342, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29327670

RESUMO

To identify yeasts involved in white-colony formation on Japanese commercial kimchi products, three types of kimchi were prepared and fermented at four different temperatures. At 4 °C, yeast colonies did not appear until 35 days, while more rapid white-colony formation occurred at higher temperatures (10, 15, and 25 °C). Combination of PCR-DGGE and direct isolation of yeasts from white colonies revealed that Kazachstania exigua and K. pseudohumilis were responsible for the white-colony formation. Inoculation of the isolated Kazachstania strains into fresh kimchi successfully reproduced white-colony formation at 15 °C but not at 4 °C. Growth experiments in liquid medium revealed that Kazachstania spp. grew fast at 15 °C even in the presence of acidulants, which are commonly added to Japanese kimchi products for prevention of yeast growth. These results suggest that white-colony formation on Japanese kimchi is caused by the genus Kazachstania, and that one of important factors determining white-colony formation is its fermentation temperature.


Assuntos
Alimentos Fermentados/microbiologia , Microbiologia de Alimentos , Saccharomycetales/fisiologia , Brassica , Proliferação de Células , Saccharomycetales/crescimento & desenvolvimento , Saccharomycetales/isolamento & purificação , Propriedades de Superfície , Temperatura
5.
J Clin Biochem Nutr ; 62(3): 259-263, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29892166

RESUMO

The objective was to evaluate the effect of replacing milk with soymilk or calcium-fortified soymilk as a part of a meal on postprandial serum phosphorus levels. This study had a randomized crossover design. Ten healthy subjects were enrolled and consumed three test meals that contained either milk, soymilk, or calcium-fortified soymilk containing the same amount of calcium as milk. Blood samples were collected at 0, 30, 60, 120, 240 and 360 min and urine samples were collected from 0 to 360 min after consuming the test meal. Serum phosphorus levels decreased the most after the ingestion of the soymilk meal, and the least after the ingestion of the milk meal. After the ingestion of each meal, serum intact parathyroid hormone levels showed an initial drop followed by a gradual rise, and these changes were more pronounced for the soymilk meal than for the milk meal and the soymilk + calcium meal. Our study shows that replacing milk with soymilk as a part of a meal may suppress the postprandial elevation in serum phosphorus levels, even when the soymilk contains the same amount of calcium as milk.

6.
Jpn J Antibiot ; 69(2): 113-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27544979

RESUMO

We herein discovered a highly resistant clinical isolate of Pseudomonas aeruginosa with MICs to amikacin, gentamicin, and arbekacin of 128 µg/mL or higher in a drug sensitivity survey of 92 strains isolated from the specimens of Yoka hospital patients between January 2009 and October 2010, and Achromobacter xylosoxidans was separated from this P. aeruginosa isolate. The sensitivity of this bacterium to 29 antibiotics was investigated. The MICs of this A. xylosoxidans strain to 9 aminoglycoside antibiotics were: amikacin, gentamicin, arbekacin, streptomycin, kanamycin, neomycin, and spectinomycin, 1,024 µg/mL or ≥ 1,024 µg/mL; netilmicin, 512 µg/mL; and tobramycin, 256 µg/mL. This strain was also resistant to dibekacin. This aminoglycoside antibiotic resistant phenotype is very rare, and we are the first report the emergence of A. xylosoxidans with this characteristic.


Assuntos
Achromobacter denitrificans/efeitos dos fármacos , Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana
7.
Biol Pharm Bull ; 38(9): 1309-19, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26328486

RESUMO

Doxorubicin (DOX) is widely used for the treatment of a wide range of cancers such as breast and lung cancers, and malignant lymphomas, but is generally less efficacious in gastrointestinal cancers. The most accepted explanation for the DOX refractoriness is its resistance development. Here, we established DOX-resistant phenotypes of human gastric MKN45 and colon LoVo cells by continuous exposure to incremental concentrations of the drug. While the parental MKN45 and LoVo cells expressed carbonyl reductase 1 (CBR1) highly and moderately, respectively, the gain of DOX resistance further elevated the CBR1 expression. Additionally, the DOX-elicited cytotoxicity was lowered by overexpression of CBR1 and inversely strengthened by knockdown of the enzyme using small interfering RNA or pretreating with the specific inhibitor quercetin, which also reduced the DOX refractoriness of the two resistant cells. These suggest that CBR1 is a key enzyme responsible for the DOX resistance of gastrointestinal cancer cells and that its inhibitor is useful in the adjuvant therapy. Although CBR1 is known to metabolize DOX to a less toxic anticancer metabolite doxorubicinol, its overexpression in the parental cells hardly show significant reductase activity toward low concentration of DOX. In contrast, the overexpression of CBR1 increased the reductase activity toward an oxidative stress-derived cytotoxic aldehyde 4-oxo-2-nonenal. The sensitivity of the DOX-resistant cells to 4-oxo-2-nonenal was lower than that of the parental cells, and the resistance-elicited hyposensitivity was almost completely ameliorated by addition of the CBR1 inhibitor. Thus, CBR1 may promote development of DOX resistance through detoxification of cytotoxic aldehydes, rather than the drug's metabolism.


Assuntos
Oxirredutases do Álcool/biossíntese , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Linhagem Celular Tumoral , Neoplasias Gastrointestinais/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Quercetina/farmacologia , Regulação para Cima
8.
JMA J ; 7(2): 292-294, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38721068

RESUMO

Galantamine is a cholinesterase inhibitor employed in Alzheimer's disease management. Cholinesterase inhibitors are associated with potential cholinergic side effects that, when severe, can result in cholinergic crises. Although crises induced by other cholinesterase inhibitors, such as distigmine and rivastigmine, have been reported, cases of galantamine-induced cholinergic crises remain undocumented. This study presents a case of cholinergic crisis triggered by galantamine overdose in an 89-year-old woman weighing 37 kg with Alzheimer's disease history, even though her serum cholinesterase levels were normal. The patient overdosed on 264 mg of galantamine, leading to rapid deterioration, marked by restlessness, tremors, sweating, diarrhea, pharyngeal gurgling, and severe hypoxia. Upon arrival at the emergency department, the patient exhibited pinpoint pupils, compromised airway, and low oxygen saturation, necessitating immediate intubation and transfer to the intensive care unit. After 72 h, the patient successfully recovered and was weaned off mechanical ventilation, maintaining normal serum cholinesterase levels. Animal studies suggest a lethal galantamine threshold of 3 to 6 mg/kg in humans. Unlike other cholinesterase inhibitors that typically reduce serum cholinesterase levels during cholinergic crises, galantamine appears to selectively inhibit acetylcholinesterase, possibly sparing butyrylcholinesterase. This selectivity may explain the normal serum cholinesterase levels.

9.
BMJ Ment Health ; 27(1)2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38960880

RESUMO

BACKGROUND: The fast-growing migrant population in Japan and globally poses challenges in mental healthcare, yet research addressing migrants' mental health treatment engagement remains limited. OBJECTIVE: This study examined language proficiency, demographic and clinical characteristics as predictors of early treatment discontinuation among migrants. METHODS: Electronic health record data from 196 adult migrants, identified from 14 511 patients who received mental health outpatient treatment during 2016 and 2019 at three central hospitals in the Tokyo-Yokohama metropolitan region of Japan, were used. We conducted multivariable regression models to identify predictors of early discontinuation within 3 months. FINDINGS: The study cohort (65% women, age range: 18-90 years, from 29 countries or regions) included 23% non-Japanese speakers. Japanese and non-Japanese speakers had similar discontinuation rates (26% vs 22%). Multivariable models revealed younger age (OR=0.97; 95% CI: 0.95, 0.99; p=0.016) and those with a primary diagnosis other than a schizophrenia spectrum disorder (OR=3.99; 95% CI: 1.36, 11.77; p=0.012) or a neurotic, stress-related and somatoform disorder (OR=2.79; 95% CI: 1.14, 6.84; p=0.025) had higher odds of early discontinuation. These effects were more pronounced among the Japanese speakers with significant language-by-age and language-by-diagnoses interactions. CONCLUSION: Younger age and having a primary diagnosis other than a schizophrenia spectrum disorder or a neurotic, stress-related and somatoform disorder increased vulnerability for discontinuing mental health treatment early in Japanese-speaking migrants but not for migrants with limited Japanese proficiency. CLINICAL IMPLICATIONS: Understanding language needs within a context of mental health treatment should go beyond assumed or observed fluency. Unmet language needs might increase vulnerability for treatment disengagement among migrants. Targeted clinical efforts are crucial for enhancing early treatment engagement and informing health practices in Japan and countries with growing migrant populations.


Assuntos
Migrantes , Humanos , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Japão/etnologia , Japão/epidemiologia , Idoso , Migrantes/psicologia , Migrantes/estatística & dados numéricos , Adolescente , Adulto Jovem , Idoso de 80 Anos ou mais , Serviços de Saúde Mental/estatística & dados numéricos , Idioma , Transtornos Mentais/epidemiologia , Transtornos Mentais/terapia , Assistência Ambulatorial/estatística & dados numéricos , Pacientes Ambulatoriais/estatística & dados numéricos , Pacientes Ambulatoriais/psicologia
10.
Intern Med ; 62(17): 2513-2516, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36476545

RESUMO

Vasospastic angina (VSA) can be worsened by oral nonselective beta-blockers. Ophthalmic carteolol eye drops are nonselective beta-blockers and effective against glaucoma and ocular hypertension. Systemic effects of ophthalmic beta-blockers on VSA have not yet been reported. We herein report a case of VSA that developed after a patient started carteolol eye drops for ocular hypertension. Even though benidipine, a calcium channel blocker, was started, a VSA attack with incessant non-sustained ventricular tachycardia occurred. Once the carteolol eyedrops were discontinued, the VSA resolved. This case demonstrates that carteolol eye drops can induce life-threatening VSA.


Assuntos
Angina Pectoris Variante , Carteolol , Vasoespasmo Coronário , Glaucoma , Hipertensão Ocular , Humanos , Carteolol/efeitos adversos , Vasoespasmo Coronário/induzido quimicamente , Vasoespasmo Coronário/tratamento farmacológico , Soluções Oftálmicas/efeitos adversos , Antagonistas Adrenérgicos beta/efeitos adversos , Hipertensão Ocular/induzido quimicamente , Hipertensão Ocular/tratamento farmacológico
11.
Artigo em Inglês | MEDLINE | ID: mdl-21785259

RESUMO

Sulfatide is a myelin glycolipid that functions in the formation of paranodal axo-glial junctions in vivo and in the regulation of oligodendrocyte differentiation in vitro. Cerebroside sulfotransferase (CST) catalyzes the production of two sulfated glycolipids, sulfatide and proligodendroblast antigen, in oligodendrocyte lineage cells. Recent studies have demonstrated significant increases in oligodendrocytes from the myelination stage through adulthood in brain and spinal cord under CST-deficient conditions. However, whether these result from excess migration or in situ proliferation during development is undetermined. In the present study, CST-deficient optic nerves were used to examine migration and proliferation of oligodendrocyte precursor cells (OPCs) under sulfated glycolipid-deficient conditions. In adults, more NG2-positive OPCs and fully differentiated cells were observed. In developing optic nerves, the number of cells at the leading edge of migration was similar in CST-deficient and wild-type mice. However, BrdU(+) proliferating OPCs were more abundant in CST-deficient mice. These results suggest that sulfated glycolipids may be involved in proliferation of OPCs in vivo.


Assuntos
Linhagem da Célula , Oligodendroglia/patologia , Nervo Óptico/patologia , Sulfotransferases/deficiência , Envelhecimento/patologia , Animais , Antígenos/metabolismo , Axônios/metabolismo , Axônios/patologia , Contagem de Células , Morte Celular , Proliferação de Células , Transportador 1 de Aminoácido Excitatório/metabolismo , Camundongos , Camundongos Knockout , Proteína Proteolipídica de Mielina/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Nervo Óptico/crescimento & desenvolvimento , Nervo Óptico/metabolismo , Proteoglicanas/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Sulfoglicoesfingolipídeos/metabolismo , Sulfotransferases/metabolismo
12.
Yakugaku Zasshi ; 141(9): 1109-1116, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34471011

RESUMO

Occupational exposure of pharmacists to drugs during powder drug preparation in dispensing pharmacies was investigated. First, we determined frequently prescribed tipepidine hibenzate and ambroxol hydrochloride suspended in the air of the dispensing room. The median concentration of the drugs in the air was 0.01 µg/m3 and 0.02 µg/m3, respectively; these values indicate that the air in the dispensing room was contaminated with powder drug. To estimate drug exposure during powder drug preparation, drug dust was collected near the nose of workers. Analysis of the active ingredients of the drugs used in the preparation revealed that eight drugs, including bethanechol, l-carbocisteine, and zonisamide, were detected in the range of 1.5-1220 µg/m3. Assuming that the respiratory volume of an adult was 0.008 m3/min, it was estimated that 0.4-36 µg of the ingredients were exposed per prescription by multiplying concentration, respiratory volume and sampling time (3-5 min). Furthermore, the effect of wearing a medical mask on the drug powder exposure was evaluated using a self-made apparatus. When the amount of drug powder collected on filters that is either covered with or without a medical mask was compared, the covered filter exhibited reduced drug powder accumulation to less than 10% the amount collected on the uncovered filter. The present data suggested that a medical mask might decrease the drug dust allergies in dispensing pharmacists.


Assuntos
Poluentes Ocupacionais do Ar/análise , Poluição do Ar em Ambientes Fechados/análise , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Máscaras , Exposição Ocupacional/análise , Preparações Farmacêuticas/análise , Farmácias/estatística & dados numéricos , Farmacêuticos , Poluentes Ocupacionais do Ar/efeitos adversos , Poluição do Ar em Ambientes Fechados/efeitos adversos , Poluição do Ar em Ambientes Fechados/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Japão , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/prevenção & controle , Exposição Ocupacional/estatística & dados numéricos , Pós
13.
MedEdPORTAL ; 17: 11135, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33816796

RESUMO

Introduction: As the clinical applications of medical genetics and genomics continue to expand, nongenetics professionals increasingly find themselves in the position of managing patients with genetic conditions. To prepare medical students to handle this future practice demand, it is imperative that they obtain skills and confidence in utilizing credible medical genetics resources to care for patients with genetic conditions. To this end, we developed active learning materials to introduce first-year medical students to these resources. Methods: This approximately 2-hour session targeted first-year medical students (123 students) and combined flipped classroom and small-group collaborative case-based learning models. Students first completed a hands-on preclass exercise, which guided them in navigating the Online Mendelian Inheritance in Man website, and then attended an in-person small-group classroom activity, which provided the opportunity to apply information obtained from credible medical genetics resources to a patient case. At the conclusion of the classroom activity, students voluntarily completed an anonymous survey. Results: Results of student postsession surveys showed that, regardless of previous exposure to medical genetics resources, this session increased both confidence in skills and future intention to use medical genetics resources. Discussion: Since the majority of students were unfamiliar with using specialized medical genetics resources prior to this educational intervention, the session functioned as a practical introduction to these essential resources. We propose that equipping medical students with skills that support inquiry-oriented learning, particularly in the early stage of training, can cultivate the practice of lifelong learning in medical genetics.


Assuntos
Genética Médica , Aprendizagem Baseada em Problemas , Estudantes de Medicina , Genética Médica/educação , Humanos , Inquéritos e Questionários
14.
J Neurosci ; 29(26): 8363-71, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19571127

RESUMO

Conduction velocity (CV) of myelinated axons has been shown to be regulated by oligodendrocytes even after myelination has been completed. However, how myelinating oligodendrocytes regulate CV, and what the significance of this regulation is for normal brain function remain unknown. To address these questions, we analyzed a transgenic mouse line harboring extra copies of the myelin proteolipid protein 1 (plp1) gene (plp1(tg/-) mice) at 2 months of age. At this stage, the plp1(tg/-) mice have an unaffected myelin structure with a normally appearing ion channel distribution, but the CV in all axonal tracts tested in the CNS is greatly reduced. We also found decreased axonal diameters and slightly abnormal paranodal structures, both of which can be a cause for the reduced CV. Interestingly the plp1(tg/-) mice showed altered anxiety-like behaviors, reduced prepulse inhibitions, spatial learning deficits and working memory deficit, all of which are schizophrenia-related behaviors. Our results implicate that abnormalities in the neuron-glia interactions at the paranodal junctions can result in reduced CV in the CNS, which then induces behavioral abnormalities related to schizophrenia.


Assuntos
Sistema Nervoso Central/patologia , Transtornos Cognitivos , Regulação da Expressão Gênica , Proteína Proteolipídica de Mielina/genética , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa/genética , Adaptação Psicológica/fisiologia , Análise de Variância , Animais , Axônios/patologia , Axônios/fisiologia , Axônios/ultraestrutura , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/ultraestrutura , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Comportamento Exploratório/fisiologia , Força da Mão/fisiologia , Inibição Psicológica , Canal de Potássio Kv1.2/metabolismo , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/ultraestrutura , Neuroglia/fisiologia , Neurônios/patologia , Testes Neuropsicológicos , Limiar da Dor/fisiologia , Desempenho Psicomotor/fisiologia , Nós Neurofibrosos/patologia , Nós Neurofibrosos/ultraestrutura , Reflexo de Sobressalto/genética , Natação/fisiologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31874288

RESUMO

Although zinc is an essential element for organisms, excess zinc exposure is harmful. We assessed the possible negative influence of zinc (Zn) on the freshwater fish Danio rerio during its early life stage by using Organization for Economic Cooperation and Development test guideline no. 210. Lethality of Zn after hatching occurred in a concentration dependent manner. The LC50 and lowest observed effect concentration of mortality values in the present toxicity assay were 2.31 mg/L (95% confidence limit: 1.81-3.05) and 1.5 mg/L, respectively. These values were close to the reported concentration recorded in aquatic environments. Growth inhibition was observed at 15 and 30 days post-hatching with Zn exposure of 1.5 mg/L. In general, the growth hormone (Gh)/insulin-like growth factor-I (Igf-1) axis is important for growth in fishes, and Zn exposure induced a significant reduction of igf-1 expression at the concentration that caused growth inhibition. These findings suggest that the observed growth inhibition was induced by the suppression of igf-1 expression. In addition, these results suggest that by examining gene expression on the Gh/Igf-1 axis, it may be possible to predict growth suppression by chemical exposure.


Assuntos
Cloretos/toxicidade , Larva/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Compostos de Zinco/toxicidade , Zinco/toxicidade , Zigoto , Animais , Desenvolvimento Embrionário , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Larva/metabolismo , Dose Letal Mediana , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Zigoto/crescimento & desenvolvimento , Zigoto/metabolismo
16.
Yakugaku Zasshi ; 139(6): 955-961, 2019 Jun 01.
Artigo em Japonês | MEDLINE | ID: mdl-30944262

RESUMO

Reduction of corticosteroid responsiveness is one of the important clinical problems in chronic obstructive pulmonary disease (COPD). In this study, we determined the effects of neutralization of tumor necrosis factor-α (TNF-α) on corticosteroid insensitivity in mice models of airway inflammation induced by poly(I:C) and tobacco smoke (TS) exposure. Mice (male A/J strain, 5 weeks old) were exposed to TS for 10 d, or TS for 11 d and poly(I:C) for 3 d. Anti-TNF-α antibody was intranasally treated once every other day 2 h before the TS exposure, and dexamethasone 21-phosphate (DEX) was treated 30 min before the TS or poly(I:C) exposure. On the next day of the last stimulation, mice were sacrificed. The combination treatment of DEX and TNF-α neutralization was significantly attenuated the increase of the numbers of inflammatory cells in BALF and the TNF-α mRNA expression levels induced by TS and poly(I:C) exposure, even though TNF-α neutralization alone had little effect. These data indicated that neutralization of TNF-α restores corticosteroid responsiveness. Therefore, our study suggests that targeting TNF-α signaling pathway provides a new therapeutic approach to corticosteroid refractory airway diseases.


Assuntos
Dexametasona/análogos & derivados , Exposição Ambiental/efeitos adversos , Glucocorticoides/administração & dosagem , Nicotiana/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/etiologia , RNA de Cadeia Dupla/efeitos adversos , Transdução de Sinais , Fumar/efeitos adversos , Fator de Necrose Tumoral alfa , Administração Intranasal , Animais , Anticorpos/administração & dosagem , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Resistência a Medicamentos , Inflamação , Masculino , Camundongos Endogâmicos A , Terapia de Alvo Molecular , Doença Pulmonar Obstrutiva Crônica/genética , Fator de Necrose Tumoral alfa/imunologia
17.
Plast Reconstr Surg Glob Open ; 4(10): e1078, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27826474

RESUMO

Various techniques for nail reconstruction have been reported until now; however, a simple one providing good esthetic results was difficult to find. Arterialized venous toenail flap is a free flap that includes the nail bed and matrix with a pedicle formed solely by the subcutaneous vein of the toe. The use of this flap is minimally invasive and easy, and the flap has a high survival rate. The mechanism of graft survival remains unknown given the nonphysiologic circulation. To the best of our knowledge, no studies have explained this mechanism with reference to detailed postoperative course. We herein present 2 cases of nail reconstruction performed using arterialized venous toenail flap. We analyzed the postoperative course in detail, which enabled us to postulate on the mechanism of graft survival.

18.
Chem Biol Interact ; 256: 142-53, 2016 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-27417252

RESUMO

Cisplatin (cis-diamminedichloroplatinum, CDDP) is one of the most effective chemotherapeutic drugs that are used for treatment of patients with gastrointestinal cancer cells, but its continuous administration often evokes the development of chemoresistance. In this study, we investigated alterations in antioxidant molecules and functions using a newly established CDDP-resistant variant of gastric cancer MKN45 cells, and found that aldo-keto reductase 1B10 (AKR1B10) is significantly up-regulated with acquisition of the CDDP resistance. In the nonresistant MKN45 cells, the sensitivity to cytotoxic effect of CDDP was decreased and increased by overexpression and silencing of AKR1B10, respectively. In addition, the AKR1B10 overexpression markedly suppressed accumulation and cytotoxicity of 4-hydroxy-2-nonenal that is produced during lipid peroxidation by CDDP treatment, suggesting that the enzyme acts as a crucial factor for facilitation of the CDDP resistance through inhibiting induction of oxidative stress by the drug. Transient exposure to CDDP and induction of the CDDP resistance decreased expression of peroxisome proliferator-activated receptor-γ (PPARγ) in MKN45 and colon cancer LoVo cells. Additionally, overexpression of PPARγ in the cells elevated the sensitivity to the CDDP toxicity, which was further augmented by concomitant treatment with a PPARγ ligand rosiglitazone. Intriguingly, overexpression of AKR1B10 in the cells resulted in a decrease in PPARγ expression, which was recovered by addition of an AKR1B10 inhibitor oleanolic acid, inferring that PPARγ is a downstream target of AKR1B10-dependent mechanism underlying the CDDP resistance. Combined treatment with the AKR1B10 inhibitor and PPARγ ligand elevated the CDDP sensitivity, which was almost the same level as that in the parental cells. These results suggest that combined treatment with the AKR1B10 inhibitor and PPARγ ligand is an effective adjuvant therapy for overcoming CDDP resistance of gastrointestinal cancer cells.


Assuntos
Aldeído Redutase/genética , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Neoplasias Gastrointestinais/tratamento farmacológico , Trato Gastrointestinal/efeitos dos fármacos , PPAR gama/genética , Aldeído Redutase/metabolismo , Aldo-Ceto Redutases , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
PLoS One ; 10(11): e0142617, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26581089

RESUMO

Disabled elderly individuals with kyphosis or loss of muscle strength often display forward head posture (FHP). This study aimed to determine the utility of a wheelchair incorporating pelvic support in preventing FHP in disabled elderly individuals. In this study, 14 disabled elderly individuals (87.1 ± 8.1 years) were selected. A wheelchair incorporating pelvic support (RX_ABS Lo) and a basic wheelchair (RX-1) were used. Each individual sat on both wheelchairs for 30 minutes. RX_ABS Lo has two belts to support the pelvic and thorax. Postures were recorded in the sagittal plane using a video camera. Cervical and trunk angles from horizontal were measured every 5 minutes. Simultaneously, contact areas and total pressures applied to the wheelchair seats and back supports were measured every 5 minutes. Comparisons of area under the curve values between the wheelchairs were performed using the paired t-test. Comparisons of time-dependent parameters for each wheelchair were performed using repeated one-way ANOVA. Cervical angles were greater when using RX_ABS Lo than RX-1. Although cervical angles were unchanged during 30 minutes when using RX_ABS Lo, the angles were significantly decreased after 30 minutes of using RX-1. Back support pressures and contact areas were greater for RX_ABS Lo than for RX-1. No significant difference in back support pressure distributions was observed during 30 minutes in the wheelchairs. The RX_ABS Lo may have utility in improving FHP by increasing cervical angles and improving stability with a back support to the upper thorax, lower thorax, and pelvis during prolonged sitting.


Assuntos
Desenho de Equipamento , Cabeça/fisiopatologia , Cifose/fisiopatologia , Pescoço/fisiopatologia , Cadeiras de Rodas , Idoso , Fenômenos Biomecânicos , Feminino , Humanos , Masculino , Força Muscular/fisiologia , Pelve/fisiologia , Postura/fisiologia , Tórax/fisiopatologia
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