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1.
Mol Pharm ; 21(7): 3144-3150, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38862418

RESUMO

α1-Acid glycoprotein (AGP) is a primary binding protein for many basic drugs in plasma. The number of drugs that bind to AGP, such as molecular target anticancer drugs, has been continuously increasing. Since the plasma level of AGP fluctuates under various pathological conditions such as inflammation, it is important to evaluate the contribution of AGP to drug pharmacokinetics. Here, we generated conventional AGP-knockout (AGP-KO) mice and used them to evaluate the contribution of AGP. The pharmacokinetics of drugs that bind to two AGP variants (F1*S or A variants) or albumin were evaluated. Imatinib (a F1*S-binding drug) and disopyramide (an A-binding drug) or ibuprofen (an albumin-binding drug) were administered to wild-type (WT) and AGP-KO. The plasma level of imatinib and disopyramide decreased rapidly in AGP-KO as compared to WT. In AGP-KO, AUC and t1/2 were decreased, then CLtot was increased. Compared with disopyramide, imatinib pharmacokinetics showed more marked changes in AGP-KO as compared to WT. The results seemed to be due to the difference in plasma level of each AGP variant (F1*S:A = 2-3:1). No differences were observed in ibuprofen pharmacokinetics between the WT and AGP-KO mice. In vitro experiments using plasma from WT and AGP-KO showed that unbound fractions of imatinib and disopyramide were higher in AGP-KO. These results suggest that the rapid elimination of imatinib and disopyramide in AGP-KO could be due to decreased protein binding to AGP. Taken together, the AGP-KO mouse could be a potential animal model for evaluating the contribution of AGP to the pharmacokinetics of various drugs.


Assuntos
Ibuprofeno , Mesilato de Imatinib , Camundongos Knockout , Orosomucoide , Animais , Orosomucoide/metabolismo , Orosomucoide/genética , Camundongos , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/sangue , Ibuprofeno/farmacocinética , Ibuprofeno/administração & dosagem , Masculino , Ligação Proteica , Camundongos Endogâmicos C57BL
2.
Cancers (Basel) ; 16(1)2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38201587

RESUMO

Although benign hepatocellular adenomas (HCA) are very rare, recent observations have shown their occurrence in patients with diabetes mellitus. Consequently, most of these cases are treated by resection due to concerns regarding their potential progression to hepatocarcinoma (HCC). This decision is largely driven by the limited number of studies on HCC subtyping and the lack of molecular and biological insights into the carcinogenic potential of benign tumors. This study aimed to comprehensively investigate the subtype classification of HCA and to compare and analyze gene expression profiling between HCA and HCC tissues. One fresh inflammatory HCA (I-HCA), three non-B non-C HCCs, two hepatitis B virus-HCCs, and one normal liver tissue sample were subjected to single-cell RNA sequencing (scRNA-seq). Comparative analysis of scRNA-seq among different tissues showed that phospholipase A2 group IIA (PLA2G2A) mRNA was specifically expressed in I-HCA, following RNA-seq analysis in formalin-fixed paraffin-embedded tissues from other HCAs. Immunohistochemistry using the PLA2G2A antibody in these tissues indicated that the positive reaction was mainly observed in hepatocytes of I-HCAs and stromal cells surrounding the tumor tissue in HCC were also stained. According to a clinical database, PLA2G2A expression in HCC does not correlate with poor prognosis. This finding may potentially help develop a new definition for I-HCA, resulting in a significant clinical contribution, but it requires validation with other fresh HCA samples.

3.
Toxins (Basel) ; 13(12)2021 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-34941746

RESUMO

Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial-mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.


Assuntos
Fibrose/induzido quimicamente , Indicã/farmacologia , Nefropatias/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/farmacologia , NADPH Oxidases/metabolismo , Ornitina-Oxo-Ácido Transaminase/metabolismo , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Túbulos Renais/citologia , Macrófagos/efeitos dos fármacos , NADPH Oxidases/genética , Ornitina-Oxo-Ácido Transaminase/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Mol Pharm ; 18(12): 4322-4330, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34734526

RESUMO

Parathyroid hormone-related protein (PTHrP), which is secreted from a tumor, contributes to the progression of cachexia, a condition that is observed in half of all cancer patients. Although drug clearance was reported to decrease in patients with cancer cachexia, the details have not been clarified. The present study reports on an investigation of whether PTHrP is involved in the alternation of drug metabolism in cases of cancer cachexia. Cancer cachexia model rats with elevated serum PTHrP levels showed a significant decrease in hepatic and intestinal CYP3A2 protein expression. When midazolam, a CYP3A substrate drug, was administered intravenously or orally to the cancer cachexia rats, its area under the curve (AUC) was increased by about 2 and 5 times, as compared to the control group. Accordingly, the bioavailability of midazolam was increased by about 3 times, thus enhancing its pharmacological effect. In vitro experiments using HepG2 cells and Caco-2 cells showed that the addition of serum from cancer cachexia rats or active PTHrP (1-34) to each cell resulted in a significant decrease in the expression of CYP3A4 mRNA. Treatment with a cell-permeable cAMP analog also resulted in a decreased CYP3A4 expression. Pretreatment with protein kinase A (PKA), protein kinase C (PKC), and nuclear factor-kappa B (NF-κB) inhibitors recovered the decrease in CYP3A4 expression that was induced by PTHrP (1-34). These results suggest that PTHrP suppresses CYP3A expression via the cAMP/PKA/PKC/NF-κB pathway. Therefore, it is likely that PTHrP would be involved in the changes in drug metabolism observed in cancer cachexia.


Assuntos
Caquexia/metabolismo , Citocromo P-450 CYP3A/genética , Neoplasias/complicações , Proteína Relacionada ao Hormônio Paratireóideo/fisiologia , Animais , Células CACO-2 , Células Hep G2 , Humanos , Fígado/enzimologia , Masculino , Midazolam/farmacocinética , NF-kappa B/fisiologia , Proteína Quinase C/fisiologia , Ratos , Ratos Sprague-Dawley
5.
J Cachexia Sarcopenia Muscle ; 12(6): 1832-1847, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34599649

RESUMO

BACKGROUND: Sarcopenia with chronic kidney disease (CKD) progression is associated with life prognosis. Oxidative stress has attracted interest as a trigger for causing CKD-related muscular atrophy. Advanced oxidation protein products (AOPPs), a uraemic toxin, are known to increase oxidative stress. However, the role of AOPPs on CKD-induced muscle atrophy remains unclear. METHODS: In a retrospective case-control clinical study, we evaluated the relationship between serum AOPPs levels and muscle strength in haemodialysis patients with sarcopenia (n = 26, mean age ± SEM: 78.5 ± 1.4 years for male patients; n = 22, mean age ± SEM: 79.1 ± 1.5 for female patients), pre-sarcopenia (n = 12, mean age ± SEM: 73.8 ± 2.0 years for male patients; n = 4, mean age ± SEM: 74.3 ± 4.1 for female patients) or without sarcopenia (n = 12, mean age ± SEM: 71.3 ± 1.6 years for male patients; n = 7, mean age ± SEM: 77.7 ± 1.6 for female ). The molecular mechanism responsible for the AOPPs-induced muscle atrophy was investigated by using 5/6-nephrectomized CKD mice, AOPPs-overloaded mice, and C2C12 mouse myoblast cells. RESULTS: The haemodialysis patients with sarcopenia showed higher serum AOPPs levels as compared with the patients without sarcopenia. The serum AOPPs levels showed a negative correlation with grip strength (P < 0.01 for male patients, P < 0.01 for female patients) and skeletal muscle index (P < 0.01 for male patients). Serum AOPPs levels showed a positive correlation with cysteinylated albumin (Cys-albumin), a marker of oxidative stress (r2  = 0.398, P < 0.01). In the gastrocnemius of CKD mice, muscle AOPPs levels were also increased, and it showed a positive correlation with atrogin-1 (r2  = 0.538, P < 0.01) and myostatin expression (r2  = 0.421, P < 0.05), but a negative correlation with PGC-1α expression (r2  = 0.405, P < 0.05). Using C2C12 cells, AOPPs increased atrogin-1 and myostatin expression through the production of reactive oxygen species via CD36/NADPH oxidase pathway, and decreased myotube formation. AOPPs also induced mitochondrial dysfunction. In the AOPPs-overloaded mice showed that decreasing running time and hanging time accompanied by increasing AOPPs levels and decreasing cross-sectional area in gastrocnemius. CONCLUSIONS: Advanced oxidation protein products contribute to CKD-induced sarcopenia, suggesting that AOPPs or its downstream signalling pathway could be a therapeutic target for the treatment of CKD-induced sarcopenia. Serum AOPPs or Cys-albumin levels could be a new diagnostic marker for sarcopenia in CKD.


Assuntos
Insuficiência Renal Crônica , Sarcopenia , Produtos da Oxidação Avançada de Proteínas/metabolismo , Animais , Antígenos CD36 , Feminino , Humanos , Masculino , Camundongos , NADPH Oxidases/metabolismo , Estresse Oxidativo , Oxirredutases , Insuficiência Renal Crônica/complicações , Estudos Retrospectivos , Sarcopenia/etiologia
6.
PLoS One ; 16(5): e0251599, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33984028

RESUMO

Chronic HIV infection may exacerbate atherosclerotic vascular disease, which at advanced stages presents as necrotic plaques rich in crystalline cholesterol. Such lesions can catastrophically rupture precipitating myocardial infarct and stroke, now important causes of mortality in those living with HIV. However, in this population little is known about plaque structure relative to crystalline content and its chemical composition. Here, we first interrogated plaque crystal structure and composition in atherosclerotic SIV-infected macaques using non-linear optical microscopy. By stimulated Raman scattering and second harmonic generation approaches both amorphous and crystalline plaque lipid was detected and the crystal spectral profile indicated a cholesterol ester (CE) dominated composition. Versus controls, SIV+ samples had a greater number of cholesterol crystals (CCs), with the difference, in part, accounted for by crystals of a smaller length. Given the ester finding, we profiled HIV+ plaques and also observed a CE crystalline spectral signature. We further profiled plaques from Ldlr-/- mice fed a high fat diet, and likewise, found CE-dominate crystals. Finally, macrophage exposure to CCs or AcLDL induced auto-fluorescent puncta that co-stained with the LC3B autophagy sensor. In aggregate, we show that atheromatous plaques from mice, macaques and humans, display necrotic cores dominated by esterified CCs, and that plaque macrophages may induce autophagic vesicle formation upon encountering CCs. These findings help inform our knowledge of plaque core lipid evolution and how the process may incite systemic inflammation.


Assuntos
Ésteres do Colesterol/análise , Infecções por HIV/patologia , Placa Aterosclerótica/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Animais , HIV/isolamento & purificação , Infecções por HIV/complicações , Macaca , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Imagem Óptica , Placa Aterosclerótica/complicações , Células RAW 264.7 , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Vírus da Imunodeficiência Símia/isolamento & purificação
8.
Sci Rep ; 11(1): 7953, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846468

RESUMO

The molecular mechanism for acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) continues to be unclear. In this study, we investigated the pathophysiological role of the acute phase protein α1-acid glycoprotein (AGP) in AKI and its progression to CKD using AGP KO mice. Plasma AGP levels in WT mice were increased by about 3.5-fold on day 1-2 after renal ischemia-reperfusion (IR), and these values then gradually decreased to the level before renal IR on day 7-14. On day 1 after renal IR, the AGP KO showed higher renal dysfunction, tubular injury and renal inflammation as compared with WT. On day 14, renal function, tubular injury and renal inflammation in WT had recovered, but the recovery was delayed, and renal fibrosis continued to progress in AGP KO. These results obtained from AGP KO were rescued by the administration of human-derived AGP (hAGP) simultaneously with renal IR. In vitro experiments using RAW264.7 cells showed hAGP treatment suppressed the LPS-induced macrophage inflammatory response. These data suggest that endogenously induced AGP in early renal IR functions as a renoprotective molecule via its anti-inflammatory action. Thus, AGP represents a potential target molecule for therapeutic development in AKI and its progression CKD.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Anti-Inflamatórios/uso terapêutico , Progressão da Doença , Insuficiência Renal Crônica/tratamento farmacológico , alfa-Macroglobulinas/uso terapêutico , Injúria Renal Aguda/sangue , Injúria Renal Aguda/complicações , Animais , Anti-Inflamatórios/farmacologia , Humanos , Inflamação/sangue , Inflamação/complicações , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Testes de Função Renal , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Traumatismo por Reperfusão/sangue , alfa-Macroglobulinas/administração & dosagem , alfa-Macroglobulinas/farmacologia
9.
Toxins (Basel) ; 12(8)2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32764271

RESUMO

Adipose tissue inflammation appears to be a risk factor for the progression of chronic kidney disease (CKD), but the effect of CKD on adipose tissue inflammation is poorly understood. The purpose of this study was to clarify the involvement of uremic toxins (indoxyl sulfate (IS), 3-indoleacetic acid, p-cresyl sulfate and kynurenic acid) on CKD-induced adipose tissue inflammation. IS induces monocyte chemoattractant protein-1 (MCP-1) expression and reactive oxygen species (ROS) production in the differentiated 3T3L-1 adipocyte. An organic anion transporter (OAT) inhibitor, an NADPH oxidase inhibitor or an antioxidant suppresses the IS-induced MCP-1 expression and ROS production, suggesting the OAT/NADPH oxidase/ROS pathway is involved in the action of IS. Co-culturing 3T3L-1 adipocytes and mouse macrophage cells showed incubating adipocytes with IS increased macrophage infiltration. An IS-overload in healthy mice increased IS levels, oxidative stress and MCP-1 expression in epididymal adipose tissue compared to unloaded mice. Using 5/6-nephrectomized mice, the administration of AST-120 suppressed oxidative stress and the expression of MCP-1, F4/80 and TNF-α in epididymal adipose tissue. These collective data suggest IS could be a therapeutic target for the CKD-related inflammatory response in adipose tissue, and that AST-120 could be useful for the treatment of IS-induced adipose tissue inflammation.


Assuntos
Tecido Adiposo/metabolismo , Indicã/metabolismo , Inflamação/metabolismo , NADPH Oxidases/metabolismo , Insuficiência Renal Crônica/metabolismo , Células 3T3-L1 , Tecido Adiposo/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Proteínas de Ligação ao Cálcio/metabolismo , Carbono/farmacologia , Carbono/uso terapêutico , Quimiocina CCL2/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Óxidos/farmacologia , Óxidos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
10.
Sci Rep ; 10(1): 11424, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651445

RESUMO

Renal fibrosis is a major factor in the progression of chronic kidney disease and the final common pathway of kidney injury. Therefore, the effective therapies against renal fibrosis are urgently needed. The objective of this study was to investigate the effect of Am80, a synthetic retinoic acid receptor (RAR) agonist, in the treatment of renal interstitial fibrosis using unilateral ureteral obstruction (UUO) mice. The findings indicate that Am80 treatment suppressed renal fibrosis and inflammation to the same degree as the naturally-occuring retinoic acid, all-trans retinoic acid (atRA). But the adverse effect of body weight loss in Am80-treated mice was lower compared to the atRA treatment. The hepatic mRNA levels of alpha-1-acid glycoprotein (AGP), a downstream molecule of RAR agonist, was increased following administration of Am80 to healthy mice. In addition, increased AGP mRNA expression was also observed in HepG2 cells and THP-1-derived macrophages that had been treated with Am80. AGP-knockout mice exacerbated renal fibrosis, inflammation and macrophage infiltration in UUO mice, indicating endogenous AGP played an anti-fibrotic and anti-inflammatory role during the development of renal fibrosis. We also found that no anti-fibrotic effect of Am80 was observed in UUO-treated AGP-knockout mice whereas atRA treatment tended to show a partial anti-fibrotic effect. These collective findings suggest that Am80 protects against renal fibrosis via being involved in AGP function.


Assuntos
Benzoatos/farmacologia , Rim/efeitos dos fármacos , Orosomucoide/metabolismo , Receptores do Ácido Retinoico/agonistas , Tetra-Hidronaftalenos/farmacologia , Animais , Fibrose/tratamento farmacológico , Células Hep G2 , Humanos , Inflamação , Rim/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/metabolismo , Células THP-1
11.
Clin Biochem ; 81: 20-26, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32380091

RESUMO

OBJECTIVES: Cardiovascular disease is one of the major causes of death in patients with end-stage kidney disease who have undergone kidney transplantation. Since the complication of cardiovascular disease in patients with chronic kidney disease is strongly linked to oxidative stress, understanding the oxidative stress condition after kidney transplantation would be of great importance for the prevention of cardiovascular disease. This study examined whether improvement of renal function after kidney transplantation has an impact on the redox state of the Cys34 residue of albumin that reflects the level of oxidative stress in blood. DESIGN & METHODS: We enrolled 23 patients with end-stage renal failure who received kidney transplantation. All patients were followed for 180 days after transplantation. The fractions of albumin isoforms were determined by the electrospray ionization time-of-flight mass spectrometry (ESI-TOFMS) method. RESULTS: Serum creatinine decreased significantly immediately after kidney transplantation, suggesting successful transplantations. The ESI-TOFMS method identified three albumin isoforms cysteinylated at the Cys34 residue (Cys-Cys34-albumin) and the three corresponding albumin isoforms without Cys34 cysteinylation. The fraction of total Cys-Cys34-albumin decreased transiently after kidney transplantation, and was followed by an elevation at day 7 and gradual decrease thereafter until day 180. Meanwhile, reduced albumin concentration did not change until day 14 after kidney transplantation, then showed a significant increase compared to pre-transplant level at day 30 and remained stably elevated until day 180. CONCLUSIONS: Actual reduced albumin levels were found to exceed pre-transplant levels on or after day 30 following kidney transplantation unlike immediate restoration of renal function. Renal function was recovered immediately following kidney transplantation, but reduced albumen concentration increased above the pre-transplant levels only from day 30 after transplantation.


Assuntos
Cisteína/química , Falência Renal Crônica/terapia , Transplante de Rim/métodos , Estresse Oxidativo , Albumina Sérica/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Processamento de Proteína Pós-Traducional , Albumina Sérica/metabolismo
12.
Sci Rep ; 10(1): 5973, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249844

RESUMO

Oxidative stress and inflammation play a key role in the age-related decline in the respiratory function. Adipokine in relation to the metabolic and inflammatory systems is attracting growing interest in the field of respiratory dysfunction. The present clinical and experimental studies investigated the role of the disulfide bond-forming oxidoreductase A-like protein (DsbA-L) gene, which has antioxidant and adiponectin multimeric (i.e. activation) properties, on the respiratory function of the elderly. We performed a retrospective longitudinal genotype-phenotype relationship analysis of 318 Japanese relatively elderly participants (mean age ± standard deviation: 67.0 ± 5.8 years) during a health screening program and an in vitro DsbA-L knock-down evaluation using 16HBE14o-cells, a commonly evaluated human airway epithelial cell line. The DsbA-L rs1917760 polymorphism was associated with a reduction in the ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) and %FEV1 and with the elevation of the prevalence of FEV1/FVC < 70%. We also confirmed that the polymorphism was associated with a decreased respiratory function in relation to a decrease in the ratio of high-molecular-weight adiponectin/total adiponectin (as a marker of adiponectin multimerization) and an increase in the oxidized human serum albumin (as an oxidative stress marker). Furthermore, we clarified that DsbA-L knock-down induced oxidative stress and up-regulated the mucus production in human airway epithelial cells. These findings suggest that the DsbA-L gene may play a role in protecting the respiratory function of the elderly, possibly via increased systemic adiponectin functions secreted from adipocytes or through systemic and/or local pulmonary antioxidant properties.


Assuntos
Volume Expiratório Forçado/genética , Genótipo , Glutationa Transferase/genética , Polimorfismo de Nucleotídeo Único , Capacidade Vital/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Células Epiteliais/metabolismo , Feminino , Frequência do Gene , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Estudos Retrospectivos
13.
Sci Rep ; 10(1): 4313, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152335

RESUMO

Melinjo seed extract (MSE) contains large amounts of polyphenols, including dimers of trans-resveratrol (e.g. gnetin C, L, gnemonoside A, B and D), and has been shown to potentially improve obesity. However, there is no clinical evidence regarding the anti-obesity effects of MSE, and its mechanisms are also unclear. We investigated the hypothesis that MSE supplementation increases the adiponectin (APN) multimerization via the up-regulation of disulfide bond A oxidoreductase-like protein (DsbA-L) under either or both physiological and obese conditions. To investigate the effect of MSE on the physiological condition, 42 healthy young volunteers were enrolled in a randomized, double-blind placebo-controlled clinical trial for 14 days. The participants were randomly assigned to the MSE 150 mg/day, MSE 300 mg/day or placebo groups. Furthermore, in order to investigate the effect of MSE on APN levels under obese conditions, we administered MSE powder (500 or 1000 mg/kg/day) to control-diet- or high-fat-diet (HFD)-fed C57BL/6 mice for 4 weeks. All participants completed the clinical trial. The administration of MSE 300 mg/day was associated with an increase in the ratio of HMW/total APN in relation to the genes regulating APN multimerization, including DsbA-L. Furthermore, this effect of MSE was more pronounced in carriers of the DsbA-L rs191776 G/T or T/T genotype than in others. In addition, the administration of MSE to HFD mice suppressed their metabolic abnormalities (i.e. weight gain, increased blood glucose level and fat mass accumulation) and increased the levels of total and HMW APN in serum and the mRNA levels of ADIPOQ and DsbA-L in adipose tissue. The present study suggests that MSE may exert beneficial effects via APN multimerization in relation to the induction of DsbA-L under both physiological and obese conditions.


Assuntos
Adiponectina/química , Regulação da Expressão Gênica/efeitos dos fármacos , Gnetum/química , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Multimerização Proteica/efeitos dos fármacos , Adiponectina/metabolismo , Adulto , Animais , Dieta Hiperlipídica/efeitos adversos , Método Duplo-Cego , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/fisiopatologia , Estudos Prospectivos , Sementes/química , Regulação para Cima , Adulto Jovem
14.
Kidney360 ; 1(5): 343-353, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-35369369

RESUMO

Background: Recent clinical studies have shown that proteinuria is a critical factor in the progression of CKD and onset of cardiovascular disease. Inflammation and infiltration of macrophages into renal tissue are implicated as causes of proteinuria. α1-Acid glycoprotein (AGP), an acute-phase plasma protein, is leaked into the urine in patients with proteinuria. However, the relationship between urinary leakage of AGP, renal inflammation, and proteinuria remains unclear. Methods: Human AGP (hAGP) was exogenously administrated for 5 consecutive days to adriamycin-induced nephropathy model mice. Results: Adriamycin treatment increased urinary AGP, accompanied by decreased plasma AGP in mice. Exogenous hAGP administration to adriamycin-treated mice suppressed proteinuria, renal histologic injury, and inflammation. hAGP administration increased renal CD163 expression, a marker of anti-inflammatory macrophages. Similar changes were observed in PMA-differentiated THP-1 cells treated with hAGP. Even in the presence of LPS, hAGP treatment increased CD163/IL-10 expression in differentiated THP-1 cells. Conclusions: AGP alleviates proteinuria and renal injury in mice with proteinuric kidney disease via induction of CD163-expressing macrophages with anti-inflammatory function. The results demonstrate that endogenous AGP could work to protect against glomerular disease. Thus, AGP supplementation could be a possible new therapeutic intervention for patients with glomerular disease.


Assuntos
Nefropatias , Orosomucoide , Animais , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Doxorrubicina/efeitos adversos , Humanos , Nefropatias/induzido quimicamente , Macrófagos/metabolismo , Camundongos , Orosomucoide/metabolismo , Receptores de Superfície Celular
15.
Kidney360 ; 1(8): 781-796, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-35372949

RESUMO

Background: Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy. Methods: Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies. Results: In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway. Conclusions: AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.


Assuntos
Produtos da Oxidação Avançada de Proteínas , Ácidos Graxos , Acetiltransferases/genética , Produtos da Oxidação Avançada de Proteínas/metabolismo , Animais , Elongases de Ácidos Graxos , Ácidos Graxos/metabolismo , Rim/metabolismo , Camundongos
16.
Sci Rep ; 8(1): 17329, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478350

RESUMO

Renal fibrosis, the characteristic feature of progressive chronic kidney disease, is associated with unremitting renal inflammation. Although it is reported that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, elicits an anti-renal fibrotic effect, its molecular mechanism is still unknown. In this study, renal fibrosis and inflammation observed in the kidney of unilateral ureteral obstruction (UUO) mice were reduced by the treatment of 1,25(OH)2D3. The plasma protein level of alpha-1-acid glycoprotein (AGP), a downstream molecule of 1,25(OH)2D3, was increased following administration of 1,25(OH)2D3. Additionally, increased mRNA expression of ORM1, an AGP gene, was observed in HepG2 cells and THP-1-derived macrophages that treated with 1,25(OH)2D3. To investigate the involvement of AGP, exogenous AGP was administered to UUO mice, resulting in attenuated renal fibrosis and inflammation. We also found the mRNA expression of CD163, a monocyte/macrophage marker with anti-inflammatory potential, was increased in THP-1-derived macrophages under stimulus from 1,25(OH)2D3 or AGP. Moreover, AGP prevented lipopolysaccharide-induced macrophage activation. Thus, AGP could be a key molecule in the protective effect of 1,25(OH)2D3 against renal fibrosis. Taken together, AGP may replace vitamin D to function as an important immune regulator, offering a novel therapeutic strategy for renal inflammation and fibrosis.


Assuntos
Nefropatias/patologia , Nefropatias/prevenção & controle , Orosomucoide/metabolismo , Vitamina D/análogos & derivados , Animais , Modelos Animais de Doenças , Fibrose , Células Hep G2 , Humanos , Nefropatias/etiologia , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos ICR , Orosomucoide/genética , Obstrução Ureteral/complicações , Vitamina D/farmacocinética , Vitamina D/farmacologia
17.
CPT Pharmacometrics Syst Pharmacol ; 7(6): 384-393, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29569850

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity. Disulfide bond-forming oxidoreductase A-like protein (DsbA-L) is known to be a key molecule in protection against obesity and obesity-induced inflammation. In the present study, we used a modeling and simulation approach in an attempt to develop body mass index (BMI) and BMI-based NAFLD prediction models incorporating the DsbA-L polymorphism to predict the BMI and NAFLD in 341 elderly subjects. A nonlinear mixed-effect model best represented the sigmoidal relationship between the BMI and the logit function of the probability of NAFLD prevalence. The final models for BMI and NAFLD showed that DsbA-L rs1917760 polymorphism, age, and gender were associated with the BMI, whereas gender, patatin-like phospholipase 3 rs738409 polymorphism, HbA1c, and high-density and low-density lipoprotein cholesterol levels were associated with the risk of NAFLD. This information may aid in the genetic-based prevention of obesity and NAFLD in the general elderly population.


Assuntos
Glutationa Transferase/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/epidemiologia , Polimorfismo de Nucleotídeo Único , Adiponectina/metabolismo , Idoso , Índice de Massa Corporal , Peso Corporal , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Japão/epidemiologia , Estudos Longitudinais , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Dinâmica não Linear , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Prevalência , Estudos Retrospectivos
18.
J Pharm Sci ; 107(3): 848-855, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29074377

RESUMO

Chronic kidney disease (CKD) is accompanied by a variety of complications, typically renal anemia and kidney fibrosis. Accordingly, it is desirable to develop the novel therapeutics that can treat these CKD conditions. Since nitric oxide (NO) has multiple functions including hypoxia inducible factor stabilizing, anti-inflammatory, anti-oxidative, and anti-apoptoic activities, the use of NO for the CKD therapy has attracted considerable interest. Here, we evaluate the therapeutic impacts of S-nitrosated human serum albumin (SNO-HSA), a long-lasting NO donor, on 2 animal models of CKD. SNO-HSA increased the expression of erythropoietin (EPO), VEGF, and eNOS by stabilizing hypoxia inducible factor-1α in HepG2 and HK-2 cells. SNO-HSA increased hematopoiesis in both healthy and renal anemia rats, suggesting the promotion of EPO production. In unilateral ureteral obstruction-treated mice, SNO-HSA ameliorated kidney fibrosis by suppressing the accumulation of renal extracellular matrix. SNO-HSA also inhibited unilateral ureteral obstruction-induced α-smooth muscle actin increase and E-cadherin decrease, suggesting that SNO-HSA might suppress the accumulation of myofibroblasts, an important factor of fibrosis. SNO-HSA also inhibited the elevations of fibrosis factors, such as transforming growth factor-ß, interleukin-6, and oxidative stress, while it increased EPO production, an anti-fibrosis factor. In conclusion, SNO-HSA has the potential to function as a dual therapeutics for renal anemia and kidney fibrosis.


Assuntos
Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Compostos Nitrosos/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Albumina Sérica Humana/farmacologia , Anemia/tratamento farmacológico , Anemia/metabolismo , Animais , Linhagem Celular Tumoral , Eritropoetina/metabolismo , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Teóricos , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Wistar , Insuficiência Renal Crônica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Biochem Pharmacol ; 145: 192-201, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28843775

RESUMO

Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1-34). In Caco-2 cells, PTH (1-34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13-34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-κB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-κB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment.


Assuntos
AMP Cíclico/metabolismo , Citocromo P-450 CYP3A/metabolismo , Regulação para Baixo/fisiologia , Hormônio Paratireóideo/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Quinase C/metabolismo , Animais , Células CACO-2 , Cinacalcete/toxicidade , AMP Cíclico/genética , Citocromo P-450 CYP3A/genética , Moduladores GABAérgicos/farmacocinética , Regulação Enzimológica da Expressão Gênica/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hiperparatireoidismo/induzido quimicamente , Hiperparatireoidismo/metabolismo , Masculino , Midazolam/farmacocinética , NF-kappa B/genética , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteína Quinase C/genética , Distribuição Aleatória , Ratos , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais
20.
J Cachexia Sarcopenia Muscle ; 8(5): 735-747, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28608457

RESUMO

BACKGROUND: Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS-targeted intervention using AST-120, which inhibits IS accumulation, or mitochondria-targeted intervention using L-carnitine or teneligliptin, a dipeptidyl peptidase-4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice. METHODS: The in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6-nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non-treatment group and AST-120, L-carnitine, or teneligliptin treatment groups. RESULTS: In C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC-1α and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co-incubation with an anti-oxidant, ascorbic acid, L-carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin-6 and atrophy-related factors such as myostatin and atrogin-1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG-1α and increased muscular autophagy, as reflected by decreased mitochondria-rich type I fibres. An AST-120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L-carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level. CONCLUSIONS: Our results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS-targeted and mitochondria-targeted interventions for treating CKD-induced muscle atrophy and decreased exercise endurance.


Assuntos
Indicã/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Sarcopenia/tratamento farmacológico , Sarcopenia/etiologia , Animais , Antioxidantes/metabolismo , Biomarcadores , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Creatinina/sangue , Creatinina/urina , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Indicã/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Nitrogênio/sangue , Nitrogênio/urina , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sarcopenia/metabolismo
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