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1.
J Physiol Anthropol ; 43(1): 8, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38310267

RESUMO

BACKGROUND: The concept of metabolically obese, normal weight (MONW) has emerged to describe individuals with a normal body mass index (BMI) who are at a relatively high risk of chronic diseases. However, BMI itself is a suboptimal index for the assessment of the health risks associated with visceral fat. The triglyceride-glucose (TyG) index is considered to be a reliable and cost-effective marker of insulin resistance. Therefore, in the present study, we aimed to determine the TyG index cut-off values that could be used to define MONW in older people and to determine the usefulness of these values for the prediction of chronic diseases. METHODS: A total of 4,721 participants in the Korea National Health and Nutritional Examination Survey who were ≥ 60 years of age and did not have underweight or obesity were included. MONW was defined using the criteria for metabolic syndrome (MS), and the TyG index was calculated on the basis of the fasting plasma triglyceride and glucose concentrations. Chronic diseases, including T2DM, hypertension, and non-alcoholic fatty liver disease (NAFLD), were diagnosed. RESULTS: The prevalence of MS increased from the lowest to the highest TyG index tertile. The cut-off values of the TyG index for MONW were calculated as 8.88 and 8.80 for males and females, respectively. MONW, defined using these cut-off values, was associated with high odds ratios for NAFLD, T2DM, and hypertension in both males and females. CONCLUSIONS: The TyG index cut-off values calculated in the present study can be used to discriminate individuals with MONW from other older individuals without obesity and to predict the risk of chronic diseases. These findings show that the TyG index is an effective and cost-efficient method of assessing the risk of chronic diseases in people with MONW.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Masculino , Feminino , Humanos , Idoso , Peso Corporal , Triglicerídeos , Glucose , Índice de Massa Corporal , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/epidemiologia , Síndrome Metabólica/epidemiologia , Glicemia , Diabetes Mellitus Tipo 2/complicações , Doença Crônica
2.
Ann Geriatr Med Res ; 27(3): 258-265, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37673691

RESUMO

BACKGROUND: Insulin resistance (IR) negatively affects several risk factors of chronic kidney disease (CKD). This cross-sectional study investigated whether the triglyceride-glucose (TyG) index, which reflects IR, was independently associated with CKD in a geriatric population, regardless of obesity and sex. METHODS: The analysis included 7,326 individuals (2,864 males and 4,462 females) aged ≥60 years. Non-obesity or obesity was evaluated using a body mass index cutoff of 25 kg/m2. The TyG index was calculated as ln [triglyceride concentration (mg/dL)×fasting plasma glucose concentration (mg/dL)]/2. All participants were categorized into three groups according to TyG tertiles. Moderate-to-severe CKD (MSCKD) was defined as an estimated glomerular filtration rate (eGFR) of <45.0 mL/min/1.73 m2. RESULTS: In males and females with or without obesity, a trend test showed a decreasing tendency in the eGFR from the lowest to highest TyG tertiles. Males without obesity and females with obesity in the middle and highest tertiles of the TyG index were 2.342 and 2.393, and were 2.313 and 3.516 times more likely to have MSCKD, respectively. Those with or without obesity in the highest tertile of the TyG index were 1.736 and 2.374 times more likely to have MSCKD, respectively. CONCLUSION: Geriatric populations with an increased TyG index have a high risk of MSCKD regardless of obesity and sex. Our findings suggest that increased IR is associated with CKD in the geriatric population independent of obesity and sex.

3.
Sci Data ; 10(1): 547, 2023 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-37604898

RESUMO

After the Fukushima nuclear accident, the Japanese government implemented extensive decontamination work in 137Cs contaminated catchments for residents' health and local revitalization. Whether dramatic land use changes in the upstream decontaminated regions affected river suspended sediment (SS) and particulate 137Cs discharge downstream remain unknown because of the poor quantification on land cover changes and long-term river SS dynamics. We here introduce a 6-year concurrent database of the Niida River Basin, a decontaminated catchment, including the first available vector decontamination maps, satellite images in decontaminated regions with a spatial resolution of 10 m, and long-term river monitoring datasets spanning decontamination (2013-2016) and subsequent natural restoration stages (2017-2018). These datasets allow us, for the first time, to directly link the transport dynamics of river SS (particulate 137Cs) to land use changes caused by humans in real-time, which provide fundamental data for better understanding the river response of sediment to land use change. Moreover, the data obtained by interdisciplinary methods offer a template for land use change impact assessment in other river basins.

4.
Nutrients ; 15(3)2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36771263

RESUMO

PURPOSE: This population-based cross-sectional study aimed to determine whether the triglyceride-glucose index (TyG index) is associated with sarcopenic obesity (SO) and whether it would be a helpful indicator of SO. METHODS: A total of 3821 participants aged ≥ 60 years were selected for the study group, and 4919 participants aged 20-39 years were included as a reference group. The participants were allocated to sarcopenia, obesity, and SO groups depending on if their body mass index (BMI) was ≥25 kg/m2 and their sarcopenia index was ≤1 standard deviation (SD) lower than the mean of the reference group. The sex-specific differences and trends among the participants were analyzed by using the TyG index tertiles, and appropriate cut-off values of the TyG index for SO were calculated. RESULTS: As the TyG index increased, BMI increased, but the sarcopenia index decreased in both sexes. Males and females in the middle and highest tertiles of the TyG index were 1.775 and 3.369, and they were 1.993 and 3.157 times more likely to have SO, respectively. The cut-off values of the TyG index for SO in males and females were ≥8.72 and 8.67, respectively. CONCLUSION: A high TyG index is positively associated with SO, and the TyG index may be considered a potential indicator of SO.


Assuntos
Resistência à Insulina , Sarcopenia , Masculino , Feminino , Humanos , Idoso , Glucose , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Triglicerídeos , Fatores de Risco , Estudos Transversais , Glicemia , Obesidade/complicações , Biomarcadores
5.
Int J Mol Sci ; 23(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36555105

RESUMO

Metabolic syndrome is associated with the development of chronic kidney disease (CKD). We previously demonstrated that aged kidneys are prone to developing tertiary lymphoid tissues (TLTs) and sustain inflammation after injury, leading to CKD progression; however, the relationship between renal TLT and metabolic syndrome is unknown. In this study, we demonstrated that a high-fat diet (HFD) promoted renal TLT formation and inflammation via sterol O-acyltransferase (SOAT) 1-dependent mechanism. Mice fed a HFD prior to ischemic reperfusion injury (IRI) exhibited pronounced renal TLT formation and sustained inflammation compared to the controls. Untargeted lipidomics revealed the increased levels of cholesteryl esters (CEs) in aged kidneys with TLT formation after IRI, and, consistently, the Soat1 gene expression increased. Treatment with avasimibe, a SOAT inhibitor, attenuated TLT maturation and renal inflammation in HFD-fed mice subjected to IRI. Our findings suggest the importance of SOAT1-dependent CE accumulation in the pathophysiology of CKDs associated with TLT.


Assuntos
Doenças Metabólicas , Síndrome Metabólica , Insuficiência Renal Crônica , Traumatismo por Reperfusão , Animais , Camundongos , Síndrome Metabólica/metabolismo , Dieta Hiperlipídica/efeitos adversos , Esterol O-Aciltransferase/genética , Esterol O-Aciltransferase/metabolismo , Rim/metabolismo , Tecido Linfoide/metabolismo , Inflamação/metabolismo , Fibrose , Insuficiência Renal Crônica/metabolismo , Doenças Metabólicas/metabolismo , Traumatismo por Reperfusão/metabolismo , Camundongos Endogâmicos C57BL
6.
J Gen Fam Med ; 23(3): 140-148, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35509345

RESUMO

Background: Decreased pulmonary function and poor deglutition are a major risk factor for poststroke aspiration pneumonia. We analyzed the benefits of pulmonary training on pulmonary function, deglutition, and quality of life (QOL) in community-dwelling, frail elderly people with chronic stroke. Method: This study was designed as an open, randomized, controlled pilot trial. The participants, who were frail older adults with a history of stroke, were randomized to 2 rehabilitation groups: intervention group (n = 15) and control (n = 15). All participants (65-94 years) attended twelve 20-min sessions twice a week for 6 weeks of either standard rehabilitation (control group) or standard rehabilitation with pulmonary training including home pulmonary exercise (intervention group). The main outcome measures were pulmonary function (%MIP), deglutition (DRACE), and QOL (SF8ï½¥PCS), while secondary outcomes were muscle strength (grip and abdominal), thorax flexibility, 6-min walk distance, and activities in daily living. All outcomes were measured both prior to training and after the 12 sessions. Results: The intervention group showed significant improvement in %MIP (95% CI, 2.9-31.6; p < 0.01), DRACE (95% CI, -4.1-0.1; p < 0.01), and SF8ï½¥PCS (95% CI, 2.5-7.2; p < 0.01) compared with controls. There were no cognitive function decline and higher brain dysfunction. Conclusions: These results suggest that the addition of pulmonary training including home pulmonary exercise to a standard rehabilitation program could improve pulmonary function, deglutition, and QOL in frail elderly people with chronic stroke.

7.
CEN Case Rep ; 11(4): 428-435, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35267179

RESUMO

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is life-threatening without treatment, but aggressive immunosuppression increases the risk of exacerbating a coexisting infection. Finding the balance between efficacy and safety of immunosuppression is challenging. We describe a 74-year-old man who was diagnosed with AAV following the aggravation of chronic pulmonary aspergillosis that required an aggressive antifungal agent. The laboratory data on admission demonstrated severe kidney failure requiring hemodialysis. Due to the active infection, we chose intravenous immunoglobulin (IVIg) as a low-risk initial treatment, which remarkably improved renal dysfunction (serum creatinine; 16.7 mg/dL-3.7 mg/dL) and systemic inflammation. Renal biopsy that was performed after renal recovery revealed atypical ANCA-associated nephritis without cellular crescents but with massive arteritis with multiple vascular sizes and diffuse interstitial inflammation. Despite these active AAV findings, adding plasma exchange therapy (PE) and low-dose steroids were sufficient to induce remission. The main pathogenesis of severe renal impairment was probably the reduction of blood flow, resulting from occlusions of small arteries by inflammatory cell infiltration and vascular endothelial injury due to AAV. Combination treatment with antifungal agents, IVIg, PE, and low-dose steroid treatment led to complete resolution of vasculitis. The specific histological findings and the good response to treatments suggest that pulmonary aspergillosis might trigger vasculitis through induction of ANCA antigen expression. IVIg could be an important option especially for cases of AAV associated with pulmonary aspergillosis.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Aspergilose Pulmonar Invasiva , Masculino , Humanos , Idoso , Anticorpos Anticitoplasma de Neutrófilos , Imunoglobulinas Intravenosas , Aspergilose Pulmonar Invasiva/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Inflamação/complicações
9.
Sci Total Environ ; 821: 153408, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35090916

RESUMO

This study presents the temporal variations in riverine 137Cs concentrations and fluxes to the ocean during high-flow events in three coastal river catchments contaminated by the Fukushima Daiichi Nuclear Power Plant accident. River water samples were collected at points downstream in the Niida, Ukedo, and Takase Rivers during three high-flow events that occurred in 2019-2020. Variations in both the dissolved and particulate 137Cs concentrations appeared to reflect the spatial pattern of the 137Cs inventory in the catchments, rather than variations in physico-chemical properties of water and suspended solid. Negative relationships between the 137Cs concentration and δ15N in suspended solid were found in all rivers during the intense rainfall events, suggesting an increased contribution of sediment from forested areas to the elevation of particulate 137Cs concentration. The 137Cs flux ranged from 0.33 to 19 GBq, depending on the rainfall erosivity. The particulate 137Cs fluxes from the Ukedo River were relatively low compared with the other two rivers and were attributed to the effect of the Ogaki Dam reservoir upstream. The percentage of 137Cs desorbed in seawater relative to 137Cs in suspended solids ranged from 2.8% to 6.6% and tended to be higher with a higher fraction of exchangeable 137Cs. The estimated potential release of 137Cs desorbed from suspended solids to the ocean was 0.022-0.57 GBq, and its ratio to the direct flux of dissolved 137Cs was 0.12-6.2. Episodic sampling during high-flow events demonstrated that the particulate 137Cs flux depends on catchment characteristics and controls 137Cs transfer to the ocean.


Assuntos
Acidente Nuclear de Fukushima , Monitoramento de Radiação , Poluentes Radioativos da Água , Radioisótopos de Césio/análise , Japão , Poluentes Radioativos da Água/análise
10.
BJU Int ; 129(4): 534-541, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34383381

RESUMO

OBJECTIVES: To compare the urinary pH, recurrence-free survival (RFS), and safety of adjuvant intravesical therapy in patients with non-muscle-invasive bladder cancer (NMIBC) receiving mitomycin C (MMC) therapy and MMC + cytosine arabinoside (Ara-C) therapy. PATIENTS AND METHODS: A total of 165 patients with NMIBC from six hospitals were randomly allocated to two groups: weekly instillation of MMC + Ara-C (30 mg/30 mL + 200 mg/10 mL) for 6 weeks and the same instillation schedule of MMC (30 mg/40 mL). The primary outcome was RFS, and secondary outcomes were urinary pH and toxicity in the two groups. RESULTS: A total of 81 and 87 patients were randomised into the MMC and MMC + Ara-C groups, respectively. Overall, the RFS in the MMC + Ara-C group was significantly longer (P = 0.018) than that in the MMC group. A similar significant difference was detected in patients with intermediate-risk NMIBC, but not in those with high-risk NMIBC. The mean (SD) urinary pH was significantly higher in the MMC + Ara-C group than in the MMC group, at 6.56 (0.61) vs 5.78 (0.64) (P < 0.001), and the frequency of a urinary pH of >7.0 in the MMC and MMC + Ara-C groups was 6.3% and 26.7%, respectively (P < 0.001). Multivariate analysis models including clinicopathological features and second transurethral resection demonstrated that increased urinary pH was associated with better outcomes (hazard ratio 0.18, 95% confidential interval 0.18-0.038; P < 0.001). In all, there were 14 and 10 adverse events in the MMC and MMC + Ara-C groups, respectively, without a significant difference (P = 0.113). CONCLUSIONS: Our randomised clinical trial suggested that intravesical therapy with MMC and Ara-C is useful and safe for patients with intermediate-risk NMIBC. Increase in urinary pH with Ara-C is speculated as a mechanism for increased anti-cancer effects.


Assuntos
Mitomicina , Neoplasias da Bexiga Urinária , Administração Intravesical , Antibióticos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Feminino , Humanos , Masculino , Mitomicina/uso terapêutico , Neoplasias da Bexiga Urinária/cirurgia
11.
J Clin Invest ; 132(2)2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34813503

RESUMO

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.


Assuntos
Injúria Renal Aguda/imunologia , Envelhecimento/imunologia , Ligante CD30/imunologia , Antígeno Ki-1/imunologia , Tecido Linfoide/imunologia , Transdução de Sinais/imunologia , Injúria Renal Aguda/genética , Envelhecimento/genética , Animais , Ligante CD30/genética , Linfócitos T CD4-Positivos/imunologia , Antígeno Ki-1/genética , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/genética
12.
Front Oncol ; 11: 754365, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804943

RESUMO

Metastatic brain tumors are regarded as the most advanced stage of certain types of cancer; however, chemotherapy has played a limited role in the treatment of brain metastases. Here, we established murine models of brain metastasis using cell lines derived from human brain metastatic tumors, and aimed to explore the antitumor efficacy of perifosine, an orally active allosteric Akt inhibitor. We evaluated the effectiveness of perifosine by using it as a single agent in ectopic and orthotopic models created by injecting the DU 145 and NCI-H1915 cell lines into mice. Initially, the injected cells formed distant multifocal lesions in the brains of NCI-H1915 mice, making surgical resection impractical in clinical settings. We determined that perifosine could distribute into the brain and remain localized in that region for a long period. Perifosine significantly prolonged the survival of DU 145 and NCI-H1915 orthotopic brain tumor mice; additionally, complete tumor regression was observed in the NCI-H1915 model. Perifosine also elicited much stronger antitumor responses against subcutaneous NCI-H1915 growth; a similar trend of sensitivity to perifosine was also observed in the orthotopic models. Moreover, the degree of suppression of NCI-H1915 tumor growth was associated with long-term exposure to a high level of perifosine at the tumor site and the resultant blockage of the PI3K/Akt signaling pathway, a decrease in tumor cell proliferation, and increased apoptosis. The results presented here provide a promising approach for the future treatment of patients with metastatic brain cancers and emphasize the importance of enriching a patient population that has a higher probability of responding to perifosine.

14.
Sci Rep ; 11(1): 6685, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758275

RESUMO

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in regulating cell growth, survival, and metastasis. STAT3 signaling is constitutively activated in various types of hematologic or solid malignancies. YHO-1701 has been developed as an orally available STAT3 inhibitor. Herein, YHO-1701 in combination with molecular-targeted agents was evaluated. Additive or synergistic effects were observed in a broad spectrum of "combination treatment + cell line" pairs. Of particular interest was the synergistic effect observed when YHO-1701 was combined with imatinib or dasatinib [breakpoint cluster region-abelson (BCR-ABL) inhibitors], osimertinib [epidermal growth factor receptor (EGFR) inhibitor], crizotinib, alectinib, or ceritinib [anaplastic lymphoma kinase (ALK) inhibitors]. The results further showed a close relationship between these synergistic effects and the cellular levels of the key molecules involved in the target pathways for YHO-1701 and each combination drug. The combination of YHO-1701 with alectinib resulted in significantly greater antitumor activity without exhibiting body weight loss in an NCI-H2228 [echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion] xenograft mouse model. Our results strongly suggest that the logical strategy in combination with the novel STAT3 inhibitor YHO-1701 and other mechanistically different targeted agents, could be a promising approach in future clinical settings.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Camundongos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem
15.
CEN Case Rep ; 10(4): 461-467, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33683583

RESUMO

Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder with genetic defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, leading to recurrent severe infections and granuloma formation. Genitourinary involvement, including obstructive granulomas, infections, nephrotoxicity of anti-infective agents, and amyloidosis, is frequently observed in patients with CGD, whereas the clinical and pathological details of the less commonly reported glomerular disease remain obscure. Here, we report the case of a patient with CGD who developed rapidly progressive IgA vasculitis-associated nephritis (IgAVN) and review the literature on biopsy-proven glomerular diseases in patients with CGD. A 22-year-old male patient with CGD developed rapidly progressive glomerulonephritis (RPGN) following peripheral purpura and was diagnosed with crescentic IgAVN based on the renal biopsy evaluation. There was no evidence of active infections, and he received pulse intravenous methylprednisolone followed by oral prednisolone. His renal function returned to normal within 4 weeks, and his proteinuria and microhematuria finally resolved. The present case and literature review indicate that IgAVN and IgA nephropathy with RPGN are the most common causes of glomerular disease in patients with CGD. Clinicians should be aware of the possibility of these diseases as causes of RPGN in CGD, because delays in diagnosis and appropriate treatment may affect renal outcomes.


Assuntos
Glomerulonefrite por IGA/tratamento farmacológico , Doença Granulomatosa Crônica/complicações , Vasculite por IgA/complicações , Imunossupressores/administração & dosagem , Metilprednisolona/administração & dosagem , Glomerulonefrite por IGA/etiologia , Glomerulonefrite por IGA/patologia , Humanos , Glomérulos Renais/ultraestrutura , Masculino , Adulto Jovem
16.
Sci Data ; 7(1): 433, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33319799

RESUMO

Radiocesium released from the Fukushima Daiichi nuclear power plant (FDNPP) and deposited in the terrestrial environment has been transported to the sea through rivers. To study the long-term effect of riverine transport on the remediation process near the FDNPP, a monitoring project was initiated by the University of Tsukuba. It was commissioned by the Ministry of Education, Culture, Sports, Science, and Technology, and the Nuclear Regulatory Commission in June 2011, and was taken over by the Fukushima Prefectural Centre for Environmental Creation from April 2015. The activity concentration and monthly flux of radiocesium in a suspended form were measured in the project. This provides valuable measurement data to evaluate the impact of the accidentally released radiocesium on residents and the marine environment. It can also be used as verification data in the development and testing of numerical models to predict future impacts.


Assuntos
Radioisótopos de Césio/análise , Acidente Nuclear de Fukushima , Rios/química , Poluentes Radioativos da Água/análise , Monitoramento Ambiental , Japão , Centrais Nucleares
17.
Cancer Sci ; 111(5): 1774-1784, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32112605

RESUMO

The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival and invasion. Aberrant STAT3 has been demonstrated in various malignant cancers. YHO-1701 is a novel quinolinecarboxamide derivative generated from STX-0119. Here, we examined the effect of YHO-1701 on STAT3 and evaluated antitumor activity of YHO-1701 as a single agent and in combination. YHO-1701 inhibited STAT3-SH2 binding to phospho-Tyr peptide selectively and more potently than STX-0119 in biochemical assays. Molecular docking studies with STAT3 suggested more stable interaction of YHO-1701 with the SH2 domain. YHO-1701 exhibited approximately 10-fold stronger activity than STX-0119 in abrogating the STAT3 signaling pathway of human oral cancer cell line SAS. YHO-1701 also blocked multi-step events by inhibiting STAT3 dimerization and suppressed STAT3 promoter activity. As expected, YHO-1701 exerted strong antiproliferative activity against human cancer cell lines addicted to STAT3 signaling. Orally administered YHO-1701 showed statistically significant antitumor effects with long exposure to high levels of YHO-1701 at tumor sites in SAS xenograft models. Moreover, combination regimen with sorafenib led to significantly stronger antitumor activity. In addition, the suppression level of survivin (a downstream target) was superior for the combination as compared with monotherapy groups within tumor tissues. Thus, YHO-1701 had a favorable specificity for STAT3 and pharmacokinetics after oral treatment; it also contributed to the enhanced antitumor activity of sorafenib. The evidence presented here provides justification using for this approach in future clinical settings.


Assuntos
Antineoplásicos/farmacologia , Quinolinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Interleucina-6/sangue , Camundongos , Simulação de Acoplamento Molecular , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Multimerização Proteica/efeitos dos fármacos , Quinolinas/química , Quinolinas/uso terapêutico , Fator de Transcrição STAT3/química , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Survivina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Domínios de Homologia de src
18.
Environ Sci Technol ; 53(21): 12339-12347, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31490064

RESUMO

The Fukushima Daiichi Nuclear Power Plant (FDNPP) accident released the most significant quantity of radiocesium into the environment since Chernobyl, and detailed measurements over the initial 5 years provide new insights into fluvial redistribution of radiocesium. We found that the high initial activity concentration of 137Cs-bearing suspended sediment in rivers was followed by a steep exponential decline (λ1) which extended to approximately 1 year after the accident, while the rate of initial decline in radiocesium activity concentration in water was an order of magnitude higher than rates measured after Chernobyl. Fluvial transport of 137Cs to the ocean from the Abukuma river totaled 12 TBq between June 2011 and August 2015 and almost all this radiocesium (96.5%) was transported in the particulate form. The primary sources of 137Cs were paddy fields, farmland, and urban areas [plaque-forming unit (PFU)], discharging 85% of the exported 137Cs from 38% of the watershed area. After 1 year, activity concentrations were lower and exhibited a more gradual secondary decline (λ2) which was associated with reduced radiocesium losses from PFU areas, while forest areas continue to represent more stable contaminant stores.


Assuntos
Acidente Nuclear de Fukushima , Monitoramento de Radiação , Poluentes Radioativos do Solo , Poluentes Radioativos da Água , Radioisótopos de Césio , Japão , Rios
19.
Sci Total Environ ; 697: 134093, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31487585

RESUMO

To investigate the main factors that control the dissolved radiocesium concentration in river water in the area affected by the Fukushima Daiichi nuclear power plant accident, the correlations between the dissolved 137Cs concentrations at 66 sites normalized to the average 137Cs inventories for the watersheds with the land use, soil components, topography, and water quality factors were assessed. We found that the topographic wetness index is significantly and positively correlated with the normalized dissolved 137Cs concentration. Similar positive correlations have been found for European rivers because wetland areas with boggy organic soils that weakly retain 137Cs are mainly found on plains. However, for small Japanese river watersheds, the building area ratio in the watershed strongly affected the dissolved 137Cs concentration. One reason for this would be because the high concentrations of solutes, such as K+ and dissolved organic carbon, discharged in urban areas would inhibit 137Cs absorption to soil particles. A multiple regression equation was constructed to predict the normalized dissolved 137Cs concentration with the topography, land use, soil component, and water quality data as explanatory variables. The best model had the building land use as the primary predictor. When comparing two multiple regression models in which the explanatory variables were limited to (1) the land use and soil composition and (2) the water quality, the water quality model underestimated the high normalized dissolve 137Cs concentration in urban areas. This poor reproducibility indicates that the dissolved 137Cs concentration value in urban areas cannot be solely explained by the solid-liquid distribution of 137Cs owing to the influence of the water quality, but some specific 137Cs sources in urban areas would control the dissolved 137Cs concentration.

20.
CEN Case Rep ; 8(4): 292-296, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31347098

RESUMO

Occasionally, over-anticoagulation with warfarin induces acute kidney injury (AKI) characterized by glomerular hemorrhage with tubular obstruction by red blood cell casts, which is widely acknowledged as warfarin-related nephropathy. Owing to extensive use of direct oral anticoagulants, similar AKI cases have been reported among patients treated with dabigatran. Dabigatran is primarily excreted by the kidneys; thus, renal impairment is one of the risk factors for dabigatran-induced bleeding complications. Nevertheless, risk factors for dabigatran-induced anticoagulant-related nephropathy (ARN) remain partially clarified. Here, we report a histologically established case of dabigatran-induced ARN with undiagnosed IgA nephropathy in a patient with normal baseline renal function. In addition, we summarize previously published cases of biopsy-proven, dabigatran-related ARN. A 67-year-old female with normal preexisting renal function developed macrohematuria and AKI. She had been treated with dabigatran for deep vein thrombosis. A renal biopsy diagnosed ARN with inactive IgA nephropathy. After dabigatran withdrawal, her macrohematuria and renal function improved. This report demonstrates that ARN could occur in patients with normal baseline renal function. Our case and prior reports suggest that IgA nephropathy could be a risk factor for dabigatran-induced ARN.


Assuntos
Injúria Renal Aguda/patologia , Anticoagulantes/efeitos adversos , Dabigatrana/efeitos adversos , Glomerulonefrite por IGA/patologia , Injúria Renal Aguda/induzido quimicamente , Idoso , Anticoagulantes/uso terapêutico , Dabigatrana/uso terapêutico , Feminino , Glomerulonefrite por IGA/complicações , Hematúria/diagnóstico , Hematúria/etiologia , Humanos , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Trombose Venosa/tratamento farmacológico , Suspensão de Tratamento
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