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1.
Mol Pharm ; 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38949624

RESUMEN

The plasma protein α1-acid glycoprotein (AGP) primarily affects the pharmacokinetics of basic drugs. There are two AGP variants in humans, A and F1*S, exhibiting distinct drug-binding selectivity. Elucidation of the drug-binding selectivity of human AGP variants is essential for drug development and personalized drug therapy. Herein, we aimed to establish the contribution of amino acids 112 and 114 of human AGP to drug-binding selectively. Both amino acids are located in the drug-binding region and differ between the variants. Phe112/Ser114 of the A variant and its equivalent residues in the F1*S variant (Leu112/Phe114) were swapped with each other. Binding experiments were then conducted using the antiarrhythmic drug disopyramide, which selectively binds to the A variant. A significant decrease in the bound fraction was observed in each singly mutated A protein (Phe112Leu or Ser114Phe). Moreover, the bound fraction of the double A mutant (Phe112Leu/Ser114Phe) was decreased to that of wild-type F1*S. Intriguingly, the double F1*S mutant (Leu112Phe/Phe114Ser), in which residues were swapped with those of the A variant, showed only partial restoration in binding. The triple F1*S mutant (Leu112Phe/Phe114Ser/Asp115Tyr), where position 115 is thought to contribute to the difference in pocket size between variants, showed a further recovery in binding to 70% of that of wild-type A. These results were supported by thermodynamic analysis and acridine orange binding, which selectively binds the A variant. Together, these data indicate that, in addition to direct interaction with Phe112 and Ser114, the binding pocket size contributed by Tyr115 is important for the drug-binding selectivity of the A variant.

2.
Mol Pharm ; 21(7): 3144-3150, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38862418

RESUMEN

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.


Asunto(s)
Ibuprofeno , Mesilato de Imatinib , Ratones Noqueados , Orosomucoide , Animales , Orosomucoide/metabolismo , Orosomucoide/genética , Ratones , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/sangre , Ibuprofeno/farmacocinética , Ibuprofeno/administración & dosificación , Masculino , Unión Proteica , Ratones Endogámicos C57BL
3.
J Atheroscler Thromb ; 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38382967

RESUMEN

AIMS: Acute myocardial infarction (AMI) causes irreversible damage to cardiomyocytes due to the discontinuation of oxygen supply and leads to systemic oxidative stress. It has been reported that high-density lipoprotein (HDL) particles have antioxidant capacity, and reduced antioxidant capacity is associated with decreased cholesterol efflux capacity (CEC). The purpose of this study was to clarify the usefulness of CEC measurement in patients with AMI. METHODS: We investigated the association between CEC and oxidative stress status in a case-control study. This study included 193 AMI cases and 445 age- and sex-matched controls. We examined the associations of CEC with HDL-cholesterol (HDL-C) and oxidized human serum albumin (HSA), an index of systemic oxidative stress status, and the effect of aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which has been reported to affect HDL-C level and risk for MI, on these associations. RESULTS: Both bivariable and multivariable analyses showed that CEC was positively correlated with HDL-C levels in both AMI cases and controls, with a weaker correlation in AMI cases than in controls. In AMI cases, oxidized HSA levels were associated with CEC in both bivariable and multivariable analyses, but not with HDL-C. These associations did not differ among the ALDH2 genotypes. CONCLUSIONS: CEC, but not HDL-C level, reflects systemic oxidative stress status in patients with AMI. CEC measurement for patients with AMI may be useful in that it provides information on systemic oxidative stress status as well as atherosclerosis risk.

4.
Biol Pharm Bull ; 46(10): 1421-1426, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37779043

RESUMEN

Despite the fact that liver fibrosis is an intractable disease with a poor prognosis, effective therapeutic agents are not available. In this study, we focused on bone morphogenetic factor 7 (BMP7) that inhibits transforming growth factor (TGF)-ß signaling, which is involved in liver fibrosis. We prepared an albumin-fused BMP7 (HSA-BMP7) that is retained in the blood and evaluated its inhibitory effect on liver fibrosis. Bile duct ligated mice were used as an acute liver fibrosis model, and carbon tetrachloride-induced liver fibrosis mice were used as a chronic model. All mice were administered HSA-BMP7 once per week. In the mice with bile duct ligation, the administration of HSA-BMP7 significantly suppressed the infiltration of inflammatory cells, the area of fibrosis around the bile duct, and decreased in the level of hydroxyproline as compared with saline administration. The mRNA expression of TGF-ß and its downstream fibrosis-associated genes (α-SMA and Col1a2) were also suppressed by the administration of HSA-BMP7. In the carbon tetrachloride-induced liver fibrosis mice, the HSA-BMP7 administration significantly decreased the hepatic fibrosis area and the level of hydroxyproline. Based on these results, it appears that HSA-BMP7 has the potential for serving as a therapeutic agent for the treatment of liver fibrosis.


Asunto(s)
Proteína Morfogenética Ósea 7 , Cirrosis Hepática , Animales , Ratones , Albúminas , Tetracloruro de Carbono , Hidroxiprolina/metabolismo , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Factor de Crecimiento Transformador beta1/metabolismo , Proteína Morfogenética Ósea 7/farmacología
5.
Front Immunol ; 14: 1034978, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36911681

RESUMEN

Neutralizing antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being developed world over. We investigated the possibility of producing artificial antibodies from the formalin fixation and paraffin-embedding (FFPE) lung lobes of a patient who died by coronavirus disease 2019 (COVID-19). The B-cell receptors repertoire in the lung tissue where SARS-CoV-2 was detected were considered to have highly sensitive virus-neutralizing activity, and artificial antibodies were produced by combining the most frequently detected heavy and light chains. Some neutralizing effects against the SARS-CoV-2 were observed, and mixing two different artificial antibodies had a higher tendency to suppress the virus. The neutralizing effects were similar to the immunoglobulin G obtained from healthy donors who had received a COVID-19 mRNA vaccine. Therefore, the use of FFPE lung tissue, which preserves the condition of direct virus sensitization, to generate artificial antibodies may be useful against future unknown infectious diseases.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Vacunas contra la COVID-19 , Autopsia , Anticuerpos Neutralizantes , Formaldehído , Adhesión en Parafina , Receptores de Antígenos de Linfocitos B
6.
Toxins (Basel) ; 15(3)2023 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-36977070

RESUMEN

Fat atrophy and adipose tissue inflammation can cause the pathogenesis of metabolic symptoms in chronic kidney disease (CKD). During CKD, the serum levels of advanced oxidation protein products (AOPPs) are elevated. However, the relationship between fat atrophy/adipose tissue inflammation and AOPPs has remained unknown. The purpose of this study was to investigate the involvement of AOPPs, which are known as uremic toxins, in adipose tissue inflammation and to establish the underlying molecular mechanism. In vitro studies involved co-culturing mouse-derived adipocytes (differentiated 3T3-L1) and macrophages (RAW264.7). In vivo studies were performed using adenine-induced CKD mice and AOPP-overloaded mice. Fat atrophy, macrophage infiltration and increased AOPP activity in adipose tissue were identified in adenine-induced CKD mice. AOPPs induced MCP-1 expression in differentiated 3T3-L1 adipocytes via ROS production. However, AOPP-induced ROS production was suppressed by the presence of NADPH oxidase inhibitors and the scavengers of mitochondria-derived ROS. A co-culturing system showed AOPPs induced macrophage migration to adipocytes. AOPPs also up-regulated TNF-α expression by polarizing macrophages to an M1-type polarity, and then induced macrophage-mediated adipose inflammation. In vitro data was supported by experiments using AOPP-overloaded mice. AOPPs contribute to macrophage-mediated adipose inflammation and constitute a potential new therapeutic target for adipose inflammation associated with CKD.


Asunto(s)
Productos Avanzados de Oxidación de Proteínas , Insuficiencia Renal Crónica , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Activación de Macrófagos , Inflamación/metabolismo , Insuficiencia Renal Crónica/metabolismo , Obesidad , Riñón/metabolismo
7.
Nutrients ; 15(4)2023 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-36839168

RESUMEN

Circulating fatty acid composition is assumed to play an important role in metabolic dysfunction-associated fatty liver disease (MAFLD) pathogenesis. This study aimed to investigate the association between the overall balance of serum fatty acid composition and MAFLD prevalence. This cross-sectional study involved 400 Japanese individuals recruited from a health-screening program. We measured fatty acids in serum lipids using gas chromatography-mass spectrometry. The serum fatty acid composition balance was evaluated using fuzzy c-means clustering, which assigns individual data points to multiple clusters and calculates the percentage of data points belonging to multiple clusters, and serum fatty acid mass%. The participants were classified into four characteristic subclasses (i.e., Clusters 1, 2, 3, and 4), and the specific serum fatty acid composition balance (i.e., Cluster 4) was associated with a higher MAFLD prevalence. We suggest that the fuzzy c-means method can be used to determine the circulating fatty acid composition balance and highlight the importance of focusing on this balance when examining the relationship between MAFLD and serum fatty acids.


Asunto(s)
Ácidos Grasos , Enfermedad del Hígado Graso no Alcohólico , Humanos , Estudios Transversales , Análisis por Conglomerados , Cromatografía de Gases y Espectrometría de Masas
8.
J Control Release ; 355: 42-53, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36690035

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) currently affects about 25% of the world's population, and the numbers continue to rise as the number of obese patients increases. However, there are currently no approved treatments for NAFLD. This study reports on the evaluation of the therapeutic effect of a recombinant human serum albumin-fibroblast growth factor 21 analogue fusion protein (HSA-FGF21) on the pathology of NAFLD that was induced by using two high-fat diets (HFD), HFD-60 and STHD-01. The HFD-60-induced NAFLD model mice with obesity, insulin resistance, dyslipidemia and hepatic lipid accumulation were treated with HSA-FGF21 three times per week for 4 weeks starting at 12 weeks after the HFD-60 feeding. The administration of HSA-FGF21 suppressed the increased body weight, improved hyperglycemia, hyperinsulinemia, and showed a decreased accumulation of plasma lipid and hepatic lipid levels. The elevation of C16:0, C18:0 and C18:1 fatty acids in the liver that were observed in the HFD-60 group was recovered by the HSA-FGF21 administration. The increased expression levels of the hepatic fatty acid uptake receptor (CD36) and fatty acid synthase (SREBP-1c, FAS, SCD-1, Elovl6) were also suppressed. In adipose tissue, HSA-FGF21 caused an improved adipocyte hypertrophy, a decrease in the levels of inflammatory cytokines and induced the expression of adiponectin and thermogenic factors. The administration of HSA-FGF21 to the STHD-01-induced NAFLD model mice resulted in suppressed plasma ALT and AST levels, oxidative stress, inflammatory cell infiltration and fibrosis. Together, HSA-FGF21 has some potential for use as a therapeutic agent for the treatment of NAFLD.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Albúminas/metabolismo , Dieta Alta en Grasa/efectos adversos , Lípidos/farmacología , Hígado/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Albúmina Sérica Humana
9.
J Atheroscler Thromb ; 30(1): 23-38, 2023 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-35249931

RESUMEN

AIMS: High levels of high-density lipoprotein cholesterol (HDL-C) are not necessarily effective in preventing atherosclerotic cardiovascular disease, and cholesterol efflux capacity (CEC) has attracted attention regarding HDL functionality. We aimed to elucidate whether drinking habits are associated with CEC levels, while also paying careful attention to confounding factors including serum HDL-C levels, other life style factors, and rs671 (*2), a genetic polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene determining alcohol consumption habit. METHODS: A cross-sectional study was performed in 505 Japanese male subjects who were recruited from a health screening program. Associations of HDL-C and CEC levels with drinking habits and ALDH2 genotypes were examined. RESULTS: The genotype frequencies of ALDH2 *1/*1 (homozygous wild-type genotype), *1/*2 and *2/*2 (homozygous mutant genotype) were 55%, 37% and 8%, respectively. Both HDL-C and CEC levels were higher in ALDH2 *1/*1 genotype carriers than in *2 allele carriers. Although HDL-C levels were higher in subjects who had a drinking habit than in non-drinkers, CEC levels tended to be lower in subjects with ≥ 46 g/day of alcohol consumption than in non-drinkers. Furthermore, CEC levels tended to be lower in ALDH2 *1/*1 genotype carriers with a drinking habit of ≥ 46 g/day than non-drinkers, while for *2 allele carriers, CEC levels tended to be lower with a drinking habit of 23-45.9 g/day compared to no drinking habit. CONCLUSIONS: Our results suggest that heavy drinking habits may tend to decrease CEC levels, and in the ALDH2 *2 allele carriers, even moderate drinking habits may tend to decrease CEC levels.


Asunto(s)
Consumo de Bebidas Alcohólicas , Aldehído Deshidrogenasa Mitocondrial , HDL-Colesterol , Humanos , Masculino , Aldehído Deshidrogenasa Mitocondrial/genética , HDL-Colesterol/metabolismo , Estudios Transversales , Polimorfismo Genético , Consumo de Bebidas Alcohólicas/genética
10.
Cancers (Basel) ; 16(1)2023 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-38201587

RESUMEN

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.

11.
J Diabetes Res ; 2022: 6934188, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35103243

RESUMEN

AIMS: This study is aimed at clarifying the relationship between visit-to-visit variability of glycated hemoglobin (HbA1c) and the risk of diabetic kidney disease (DKD) and to identifying the most useful index of visit-to-visit variability of HbA1c. METHODS: This clinic-based retrospective longitudinal study included 699 Japanese type 2 diabetes mellitus patients. Visit-to-visit variability of HbA1c was calculated as the internal standard deviation of HbA1c (HbA1c-SD), the coefficient of variation of HbA1c (HbA1c-CV), the HbA1c change score (HbA1c-HVS), and the area under the HbA1c curve (HbA1c-AUC) with 3-year serial HbA1c measurement data, and the associations between these indices and the development/progression of DKD were examined. RESULTS: Cox proportional hazards models showed that the HbA1c-SD and HbA1c-AUC were associated with the incidence of microalbuminuria, independently of the HbA1c level. These results were verified and replicated in propensity score (PS) matching and bootstrap analyses. Moreover, the HbA1c-SD and HbA1c-AUC were also associated with oxidized human serum albumin (HSA), an oxidative stress marker. CONCLUSIONS: Visit-to-visit variability of HbA1c was an independent risk factor of microalbuminuria in association with oxidative stress among type 2 diabetes mellitus patients. HbA1c-AUC, a novel index of HbA1c variability, may be a potent prognostic indicator in predicting the risk of microalbuminuria.


Asunto(s)
Nefropatías Diabéticas/diagnóstico , Hemoglobina Glucada/análisis , Medición de Riesgo/normas , Anciano , Análisis de Varianza , Biomarcadores/análisis , Biomarcadores/sangre , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/epidemiología , Femenino , Humanos , Incidencia , Japón/epidemiología , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo
12.
Toxins (Basel) ; 13(12)2021 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-34941746

RESUMEN

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.


Asunto(s)
Fibrosis/inducido químicamente , Indicán/farmacología , Enfermedades Renales/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/farmacología , NADPH Oxidasas/metabolismo , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Línea Celular , Células Epiteliales/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Túbulos Renales/citología , Macrófagos/efectos de los fármacos , NADPH Oxidasas/genética , Ornitina-Oxo-Ácido Transaminasa/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
13.
Mol Pharm ; 18(12): 4322-4330, 2021 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-34734526

RESUMEN

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.


Asunto(s)
Caquexia/metabolismo , Citocromo P-450 CYP3A/genética , Neoplasias/complicaciones , Proteína Relacionada con la Hormona Paratiroidea/fisiología , Animales , Células CACO-2 , Células Hep G2 , Humanos , Hígado/enzimología , Masculino , Midazolam/farmacocinética , FN-kappa B/fisiología , Proteína Quinasa C/fisiología , Ratas , Ratas Sprague-Dawley
14.
J Cachexia Sarcopenia Muscle ; 12(6): 1832-1847, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34599649

RESUMEN

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.


Asunto(s)
Insuficiencia Renal Crónica , Sarcopenia , Productos Avanzados de Oxidación de Proteínas/metabolismo , Animales , Antígenos CD36 , Femenino , Humanos , Masculino , Ratones , NADPH Oxidasas/metabolismo , Estrés Oxidativo , Oxidorreductasas , Insuficiencia Renal Crónica/complicaciones , Estudios Retrospectivos , Sarcopenia/etiología
15.
Int J Mol Sci ; 22(11)2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-34070521

RESUMEN

An effective strategy is highly desirable for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Thioredoxin-1 (Trx), a redox-active protein that has anti-oxidative and anti-inflammatory properties, would be a candidate for this but its short half-life limits its clinical application. In this study, we examined the renoprotective effect of long-acting Trx that is comprised of human albumin and Trx (HSA-Trx) against AKI to CKD transition. AKI to CKD mice were created by renal ischemia-reperfusion (IR). From day 1 to day 14 after renal IR, the recovery of renal function was accelerated by HSA-Trx administration. On day 14, HSA-Trx reduced renal fibrosis compared with PBS treatment. At the early phase of fibrogenesis (day 7), HSA-Trx treatment suppressed renal oxidative stress, pro-inflammatory cytokine production and macrophage infiltration, thus ameliorating tubular injury and fibrosis. In addition, HSA-Trx treatment inhibited G2/M cell cycle arrest and apoptosis in renal tubular cells. While renal Trx protein levels were decreased after renal IR, the levels were recovered by HSA-Trx treatment. Together, HSA-Trx has potential for use in the treatment of AKI to CKD transition via its effects of modulating oxidative stress and inflammation.


Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Insuficiencia Renal Crónica/metabolismo , Tiorredoxinas/administración & dosificación , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Insuficiencia Renal Crónica/patología , Tiorredoxinas/farmacología
16.
PLoS One ; 16(5): e0251599, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33984028

RESUMEN

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.


Asunto(s)
Ésteres del Colesterol/análisis , Infecciones por VIH/patología , Placa Aterosclerótica/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Animales , VIH/aislamiento & purificación , Infecciones por VIH/complicaciones , Macaca , Masculino , Ratones , Ratones Endogámicos C57BL , Imagen Óptica , Placa Aterosclerótica/complicaciones , Células RAW 264.7 , Síndrome de Inmunodeficiencia Adquirida del Simio/complicaciones , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación
17.
Sci Rep ; 11(1): 7953, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846468

RESUMEN

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.


Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Antiinflamatorios/uso terapéutico , Progresión de la Enfermedad , Insuficiencia Renal Crónica/tratamiento farmacológico , alfa-Macroglobulinas/uso terapéutico , Lesión Renal Aguda/sangre , Lesión Renal Aguda/complicaciones , Animales , Antiinflamatorios/farmacología , Humanos , Inflamación/sangre , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiopatología , Pruebas de Función Renal , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células RAW 264.7 , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/patología , Daño por Reperfusión/sangre , alfa-Macroglobulinas/administración & dosificación , alfa-Macroglobulinas/farmacología
19.
Biol Pharm Bull ; 43(10): 1583-1590, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32999168

RESUMEN

Chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT) have an increased risk of cardiovascular disease (CVD). Cinacalcet is a calcimimetic that permits impaired endothelial functions to be recovered via inhibiting parathyroid hormone (PTH) production in SHPT patients. However, the underlying mechanism for its action remains unknown. The purpose of this study was to examine the effect of cinacalcet on the redox state of human serum albumin (HSA), a reliable marker for assessing endothelial oxidative damage in SHPT patients who were receiving hemodialysis. Cinacalcet was administered to six SHPT patients for a period of 8 weeks. After 4 weeks of treatment, cinacalcet significantly decreased the oxidized albumin ratio which is a ratio of reduced and oxidized forms of HSA via increasing reduced form of HSA. Moreover, the radical scavenging abilities of HSA that was isolated from SHPT patients were increased by cinacalcet, suggesting the recovery of the impaired vascular anti-oxidant ability. Interestingly, the oxidized albumin ratio in SHPT patients was significantly higher than that in hemodialysis patients. In addition, the changes of intact PTH levels were significantly correlated with the oxidized albumin ratio. It therefore appears that PTH may induce oxidative stress in SHPT patients. In fact, an active analogue of PTH increased the production of reactive oxygen species in human endothelial cells. Thus, cinacalcet exhibits anti-oxidative activity through its pharmacological action. Additionally, cinacalcet itself showed radical scavenging activity. In conclusion, cinacalcet improves the redox status of HSA by inhibiting PTH production and partially by its radical scavenging action.


Asunto(s)
Antioxidantes/uso terapéutico , Cinacalcet/uso terapéutico , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/tratamiento farmacológico , Diálisis Renal/tendencias , Albúmina Sérica Humana/metabolismo , Adulto , Anciano , Antioxidantes/farmacología , Hormonas y Agentes Reguladores de Calcio/farmacología , Hormonas y Agentes Reguladores de Calcio/uso terapéutico , Cinacalcet/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxidación-Reducción/efectos de los fármacos , Hormona Paratiroidea/antagonistas & inhibidores , Hormona Paratiroidea/sangre , Diálisis Renal/efectos adversos , Resultado del Tratamiento
20.
Toxins (Basel) ; 12(8)2020 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-32764271

RESUMEN

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.


Asunto(s)
Tejido Adiposo/metabolismo , Indicán/metabolismo , Inflamación/metabolismo , NADPH Oxidasas/metabolismo , Insuficiencia Renal Crónica/metabolismo , Células 3T3-L1 , Tejido Adiposo/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Proteínas de Unión al Calcio/metabolismo , Carbono/farmacología , Carbono/uso terapéutico , Quimiocina CCL2/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos ICR , Estrés Oxidativo/efectos de los fármacos , Óxidos/farmacología , Óxidos/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo
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