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DOATS score and DOAT score, COVID-19 progression prediction tools we have developed, utilize clinical information such as presence of diabetes/obesity (DO), age (A), body temperature (T), and oxygen saturation (S). They showed good predictive power, but their scoring calculation was slightly complex, leading us to develop simplified versions. This report discusses the ability of the simplified versions to assess deterioration risk in unvaccinated, mild/moderate COVID-19 patients aged <65 years. Logistic regression analysis identified independent risk factors for deterioration, to which points were assigned in order to derive overall prediction scores. The simplified versions showed high discriminating power, with the areas under the receiver operating characteristic curve for DOATS and DOAT being 0.79 and 0.77, respectively, indicating their clinical utility. Although the original versions have a slightly higher predictive power, the new versions are easier to use in emergency situations; thus, importantly, selecting the appropriate version depends on the situation.
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COVID-19 , Progressão da Doença , Humanos , COVID-19/diagnóstico , Pessoa de Meia-Idade , Masculino , Fatores Etários , Feminino , Índice de Gravidade de Doença , Fatores de Risco , Adulto , Obesidade/complicações , Modelos Logísticos , Temperatura Corporal , Curva ROC , Valor Preditivo dos Testes , Medição de Risco/métodos , Diabetes Mellitus/epidemiologiaRESUMO
RATIONALE: Serotonin syndrome is a potentially life-threatening condition resulting from the use of antidepressants, their interactions with other serotonergic medications, or poisoning. It presents with a triad of psychiatric, dysautonomic, and neurological symptoms and is sometimes fatal. While cyproheptadine is a specific treatment option, the optimal duration of its administration remains unclear. The purpose of this report is to quantitatively assess the endpoints of serotonin syndrome treatment. Based on the hypothesis that neurological pupil index (NPi) on a digital pupil recorder would correlate with the severity of the serotonin syndrome, we administered cyproheptadine using NPi as an indicator. PATIENT CONCERNS: A patient with a history of depression was brought to our hospital after he overdosed on 251 tablets of serotonin and noradrenaline reuptake inhibitors. DIAGNOSES: On day 3, the patient was diagnosed with serotonin syndrome. INTERVENTIONS: Cyproheptadine syrup was administered at 4 mg every 4 hours. The NPi of the automated pupillometer was simultaneously measured. On day 5, the NPi exceeded 3.0 cyproheptadine was discontinued. OUTCOMES: The patient was discharged on day 7. LESSONS: The lack of considerable improvement during the treatment period suggests that the patient may have improved on his own. In this case, the relationship between NPi and the severity of serotonin syndrome could not be determined.
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Doenças do Sistema Nervoso Autônomo , Síndrome da Serotonina , Masculino , Humanos , Síndrome da Serotonina/diagnóstico , Síndrome da Serotonina/tratamento farmacológico , Pupila , Serotonina , Ciproeptadina/uso terapêuticoRESUMO
The antiviral drug acyclovir (ACV) may induce drug-induced neuropsychiatric symptoms as side effects. The detailed pathogenic mechanism remains unclear; however, it is hypothesized that 9-carboxymethoxymethylguanine (CMMG), a metabolite of ACV, is the causative compound. Therefore, the blood concentrations of ACV and CMMG should be analyzed in ACV toxicity studies. However, it is rare to find methods that can sufficiently separate the ACV and CMMG peaks during simultaneous analysis of both compounds. Therefore, we intended to develop a liquid chromatography-tandem mass spectrometry method with improved peak separation of analytes. Samples were deproteinized using methanol/acetonitrile solution (6:4, v/v). Analytes were separated on an InertSustain® Amide column (3 µm, 2.1 mm × 150 mm). The mobile phase consisted of acetonitrile/10 mM ammonium formate (5:95, v/v) (A) and acetonitrile/10 mM ammonium formate (95:5, v/v, pH 5.0) (B) and samples were eluted in the gradient mode. The separation of analytes was satisfactory and the peak shapes were good. Linear regression models weighted 1/x2 were obtained in the range of 0.25-10 µg/mL. The range of quality control (QC) bias was between 3.6% and 19.8%, and the within-run and between-run precisions of QC were within 13.5%. Recovery ranged from 83.6% to 103.7%, but ion suppression was observed. Samples from a patient with ACV encephalopathy were analyzed using this method. The resulting blood ACV and CMMG concentrations were 8.2 and 8.5 µg/mL, respectively. This method, with sufficient separation of ACV and CMMG, proved useful for use in ACV toxicity studies.
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Aciclovir , Antivirais , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Massas em Tandem , Aciclovir/sangue , Humanos , Cromatografia Líquida , Antivirais/sangue , Reprodutibilidade dos Testes , Guanina/análogos & derivados , Guanina/sangue , Limite de Detecção , Modelos LinearesRESUMO
AIM: Several studies have shown the efficacy and safety of low-molecular-weight heparin use in coronavirus disease 2019 (COVID-19), but that of unfractionated heparin (UFH) has not been investigated. We investigated the prevalence of bleeding complications during UFH administration, its impact on mortality, and the risk factors of bleeding outcomes associated with UFH. METHODS: This retrospective cohort study was conducted at a single-center tertiary care hospital, including hospitalized patients with COVID-19. The primary outcomes were measured as the prevalence of bleeding complications during hospitalization, and the secondary outcomes were thromboembolic events and 60-day mortality rates. Logistic regression analysis and propensity score matching were used to assess risk factors for bleeding complications and their impact on mortality. RESULTS: Among 1035 included patients, 516 patients were treated with UFH. Twelve (2.3%) patients in the UFH group experienced major bleeding. The prevalence of major bleeding in patients treated with therapeutic-dose UFH was 9.2%. Logistic regression analysis showed that age ≥ 60 years (adjusted odds ratio [aOR], 3.89; 95% confidence interval [CI], 1.01-15.0; Pï¼.05) and COVID-19 severity (aOR, 35.9; 95% CI, 4.57-282; Pï¼.05) were associated with major bleeding complications. After propensity score matching, 11 major and 11 non-major bleeding cases (including minor bleeding) were matched. The 60-day cumulative mortality rate between the two groups did not differ significantly (P=.13, log-rank test). CONCLUSIONS: The incidence of major bleeding in COVID-19 patients using therapeutic-dose UFH was relatively high. Critical COVID-19 and older age were risk factors for bleeding complications.
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Anticoagulantes , COVID-19 , Hemorragia , Heparina , Humanos , Masculino , Feminino , Japão/epidemiologia , Estudos Retrospectivos , Hemorragia/epidemiologia , Hemorragia/induzido quimicamente , COVID-19/epidemiologia , COVID-19/complicações , COVID-19/mortalidade , Heparina/efeitos adversos , Idoso , Pessoa de Meia-Idade , Incidência , Anticoagulantes/efeitos adversos , Fatores de Risco , SARS-CoV-2 , Tratamento Farmacológico da COVID-19 , Idoso de 80 Anos ou mais , Tromboembolia/epidemiologia , Tromboembolia/etiologiaRESUMO
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used to treat non-small cell lung cancer with EGFR mutations. However, first-generation erlotinib and second-generation afatinib often cause diarrhea, which may develop because of the association between EGFR-TKIs and the chloride channel or abnormalities in the intestinal microbiota due to disruption of the intestinal immune system. As reports on the effects of EGFR-TKIs on intestinal immunity are lacking, we aimed to determine whether the intestinal immune system is involved in the molecular effects of EGFR-TKIs on chloride channels using Caco-2 cells. Initially, we evaluated the association of chloride channels with α-defensin 5 (DEFA5), a marker of intestinal immunity. Erlotinib and afatinib significantly increased the extracellularly secreted DEFA5 level and autophagy-related 16-like 1 and X-box binding protein 1 transcript levels, indicative of enhanced granule exocytosis. Conversely, intracellular DEFA5 and Toll-like receptor 4 protein expression and tumor necrosis factor-α transcript levels decreased significantly, suggesting that Toll-like receptor 4 suppression repressed DEFA5 production. Furthermore, among the chloride channels, DEFA5 was found to significantly increase the transcript levels of cystic fibrosis transmembrane conductance regulators. These results indicate that DEFA5 plays a significant role in the mechanism of chloride channel-mediated diarrhea induced by EGFR-TKIs. Therefore, we successfully elucidated the potential host action of DEFA5 in cancer therapy for the first time.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , alfa-Defensinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Afatinib/efeitos adversos , Cloridrato de Erlotinib/efeitos adversos , Neoplasias Pulmonares/metabolismo , Receptor 4 Toll-Like/metabolismo , alfa-Defensinas/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Células CACO-2 , Cloretos/metabolismo , Receptores ErbB/metabolismo , Mutação , Diarreia/induzido quimicamente , Canais de Cloreto/genéticaRESUMO
Expression of α-smooth muscle actin (αSMA) is constitutive in vascular smooth muscle cells, but is induced in nonmuscle cells such as hepatic stellate cells (HSCs). HSCs play important roles in both physiological homeostasis and pathological response. HSC activation is characterized by αSMA expression, which is regulated by the TGFß-induced Smad pathway. Recently, protein kinase C (PKC) was identified to regulate αSMA expression. Diacylglycerol kinase (DGK) metabolizes a second-messenger DG, thereby controlling components of DG-mediated signaling, such as PKC. In the present study we aimed to investigate the putative role of DGKα in αSMA expression. Use of a cellular model indicated that the DGK inhibitor R59949 promotes αSMA expression and PKCδ phosphorylation. It also facilitates Smad2 phosphorylation after 30 min of TGFß stimulation. Furthermore, immunocytochemical analysis revealed that DGK inhibitor pretreatment without TGFß stimulation engenders αSMA expression in a granular pattern, whereas DGK inhibitor pretreatment plus TGFß stimulation significantly induces αSMA incorporation in stress fibers. Through animal model experiments, we observed that DGKα-knockout mice exhibit increased expression of αSMA in the liver after 48 h of carbon tetrachloride injection, together with enhanced phosphorylation levels of Smad2 and PKCδ. Together, these findings suggest that DGKα negatively regulates αSMA expression by acting on the Smad and PKCδ signaling pathways, which differentially regulate stress fiber incorporation and protein expression of αSMA, respectively.
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Actinas , Fígado , Animais , Camundongos , Actinas/metabolismo , Fígado/metabolismo , Músculo Liso/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta , Diacilglicerol QuinaseRESUMO
OBJECTIVES: Although lower-extremity muscle strength is associated with physical function, there are challenges in assessing the muscle strength of patients after hip surgery due to pain or limited cognitive function. The number of teeth is a characteristic that can be easily examined. Although the relationship between the number of teeth and physical function has been reported in recent years, there are no reports examining the relationship with prognosis in patients with hip fractures. Therefore, this study aimed to investigate the relationship between the number of teeth and physical function and length of hospital stay after hip fracture surgery and to evaluate the predictive efficacy of the number of teeth on postoperative prognosis. METHODS: This prospective cohort study was conducted in a tertiary clinical care facility. Patients aged ≥65 years who underwent hip surgery were included. A total of 101 patients (mean age: 85.1±8.0 years) were included. The factor analyzed was the number of teeth at admission. Patients were divided into two groups according to the number of teeth: those with ≥20 and those with ≤19 teeth. The outcomes were knee extension muscle strength-to-weight ratio at two weeks postoperatively and the length of hospital stay. A multiple regression analysis was performed to determine the association between the two groups. RESULTS: Of 101 patients, 79 (78.2%) had ≤19 teeth, whereas 22 (21.8%) had ≥20 teeth. The mean muscle strength-to-weight ratio and length of hospital stay were 0.26±0.11 kgf/kg and 57.5±31.4 days, respectively. Multiple regression analysis revealed that the number of teeth was significantly associated with the muscle strength-to-weight ratio (ß=-0.26, p=0.04) but not with the duration of hospitalization (ß=0.17, p=0.09). CONCLUSIONS: We suggest that assessment of the number of teeth at admission may be a useful predictor of patient physical function.
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Introduction: Fatty acids are a major nutrient in dietary fat, some of which are ligands of long-chain fatty acid receptors, including G-protein-coupled receptor (GPR) 40 and GPR120. Pretreatment with GPR40 agonists enhanced the secretion of insulin in response to elevating blood glucose levels after glucose load in a diabetes model, but pretreatment with GPR120 agonist did not ameliorate postprandial hyperglycemia. This study examined whether oral administration of linoleic acid (LA), a GPR40 and GPR120 agonist, immediately before glucose load would affect the elevation of postprandial blood glucose levels in rats. Methods: Male rats and rats with type 1 diabetes administered streptozocin were orally administered LA, trilinolein, α-linolenic acid (α-LA), oleic acid, TAK-875, or TUG-891 immediately before glucose load. Blood glucose levels were measured before, then 15, 30, 60 and 120 min after glucose load. CACO-2 cells were used to measure the uptake of [14C] α-MDG for 30 min with or without LA. Gastric content from rats administered LA was collected 15 and 30 min after glucose load, and blood samples were collected for measurement of glucagon-like peptide 1 (GLP-1) and cholecystokinin concentrations. Results: The elevation of postprandial blood glucose levels was slowed by LA but not by trilinolein in rats without promotion of insulin secretion, and this effect was also observed in rats with type 1 diabetes. The uptake of α-MDG, an SGLT-specific substrate, was, however, not inhibited by LA. Gastric emptying was slowed by LA 15 min after glucose load, and GLP-1, but not cholecystokinin, level was elevated by LA 15 min after glucose load. TUG-891, a GPR120 agonist, ameliorated postprandial hyperglycemia but TAK-875, a GPR40 agonist, did not. Pretreatment with AH7614, a GPR120 antagonist, partially canceled the improvement of postprandial hyperglycemia induced by LA. α-LA, which has high affinity with GPR120 as well as LA, slowed the elevation of postprandial blood glucose levels, but oleic acid, which has lower affinity with GPR120 than LA, did not. Conclusion: Oral administration of LA immediately after glucose load ameliorated postprandial hyperglycemia due to slowing of gastric emptying via promotion of GLP-1 secretion. The mechanisms may be associated with GPR120 pathway.
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α-Defensin 5 is known to be secreted by Paneth cells in the small intestine and plays an important role in eliminating pathogenic microorganisms. It has been reported that a decrease in α-defensin 5 level in the human small intestine is a risk of inflammatory bowel disease (IBD). Furthermore, P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter superfamily, encoded by the ABCB1/MDR1 gene, plays an important role in the front line of host defense by protecting the gastrointestinal barrier from xenobiotic accumulation and may contribute to the development and persistence of IBD. Therefore, we examined the relationship between α-defensin 5 and the expression and function of P-gp using a human gastrointestinal model cell line (Caco-2). We found that MDR1 mRNA and P-gp protein level were increased in Caco-2 cells as well as α-defensin 5 secretion corresponded with the duration of cell culture. Exposure to α-defensin 5 peptide and recombinant tumor necrosis factor-α (TNF-α) significantly increased the expression and function P-gp. The mRNA levels of interleukin (IL)-8, IL-6, TNF-α, IL-1ß, and IL-2 were also increased following exposure to TNF-α, similar to α-defensin 5 treatment. These results suggest that α-defensin 5 regulates P-gp expression and function by increasing TNF-α expression in Caco-2 cells.
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Doenças Inflamatórias Intestinais , alfa-Defensinas , Humanos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Células CACO-2 , alfa-Defensinas/genética , alfa-Defensinas/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , RNA Mensageiro/metabolismoRESUMO
Attention should be paid to cerebrospinal fluid leakage in patients with pneumorrhachis associated with vertebral body trauma. If pneumorrhachis is detected, further imaging investigation and bed rest should be considered as appropriate.
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Hypercoagulability, which can be induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays an important role in the pathogenesis of coronavirus disease 2019 (COVID-19). Although anticoagulation therapy is expected to decrease the incidence of thrombosis and mortality in COVID-19 patients, the optimal use of anticoagulation therapy has not been established, especially using unfractionated heparin (UFH). Herein, we suggest a new anticoagulation treatment protocol for the use of UFH in Japanese COVID-19 patients. This protocol considers the safety regarding UFH usage, to lower major bleeding events, and reflects the latest evidence and the current situation regarding anticoagulation therapy in Japan.
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INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in Wuhan in December 2019, and has since caused a global pandemic. The efficacy of several drugs has been evaluated, and it is now evident that tocilizumab has a beneficial effect, especially combined with corticosteroids, in patients with Coronavirus Disease 2019 (COVID-19). However, the optimal timing of tocilizumab administration has not yet been established. The goal of the present study was to determine the optimal timing of tocilizumab administration after starting corticosteroid therapy in patients with COVID-19. METHODS: We retrospectively analyzed the clinical characteristics of patients who were hospitalized for COVID-19 and treated with tocilizumab and corticosteroids in our hospital. The patients were divided into concurrent and sequential groups. The concurrent group received tocilizumab ≤24 h after corticosteroids, and the sequential group received tocilizumab >24 h after corticosteroid administration. RESULTS: The baseline clinical characteristics of tocilizumab administration were similar between the two groups. White blood cell counts were significantly lower and C-reactive protein levels were significantly higher in the concurrent group than the sequential group. In the concurrent group, tocilizumab administration led to a significant decrease in maximum body temperature. In addition, there were significantly more oxygen-free days in the concurrent group than in the sequential group. However, survival rate was not significantly different between the concurrent and the sequential groups. CONCLUSIONS: In the combination therapy with tocilizumab and corticosteroids, early administration of tocilizumab after starting corticosteroid treatment is effective when treating COVID-19.
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Tratamento Farmacológico da COVID-19 , Anticorpos Monoclonais Humanizados , Proteína C-Reativa , Humanos , Estudos Retrospectivos , SARS-CoV-2 , Resultado do TratamentoRESUMO
OBJECTIVES: This study examined the characteristics of severe patients after the Great East Japan Earthquake in 2011. METHODS: Cases in the Futaba area were extracted using the dispatch database of the doctor helicopter and flight-nurse records from March 11, 2008, till March 10, 2014. The period before March 11, 2011, was defined as 'pre-earthquake' and the period after March 11, 2011, as 'post-earthquake' to compare the recorded data. RESULTS: Of the 128 total recorded cases, 78 were dispatched during the pre-earthquake period and 50 during the post-earthquake period. The number of patients with physical trauma following the earthquake included 4 patients (33.3%) in 2011, 7 patients (43.7%) in 2012, and 13 patients (59.1%) in 2013. However, the increase in number of requests was not statistically significant (P = 0.33). All 4 incidents of physical trauma in 2011, and 3 out of 7 incidents in 2012, occurred at the power plants. A total of 4 incidents occurred at decontamination worksites in 2013. CONCLUSIONS: It is of primary importance for hospitals to anticipate physical trauma cases during the reconstruction phase following a disaster, and develop a system for patients with physical trauma in the short- and long-term.
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Desastres , Terremotos , Humanos , Japão , Aeronaves , HospitaisRESUMO
Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.
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Tratamento Farmacológico da COVID-19 , Pandemias , Anticorpos Monoclonais Humanizados , Humanos , SARS-CoV-2 , Resultado do TratamentoRESUMO
The Hokkaido medical personnel training plan connecting humans and medicine aims to train"Medical personnel for genome medicine"," Medical personnel for rare cancer and childhood cancer", and"Medical personnel who promote cancer measures according to patient's life stage". We have worked on preparing medical professionals who undergo training courses not only in the graduate school but also in the community medicine centers cooperating with central medical centers in Hokkaido. Furthermore, we have been committed to training medical staff who provide comprehensive healthcare for patients with cancer cross-regionally, cross-sectionally, and tumor-agnostically and researchers who can pursue genome medicine. The evaluation committee concluded that the plan was substantially advanced according to the evaluation guideline, and a committee member commented that the information through Web was assessable during the COVID-19 pandemic; in fact, it should be ensured by everyone. Based on these comments, we continuously work to develop human resources using content and information dissemination know-how accumulated in the Hokkaido medical personnel training plan.
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COVID-19 , Pandemias , COVID-19/prevenção & controle , Criança , Humanos , Recursos HumanosRESUMO
With the rise of COVID-19, the use of aerosol boxes when interacting with COVID-19 patients has increased. However, their use has been controversial. We have been involved in the development of a dome-shaped aerosol containment device with negative pressure (DAWN), an aerosol box that can maintain negative pressure inside at all times. There are two types of DAWN: one is mounted on a bed (bed type) and the other is mounted on a stretcher (stretcher type). Each device has its own characteristics and can be selected depending on the situation. The bed type has enough space inside to allow procedures to be performed easily. The stretcher type can be attached to a stretcher and can maintain negative pressure when the patient is being moved. Due to the negative pressure structure and easy change of nonwoven fabric adopted in both types of DAWN, it is expected to prevent the scattering of aerosol when it is removed, which is a problem of conventional aerosol boxes. DAWN will contribute to reducing the enormous psychological stress of medical personnel who treat infections, and will contribute to reducing aerosol dispersion.
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The rate of glycolysis in cancer cells is higher than that of normal cells owing to high energy demands, which results in the production of excess lactate. Monocarboxylate transporters (MCTs), especially MCT1 and MCT4, play a critical role in maintaining an appropriate pH environment through lactate transport, and their high expression is associated with poor prognosis in breast cancer. Thus, we hypothesized that inhibition of MCTs is a promising therapeutic target for adjuvant breast cancer treatment. We investigated the effect of MCT inhibition in combination with 4-hydroxytamoxifen (4-OHT), an active metabolite of tamoxifen, using two estrogen receptor (ER)-positive breast cancer cell lines, MCF-7 and T47D. Lactate transport was investigated in cellular uptake studies. The cytotoxicity of 4-OHT was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In both cell lines evaluated, MCT1 and MCT4 were constitutively expressed at the mRNA and protein levels. [14C]-L-lactate uptake by both cells was significantly inhibited by bindarit, a selective MCT4 inhibitor, but weakly affected by 5-oxoploline (5-OP), a selective MCT1 inhibitor. The results of the MTT assay showed that combination with bindarit, but not 5-OP, decreased 4-OHT sensitivity. Bindarit significantly increased the levels of hypoxia-inducible factor-1α (HIF-1α) in MCF-7 cells. Moreover, HIF-1α knockdown significantly increased 4-OHT sensitivity, whereas induction of HIF-1α by hypoxia decreased 4-OHT sensitivity in MCF-7 cells. In conclusion, pharmacological MCT4 inhibition confers resistance to 4-OHT rather than sensitivity, by increasing HIF-1α protein levels. In addition, HIF-1α inhibition represents a potential therapeutic strategy for enhancing 4-OHT sensitivity.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Proteínas Musculares/antagonistas & inibidores , Tamoxifeno/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Indazóis/farmacologia , Indazóis/uso terapêutico , Células MCF-7 , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Propionatos/farmacologia , Propionatos/uso terapêutico , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêuticoRESUMO
Valproate (VPA), an antiepileptic drug, is known to inhibit histone deacetylases (HDACs). Exposure to VPA during pregnancy increases several fetal risks. The maintenance of folate level during pregnancy is essential for adequate fetal development, and the placenta plays a critical role in supplying nutrients to the fetus. The aim of this study was to elucidate the effects of VPA on the gene expression of folate carriers and metabolizing enzymes in the rat placenta at both mid and late gestation periods. Pregnant rats were orally administered VPA on a single day or 4 days (repeated administration). Gene expression of folate carriers (Folr1, Slc19a1, Slc46a1) and metabolizing enzymes (Cth, Mtr, Mtrr, Mthfr, Dhfr) was assessed in the placenta on gestational day (GD) 13 or GD20. In the control rats, the expression of Folr1, Slc46a1, Cth, and Mthfr tended to be upregulated, whereas that of Mtrr and Dhfr was downregulated during gestation; the expression of Slc19a1 and Mtr did not change. Repeated VPA administration reduced the placental expression of Folr1and Mtr on GD20 and increased the expression of Dhfr on GD13 compared with the control. These findings indicate that administration of VPA alters the placental gene expression of folate carriers and metabolism-related enzymes.
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Placenta , Ácido Valproico , Animais , Anticonvulsivantes/uso terapêutico , Feminino , Ácido Fólico , Inibidores de Histona Desacetilases/farmacologia , Proteínas de Membrana Transportadoras , Antígenos de Histocompatibilidade Menor , Gravidez , Transportador de Folato Acoplado a Próton/genética , Ratos , Proteína Carregadora de Folato Reduzido/genéticaRESUMO
Human concentrative nucleoside transporters (CNTs) are responsible for cellular uptake of ribonucleosides; however, although it is important to better characterize CNT-subtype specificity to understand the systemic disposition of deoxyribonucleosides (dNs) and their analogs, the involvement of CNTs in transporting dNs is not fully understood. In this study, using COS-7 cells that transiently expressed CNT1, CNT2, or CNT3, we investigated if CNTs could transport not only ribonucleosides but also dNs, i.e., 2'-deoxyadenosine (dAdo), 2'-deoxyguanosine (dGuo), and 2'-deoxycytidine (dCyd). The cellular uptake study demonstrated that dAdo and dGuo were taken up by CNT2 but not by CNT1. Although dCyd was taken up by CNT1, no significant uptake was detected in COS-7 cells expressing CNT2. Similarly, these dNs were transported by CNT3. The apparent Km values of their uptake were as follows: CNT1, Km ï¼ 141 µM for dCyd; CNT2, Km ï¼ 62.4 µM and 54.9 µM for dAdo and dGuo, respectively; CNT3, Km ï¼ 14.7 µM and 34.4 µM for dGuo and dCyd, respectively. These results demonstrate that CNTs contribute not only to ribonucleoside transport but also to the transport of dNs. Moreover, our data indicated that CNT1 and CNT2 selectively transported pyrimidine and purine dNs, respectively, and CNT3 was shown to transport both pyrimidine and purine dNs.
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Desoxirribonucleosídeos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Animais , Transporte Biológico Ativo , Células COS , Chlorocebus aethiops , Desoxiadenosinas/metabolismo , Desoxicitidina/metabolismo , Desoxiguanosina/metabolismo , Humanos , Cinética , Proteínas de Membrana Transportadoras/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
Human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4) are involved in the proton-dependent transport of monocarboxylates such as L-lactate, which play an essential role in cellular metabolism and pH regulation. hMCT1 and 4 are overexpressed in a number of cancers, and polymorphisms in hMCT1 have been reported to be associated with the prognosis of some cancers. Accordingly, recent advances have focused on the inhibition of these transporters as a novel therapeutic strategy in cancers. To screen for MCT inhibitors for clinical application, it is important to study MCT function and regulation, and the effect of compounds on them, using human-derived cells. In this review, we focus on the transport function, regulation, and biology of hMCT1 and hMCT4, and the effects of genetic variation in these transporters in humans.