RESUMO
Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.
Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Inibidores do Transportador 2 de Sódio-Glicose , Sorbitol , Animais , Camundongos , Carcinoma Hepatocelular/prevenção & controle , Diabetes Mellitus/tratamento farmacológico , Modelos Animais de Doenças , Interleucina-33/metabolismo , Interleucina-33/uso terapêutico , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sorbitol/análogos & derivadosRESUMO
OBJECTIVE: Sodium-glucose cotransporter-2 (SGLT2) inhibitors exhibit cardioprotective properties in patients with diabetes. However, SGLT2 is not expressed in the heart, and the underlying molecular mechanisms are not fully understood. We investigated whether the SGLT2 inhibitor luseogliflozin exerts beneficial effects on high glucose-exposed cardiomyocytes via the suppression of sodium-hydrogen exchanger-1 (NHE-1) activity. METHODS: Mouse cardiomyocytes were incubated under normal or high glucose conditions with vehicle, luseogliflozin, or the NHE-1 inhibitor cariporide. NHE-1 activity and gene expression were evaluated by the SNARF assay and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis, respectively. Six-week-old male db/db mice were treated with vehicle or luseogliflozin for 6 weeks, and the hearts were collected for histological, RT-PCR, and western blot analyses. RESULTS: High glucose increased NHE-1 activity and transforming growth factor (Tgf)-ß2 mRNA levels in cardiomyocytes, both of which were inhibited by luseogliflozin or cariporide, whereas their combination showed no additive suppression of Tgf-ß2 mRNA levels. Luseogliflozin attenuated cardiac hypertrophy and fibrosis in db/db mice in association with decreased mRNA and protein levels of TGF-ß2. CONCLUSIONS: Luseogliflozin may suppress cardiac hypertrophy in diabetes by reducing Tgf-ß2 expression in cardiomyocytes via the suppression of NHE-1 activity.
Assuntos
Diabetes Mellitus , Miócitos Cardíacos , Trocador 1 de Sódio-Hidrogênio/metabolismo , Animais , Cardiomegalia/patologia , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Humanos , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/farmacologia , Sorbitol/análogos & derivados , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/farmacologiaRESUMO
BACKGROUND: Diabetes mellitus increases the excretion of urinary glucose from the renal glomeruli due to elevated blood glucose levels. In the renal tubules, SGLT2 is expressed and reabsorbs the excreted urinary glucose. In the pathogenesis of diabetes mellitus, glucose reabsorption by SGLT2 is increased, and SGLT2 inhibitors improve hyperglycaemia by inhibiting this reabsorption. When urinary glucose excretion is enhanced, glucose supply to skeletal muscle may be insufficient and muscle protein catabolism may be accelerated. On the other hand, SGLT2 inhibitors not only ameliorate hyperglycaemia but also improve fatty acid metabolism in muscle, which may prevent muscle atrophy. METHODS: Eight-week-old male db/m mice or db/db mice were fed a standard diet with or without the SGLT2i luseogliflozin (0.01% w/w in chow) for 8 weeks. Mice were sacrificed at 16 weeks of age, and skeletal muscle and serum lipidomes, as well as skeletal muscle transcriptome, were analysed. RESULTS: Administration of SGLT2i led to not only decreased visceral fat accumulation (P = 0.004) but also increased soleus muscle weight (P = 0.010) and grip strength (P = 0.0001). The levels of saturated fatty acids, especially palmitic acid, decreased in both muscles (P = 0.017) and sera (P = 0.041) upon administration of SGLT2i, while the content of monosaturated fatty acids, especially oleic acid, increased in both muscle (P < 0.0001) and sera (P = 0.009). Finally, the accumulation of transcripts associated with fatty acid metabolism, such as Scd1, Fasn, and Elovl6, and of muscle atrophy-associated transcripts, such as Foxo1, Mstn, Trim63, and Fbxo32, decreased following SGLT2i administration. CONCLUSIONS: Intramuscular fatty acid metabolism and gene expression were influenced by the extracellular lipidome, which was modified by SGLT2i. Hence, secondary effects, other than the hypoglycaemic effects of SGLT2i, might lead to the alleviation of sarcopenia.
Assuntos
Inibidores do Transportador 2 de Sódio-Glicose , Animais , Lipidômica , Masculino , Camundongos , Músculo Esquelético , Atrofia Muscular , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sorbitol/análogos & derivadosRESUMO
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.
Assuntos
Hiperandrogenismo , Resistência à Insulina , Síndrome do Ovário Policístico , Inibidores do Transportador 2 de Sódio-Glicose , Anidridos , Método Duplo-Cego , Feminino , Humanos , Hiperandrogenismo/tratamento farmacológico , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sorbitol/análogos & derivadosAssuntos
Diabetes Mellitus Tipo 2 , Síndrome do Ovário Policístico , Inibidores do Transportador 2 de Sódio-Glicose , Anidridos , Feminino , Humanos , Síndrome do Ovário Policístico/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sorbitol/análogos & derivadosRESUMO
Here we demonstrate that binuclear dinitrosyl iron complexes with thiol-containing ligands (glutathione and mercaptosuccinate, B-DNIC-GSH and B-DNIC-MS, respectively) exert cytotoxic effects on MCF7 human breast cancer cells. We showed that they are mediated by nitrosonium cations released from these complexes (NO+). This finding is supported by the cytotoxic effect of both B-DNICs on MCF7 cells evidenced to retain or was even promoted in the presence of N-Methyl-D-glucamine dithiocarbamate (MGD). MGD recruits an iron nitrosyl group [Fe(NO)] from the iron-dinitrosyl fragment [Fe(NO)2] of B-DNIC-MS forming stable mononitrosyl complexes of iron with MGD and releasing NO+ cations from a [Fe(NO)2] fragment.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Cátions , Ferro/química , Óxidos de Nitrogênio/química , Apoptose , Linhagem Celular Tumoral , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Glutationa/química , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Células MCF-7 , Óxido Nítrico , Sorbitol/análogos & derivados , Sorbitol/metabolismo , Marcadores de Spin , Compostos de Sulfidrila/química , Tiocarbamatos/metabolismoRESUMO
BACKGROUND: Autoimmune hypophysitis is a rare disease characterized by the infiltration of lymphocytic cells into the pituitary gland. 18F-fluorodeoxyglucose (FDG) and 18F-2-fluorodeoxy sorbitol (FDS) positron emission tomography (PET) are well-established and emerging techniques, respectively, which may aid in the diagnosis and classification of autoimmune hypophysitis. CASE PRESENTATION: Here, we report a 40-year-old female diagnosed with central diabetes insipidus and multiple pituitary hormone deficiencies, and MRI revealed homogeneous signals in the pituitary gland as well as thickened in the pituitary stalk. FDG PET localized the pituitary and pituitary stalk lesions and displayed an SUVmax of 5.5. FDS, a sensitive radiotracer for bacterial infections but remains unproven under aseptic inflammation, also demonstrated elevated radioactivity, with an SUVmax of 1.1 at 30 min and 0.73 at 120 min. Transnasal biopsy suggested a diagnosis of autoimmune hypophysitis, and the patient displayed radiological and clinical improvement after treatment with glucocorticoids and hormone replacement. CONCLUSIONS: Autoimmune hypophysitis can display elevated FDG uptake, which aids in the localization of the lesions. In addition to revealing bacterial infection specifically, FDS can also accumulate under autoimmune conditions, suggesting that it could serve as a potential radiotracer for both bacterial and aseptic inflammation. TRIAL REGISTRATION: The patient was enrolled in study NCT02450942 (clinicaltrials.gov, Registered May 21, 2015).
Assuntos
Hipofisite Autoimune/diagnóstico por imagem , Fluordesoxiglucose F18 , Compostos Radiofarmacêuticos , Sorbitol/análogos & derivados , Adulto , Antidiuréticos/uso terapêutico , Hipofisite Autoimune/tratamento farmacológico , Hipofisite Autoimune/patologia , Hipofisite Autoimune/fisiopatologia , Biópsia , Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido Neurogênico/tratamento farmacológico , Diabetes Insípido Neurogênico/fisiopatologia , Feminino , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal , Humanos , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/fisiopatologia , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Tiroxina/uso terapêuticoRESUMO
Tumor-targeting bacteria have been actively investigated as a new therapeutic tool for solid tumors. However, in vivo imaging of tumor-targeting bacteria has not been fully established. 18F-fluorodeoxysorbitol (FDS) positron emission tomography (PET) is known to be capable of imaging Gram-negative Enterobacteriaceae infection. In the present study, we aimed to validate the use of 18F-FDS PET for visualization of the colonization and proliferation of tumor-targeting Escherichia coli (E. coli) MG1655 in mouse tumor models. Methods:E. coli (5 × 107 colony forming unit) were injected intravenously into BALB/c mice bearing mouse colon cancer (CT26). Before and 1, 3, and 5 days after the bacterial injection, PET imaging was performed following i.v. injection of approximately 7.4 MBq of 18F-FDS. Regions of interest were drawn in the engrafted tumor and normal organs including the heart, liver, lung, brain, muscle, and intestine. Semiquantitative analysis was performed using maximum standardized uptake value (SUVmax). Results:18F-FDS uptake was significantly higher in tumors colonized by live E. coli MG1655 than in uncolonized tumors (p < 0.001). The PET signals in the colonized tumors at 3 days after bacterial injection were 3.1-fold higher than those in the uncolonized tumors. Tumoral 18F-FDS uptake correlated very strongly with the number of E. coli in tumors (r = 0.823, p < 0.0001). Cross sectional analysis of autoradiography, bioluminescence, and pathology revealed that the 18F-FDS uptake sites in tumors matched the locations of E. coli MG1655. Conclusion: In conclusion, 18F-FDS PET is expected to be useful for the semiquantitative visualization of tumor-targeting bacteria when bacterial cancer therapy is performed using Gram-negative Enterobacteriaceae such as E. coli.
Assuntos
Neoplasias do Colo/diagnóstico por imagem , Escherichia coli/ultraestrutura , Animais , Neoplasias do Colo/terapia , Feminino , Radioisótopos de Flúor/química , Camundongos , Camundongos Endogâmicos BALB C , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Sorbitol/análogos & derivados , Sorbitol/químicaRESUMO
AIMS/INTRODUCTION: Clinical studies have shown that treatment with inhibitors of sodium-glucose cotransporter 2 (SGLT2) significantly increases the hematocrit in patients with type 2 diabetes. To investigate whether SGLT2 inhibitors directly promote erythropoietin production independently on blood glucose reduction, the hematopoietic effect of the specific SGLT2 inhibitor, luseogliflozin, was examined in non-diabetic rats with renal anemia. MATERIALS AND METHODS: Renal anemia was induced by treatment with adenine (200 or 600 mg/kg/day, orally for 10 days) in non-diabetic Wistar-Kyoto or Wistar rats, respectively. Luseogliflozin (10 mg/kg bodyweight) or vehicle (0.5% carboxymethyl cellulose) was then administered for 6 weeks. The hematocrit and the hemoglobin (Hb), blood urea nitrogen, plasma creatinine, and plasma erythropoietin levels were monitored. RESULTS: Treatment with adenine decreased the hematocrit and the Hb level, which were associated with increases in the blood urea nitrogen and plasma creatinine levels. In Wistar-Kyoto rats treated with 200 mg/kg/day adenine, administration of luseogliflozin induced glycosuria, but did not change the blood urea nitrogen, plasma creatinine levels, hematocrit, Hb or plasma erythropoietin levels. Similarly, luseogliflozin treatment failed to change the hematocrit or the Hb levels in Wistar rats with renal anemia induced by 600 mg/kg/day of adenine. Plasma erythropoietin concentrations were also not different between luseogliflozin- and vehicle-treated rats. Similarly, in human erythropoietin-producing cells derived from pluripotent stem cells, luseogliflozin treatment did not change the erythropoietin level in the medium. CONCLUSIONS: These data suggest that SGLT2 inhibitor fails to exert hematopoietic effects in non-diabetic conditions.
Assuntos
Anemia/tratamento farmacológico , Células-Tronco Hematopoéticas/efeitos dos fármacos , Insuficiência Renal/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sorbitol/análogos & derivados , Adenina , Anemia/sangue , Anemia/induzido quimicamente , Animais , Modelos Animais de Doenças , Eritropoetina/sangue , Hematócrito , Hemoglobinas/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos WKY , Ratos Wistar , Insuficiência Renal/sangue , Insuficiência Renal/induzido quimicamente , Sorbitol/farmacologiaRESUMO
A 60-year-old Japanese woman was referred to our hospital for further examination of persistent liver dysfunction. She had been suffering from type 2 diabetes mellitus since the age of 50 years. Her hemoglobin A1c (HbA1c) value was as high as 7.8% despite treatment with dipeptidyl peptidase-4 inhibitor, metformin, and sulfonylurea. After excluding viral hepatitis, alcohol or drug-induced liver injury, and autoimmune liver diseases, liver histology evidence of macrovesicular steatosis, hepatocyte ballooning, and pericellular fibrosis confirmed a diagnosis of non-alcoholic steatohepatitis (NASH). Luseogliflozin (2.5 mg/day), a sodium-glucose cotransporter 2 inhibitor (SGLT2I), was co-administered to strengthen glycemic control. Liver enzymes and HbA1c gradually improved without any adverse events. A second liver biopsy at 15 months after luseogliflozin commencement revealed improvements in steatosis, fibrosis, and overall histological activity score. This case demonstrates that long-term luseogliflozin may be a good therapeutic option for diabetic NAFLD/NASH patients. The merits of persistent SGLT2I administration for NAFLD/NASH patients warrant validation in future studies.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sorbitol/análogos & derivados , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sorbitol/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Excess fat deposition could induce phenotypic changes of perivascular adipose tissue (PVAT remodeling), which may promote the progression of atherosclerosis via modulation of adipocytokine secretion. However, it remains unclear whether and how suppression of PVAT remodeling could attenuate vascular injury. In this study, we examined the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, luseogliflozin on PVAT remodeling and neointima formation after wire injury in mice. METHODS: Wilt-type mice fed with low-fat diet (LFD) or high-fat diet (HFD) received oral administration of luseogliflozin (18 mg/kg/day) or vehicle. Mice underwent bilateral femoral artery wire injury followed by unilateral removal of surrounding PVAT. After 25 days, injured femoral arteries and surrounding PVAT were analyzed. RESULTS: In LFD-fed lean mice, neither luseogliflozin treatment or PVAT removal attenuated the intima-to-media (I/M) ratio of injured arteries. However, in HFD-fed mice, luseogliflozin or PVAT removal reduced the I/M ratio, whereas their combination showed no additive reduction. In PVAT surrounding injured femoral arteries of HFD-fed mice, luseogliflozin treatment decreased the adipocyte sizes. Furthermore, luseogliflozin reduced accumulation of macrophages expressing platelet-derived growth factor-B (PDGF-B) and increased adiponectin gene expression. Gene expression levels of Pdgf-b in PVAT were correlated with the I/M ratio. CONCLUSIONS: Our present study suggests that luseogliflozin could attenuate neointimal hyperplasia after wire injury in HFD-fed mice partly via suppression of macrophage PDGF-B expression in PVAT. Inhibition of PVAT remodeling by luseogliflozin may be a novel therapeutic target for vascular remodeling after angioplasty.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Dieta Hiperlipídica , Artéria Femoral/efeitos dos fármacos , Neointima , Obesidade/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sorbitol/análogos & derivados , Remodelação Vascular/efeitos dos fármacos , Lesões do Sistema Vascular/tratamento farmacológico , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Modelos Animais de Doenças , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/fisiopatologia , Linfocinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Sorbitol/farmacologia , Lesões do Sistema Vascular/complicações , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/fisiopatologiaRESUMO
OBJECTIVE: Two fluorine-18-labeled analogues, 3-deoxy-3-[18F]fluoro-D-allose (3-[18F]FDA) and 6-deoxy-6-[18F]fluoro-D-allose (6-[18F]FDA), were synthesized and their potentials of diagnostic property were characterized. METHODS: In vitro rat red blood cell (RBC) transport and phosphorylation by yeast hexokinase were evaluated in comparison with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). The rate of protein binding in pooled human serum was measured by an ultrafiltration method. In vivo metabolite analysis in mice was also performed. Biodistribution, urine excretion, and in vivo renal kinetics in mice were compared with 2-deoxy-2-[18F]fluorosorbitol ([18F]FDS). RESULTS: Rat RBC uptake of 3- and 6-[18F]FDA (7.8 ± 2.5%ID and 10.2 ± 4.8%ID, respectively) was significantly lower than that of [18F]FDG (44.7 ± 8.7%ID). RBC uptake of 3-[18F]FDA was inhibited by D-glucose (30%) and cytochalasin B (40%), indicating the involvement of GLUT1-dependent transport. In contrast, 6-[18F]FDA transport was not inhibited by D-glucose and cytochalasin B. 3- and 6-[18F]FDA were not phosphorylated by yeast hexokinase under the conditions that result in 60% conversion of [18F]FDG into [18F]FDG-6-phosphate within 30 min. Serum protein binding of 3- and 6-[18F]FDA was negligible. Metabolic transformation of both tracers was not detected in plasma and urine at 30 min after injection. The highest tissue uptake of both tracers was observed in kidneys. Heart and brain uptake of both tracers was below blood levels throughout the biodistribution studies (until 120 min after injection). No significant uptake in the bone was observed, indicating the absence of de-fluorination in mice. In vivo PET imaging visualized rapid excretion of the administered 3- and 6-[18F]FDA from the kidneys, with minimal tracer accumulation in other organs. The urine excretion rate of 3-[18F]FDA was much lower than that of 6-[18F]FDA and [18F]FDS. CONCLUSIONS: 3- and 6-[18F]FDA might be unsatisfactory for tumor imaging. In contrast, these tracers demonstrated high levels of kidney uptake and excretion, low serum protein binding, and high metabolic stability as preferable properties for renal imaging. Notably, the urine excretion rate and kidney uptake kinetics of 6-[18F]FDA were comparable with those of the potential renal imaging agent [18F]FDS. Further validation studies in animal models are required to confirm the feasibility of 6-[18F]FDA as a functional renal imaging agent.
Assuntos
Sorbitol/análogos & derivados , Animais , Transporte Biológico , Proteínas Sanguíneas/metabolismo , Eritrócitos/metabolismo , Hexoquinase/metabolismo , Marcação por Isótopo , Rim/diagnóstico por imagem , Rim/metabolismo , Cinética , Masculino , Camundongos , Ratos , Sorbitol/química , Sorbitol/metabolismo , Sorbitol/farmacocinética , Distribuição TecidualRESUMO
The red maple and sugar maple (Acer rubrum and A. saccharum, respectively) contain acertannins (ginnalins and maplexins), galloylated derivatives of 1,5-anhydro-d-glucitol (1,5-AG, 1). These compounds have a variety of potential medicinal properties and we have shown that some of them promote the expression of ceramide synthase 3. We now report on the beneficial effects of ginnalin B, (6-O-galloyl-1,5-AG, 5), leading to acceleration of skin metabolism and reduction of the turnover time. Ginnalin B dose-dependently increased the relative amount of keratin 10, keratin 1, and filaggrin gene, with maximal increase of 1.7-, 2.9, and 5.2-fold at 100⯵M, respectively. The validation study showed that it had superior capacity to induce multiple stages of keratinocyte differentiation and significantly elevated the immunostaining site of keratin 10 and filaggrin in a 3-dimensional cultured human skin model, by 1.2 and 2.8-fold, respectively. Furthermore, ginnalin B caused the arrest of proliferation at the G0/G1 phase but it did not induce apoptotic cell death in normal human keratinocytes. Molecular studies revealed that ginnalin B up-regulated the levels of NOTCH1 and a concomitant increase p21 expression. Ginnalin B, therefore, represents a new class of promising functional and medical cosmetic compound and it could contribute to the maintenance of homeostasis of the epidermis.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Receptor Notch1/metabolismo , Pele/efeitos dos fármacos , Sorbitol/análogos & derivados , Antígenos de Diferenciação/metabolismo , Linhagem Celular , Proteínas Filagrinas , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Queratina-1/metabolismo , Queratina-10/metabolismo , Sorbitol/farmacologiaRESUMO
Sodium-glucose cotransporter 1 (SGLT1) is the primary transporter for glucose absorption from digested nutrients in the gastrointestinal tract. Intestinal SGLT1 inhibition reduces post-prandial hyperglycemia and enhances the increase of plasma glucagon-like peptide-1 (GLP-1) levels. SGL5213 is a novel and potent intestinal SGLT1 inhibitor. This study characterizes the pharmacological profiles of SGL5213 in rodents. Orally administered SGL5213 was hardly absorbed and its distribution was restricted to the gastrointestinal lumen. SGL5213 significantly improved post-prandial hyperglycemia in streptozotocin (STZ)-induced diabetic rats at doses of 1â¯mg/kg or more. After the oral administration of starch, SGL5213 increased the amount of residual glucose in the small intestine at 1-3â¯h and in the cecum and colon at 3-9â¯h by inhibiting glucose absorption and allowing the unabsorbed glucose to be delivered into the lower-gastrointestinal tract. In the vehicle group, the plasma total GLP-1 (tGLP-1) and tGLP-2 levels increased at 15â¯min and the plasma total glucose-dependent insulinotropic polypeptide (tGIP) level increased at 1â¯h after meal loading. SGL5213 at doses of 0.1â¯mg/kg or more enabled the plasma levels of tGLP-1 and tGLP-2 to be retained for a period of 1-6â¯h, compared with the vehicle group. In contrast, SGL5213 at doses of 0.3â¯mg/kg or more suppressed the plasma tGIP elevation after meal loading. This study demonstrated for the first time that an intestinal SGLT1 inhibitor enhanced post-prandial plasma GLP-2 secretion. These results suggest that SGL5213 might exhibit a useful pharmacological efficacy through the physiological actions of GLP-1 and GLP-2.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 2 Semelhante ao Glucagon/sangue , Glucose/metabolismo , Absorção Intestinal/efeitos dos fármacos , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Sorbitol/análogos & derivados , Sorbitol/farmacologia , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice. Luseogliflozin significantly suppressed development of renal fibrosis, prevented peritubular capillary congestion/hemorrhage, attenuated CD31-positive cell loss, suppressed hypoxia, and increased vascular endothelial growth factor (VEGF)-A expression in the kidney after ischemia/reperfusion injury. Luseogliflozin failed to induce the above-mentioned protection in animals co-treated with sunitinib, a VEGF receptor inhibitor. Additionally, luseogliflozin reduced glucose uptake and increased VEGF-A expression in the kidneys of glucose transporter 2 (GLUT2)-downregulated mice following ischemia/reperfusion and in GLUT2-knock-down cells compared with those in normal controls. Withdrawal of glucose from cultured medium, to halt glucose uptake, remarkably increased VEGF-A expression and reversed the luseogliflozin-induced increase in VEGF-A expression in the proximal tubular cells. Thus, luseogliflozin prevented endothelial rarefaction and subsequent renal fibrosis after renal ischemia/reperfusion injury through a VEGF-dependent pathway induced by the dysfunction of proximal tubular glucose uptake in tubules with injury-induced GLUT2 downregulation.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Túbulos Renais Proximais/patologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Inibidores da Angiogênese/farmacologia , Animais , Glicemia/metabolismo , Capilares/efeitos dos fármacos , Capilares/metabolismo , Capilares/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fibrose , Técnicas de Silenciamento de Genes , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Humanos , Túbulos Renais Proximais/irrigação sanguínea , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sorbitol/análogos & derivados , Sorbitol/farmacologia , Sorbitol/uso terapêutico , Sunitinibe/farmacologia , Resultado do TratamentoRESUMO
This open-label, parallel-group, multicenter study aimed to assess the effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of luseogliflozin. A single 5-mg dose of luseogliflozin was administered to Japanese patients with type 2 diabetes mellitus in the following groups: G1, normal renal function; G2, mild renal impairment; G3a, mild to moderate impairment; G3b, moderate to severe impairment; G4, severe impairment, based on estimated glomerular filtration rate (eGFR; ≥90, 60-89, 45-59, 30-44, 15-29 mL/min/1.73 m2 , respectively). While luseogliflozin pharmacokinetics were similar for patients across all renal function groups, the increase in plasma concentration was slightly slower and maximum concentration was slightly reduced in the lower eGFR groups compared with the other groups. However, luseogliflozin pharmacodynamics were affected by the severity of renal impairment. Urinary glucose excretion (UGE) increased in all groups relative to baseline levels, but the degree of UGE increase was smaller in the lower eGFR groups. Moreover, plasma glucose AUC changes from baseline tended to be smaller in the lower eGFR groups. No clear trends were observed between eGFR and incidence, type, or severity of adverse events. Thus, luseogliflozin administration should be carefully considered, as patients with renal impairment may show an insufficient response to treatment.
Assuntos
Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Renal/complicações , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Sorbitol/análogos & derivados , Adulto , Idoso , Povo Asiático , Glicemia/efeitos dos fármacos , Complicações do Diabetes/sangue , Diabetes Mellitus Tipo 2/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sorbitol/efeitos adversos , Sorbitol/farmacocinética , Sorbitol/farmacologia , Sorbitol/uso terapêutico , Adulto JovemRESUMO
Recent clinical studies have revealed the treatment of diabetic patients with sodium glucose co-transporter2 (SGLT2) inhibitors to reduce the incidence of cardiovascular events. Using nicotinamide and streptozotocin (NA/STZ) -treated ApoE KO mice, we investigated the effects of short-term (seven days) treatment with the SGLT2 inhibitor luseogliflozin on mRNA levels related to atherosclerosis in the aorta, as well as examining the long-term (six months) effects on atherosclerosis development. Eight-week-old ApoE KO mice were treated with NA/STZ to induce diabetes mellitus, and then divided into two groups, either untreated, or treated with luseogliflozin. Seven days after the initiation of luseogliflozin administration, atherosclerosis-related mRNA levels in the aorta were compared among four groups; i.e., wild type C57/BL6J, native ApoE KO, and NA/STZ-treated ApoE KO mice, with or without luseogliflozin. Short-term luseogliflozin treatment normalized the expression of inflammation-related genes such as F4/80, TNFα, IL-1ß, IL-6, ICAM-1, PECAM-1, MMP2 and MMP9 in the NA/STZ-treated ApoE KO mice, which showed marked elevations as compared with untreated ApoE KO mice. In contrast, lipid metabolism-related genes were generally unaffected by luseogliflozin treatment. Furthermore, after six-month treatment with luseogliflozin, in contrast to the severe and widely distributed atherosclerotic changes in the aortas of NA/STZ-treated ApoE KO mice, luseogliflozin treatment markedly attenuated the progression of atherosclerosis, without affecting serum lipid parameters such as high density lipoprotein, low density lipoprotein and triglyceride levels. Given that luseogliflozin normalized the aortic mRNA levels of inflammation-related, but not lipid-related, genes soon after the initiation of treatment, it is not unreasonable to speculate that the anti-atherosclerotic effect of this SGLT2 inhibitor emerges rapidly, possibly via the prevention of inflammation rather than of hyperlipidemia.
Assuntos
Aorta/metabolismo , Apolipoproteínas E/metabolismo , Aterosclerose/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Inflamação/genética , Metabolismo dos Lipídeos/genética , Inibidores do Transportador 2 de Sódio-Glicose , Sorbitol/análogos & derivados , Animais , Aterosclerose/complicações , Aterosclerose/genética , Moléculas de Adesão Celular/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Inflamação/complicações , Metabolismo dos Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Niacinamida , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Sorbitol/farmacologia , Sorbitol/uso terapêutico , Estreptozocina , Regulação para Cima/efeitos dos fármacosRESUMO
Objective and Methods An SGLT2 inhibitor (ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin, or canagliflozin) was administered to 132 outpatients with type 2 diabetes mellitus with or without other antidiabetic drugs for 6 months to evaluate its efficacy, the incidence of adverse events, and its influence on the renal function. Results The patient's mean glycated hemoglobin level significantly improved from 7.52±1.16% to 6.95±0.98% (p<0.001). The body weight of the patients was significantly reduced from 78.0±15.3 kg to 75.6±15.1 kg (p<0.001). The estimated visceral fat area was also significantly reduced from 108.4±44.6 cm2 to 94.5±45.3 cm2 (p<0.001). The waist circumference, blood pressure, serum alanine aminotransferase, γ-glutamyl transpeptidase, and uric acid levels also showed a significant decrease. The urinary albumin/creatinine ratio (U-ACR) was significantly reduced in the patients whose U-ACR levels were 30-300 mg/gCr at the baseline. The mean eGFR significantly decreased in the patients with a pre-treatment eGFR value of ≥90 mL/min/1.73 m2 but remained unchanged in the patients with a pre-treatment value of <90 mL/min/1.73 m2. A total of 13 adverse events were noted, including systemic eruption (n=1), cystitis (n=2), pudendal pruritus (n=2), nausea (n=1), malaise (n=1), a strong hunger sensation and increased food ingestion (n=1), and non-serious hypoglycemia (n=5). Conclusion SGLT2 inhibitors seemed to be useful in the treatment of obese type 2 diabetes mellitus patients. Furthermore, these data suggest that SGLT2 inhibitors may protect the renal function.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Hemoglobinas Glicadas , Humanos , Gordura Intra-Abdominal/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Sorbitol/análogos & derivados , Sorbitol/farmacologia , Sorbitol/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêuticoRESUMO
1. We evaluated potential in vitro drug interactions of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mediated by CYP inhibition, CYP induction and drug transporters using human liver microsomes, primary hepatocytes and recombinant cells-expressing efflux or uptake transporters, respectively. 2. Human CYP inhibition studies indicated that luseogliflozin was a weak inhibitor for CYP2C19 with an IC50 value of 58.3 µM, whereas it was not an inhibitor of the other eight major isoforms that were tested. The exposure of primary hepatocytes to luseogliflozin for 72 hrs weakly induced CYP3A4 at a concentration of 10 µM, whereas it did not induce CYP1A2 or CYP2B6 at concentrations of 0.1-10 µM. 3. An in vitro transport study suggested that luseogliflozin is a substrate for human P-glycoprotein (P-gp), but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Luseogliflozin weakly inhibited OATP1B3 with an IC50 value of 93.1 µM, but those for other transporters are greater than 100 µM. 4. Based on the therapeutic plasma concentration of the drug, clinically relevant drug interactions are unlikely to occur between luseogliflozin and coadministered drugs mediated by CYPs and/or transporters.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Sorbitol/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP , Animais , Transporte Biológico , Células CACO-2 , Cães , Hepatócitos , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Células Madin Darby de Rim Canino , Proteínas de Membrana Transportadoras/metabolismo , Microssomos Hepáticos , Proteínas de Neoplasias , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes , Sorbitol/farmacologiaRESUMO
It has been established that treatment of mice with sodium nitrite, S-nitrosoglutathione and the water-soluble nitroglycerine derivative isosorbide dinitrate (ISDN) as NO donors initiates in vivo synthesis of significant amounts of EPR-silent binuclear dinitrosyl iron complexes (B-DNIC) with thiol-containing ligands in the liver and other tissues of experimental mice. This effect is especially apparent if NO donors are administered to mice simultaneously with the Fe2+-citrate complex. Similar results were obtained in experiments on isolated liver and other mouse tissues treated with gaseous NÐ in vitro and during stimulation of endogenous NO synthesis in the presence of inducible NO synthase. B-DNIC appeared in mouse tissues after in vitro treatment of tissue samples with an aqueous solution of diethyldithiocarbamate (DETC), which resulted in the transfer of iron-mononitrosyl fragments from B-DNIC to the thiocarbonyl group of DETC and the formation of EPR-detectable mononitrosyl iron complexes (MNIC) with DETC. EPR-Active MNIC with N-methyl-d-glucamine dithiocarbamate (MGD) were synthesized in a similar way. MNIC-MGD were also formed in the reaction of water-soluble MGD-Fe2+ complexes with sodium nitrite, S-nitrosoglutathione and ISDN.