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1.
Sci Total Environ ; 698: 134238, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505360

RESUMO

Different biomass materials (walnut shell, coconut shell or cottonwood sawdust) were co-pyrolyzed with carbon-enriched oily sludge to produce aqueous phase sulfamethoxazole (SMZ) adsorption materials. The co-pyrolysis char was activated with K2CO3 to modify its micro-structure and functional groups. Results show that ACs prepared from the mixture contained more mesopores than biomass-based ACs, more porous and higher yield than oily sludge-based ACs. One-step activation method was more attractive than two-step activation in larger specific surface area (up to almost 4 times), wider pore size distribution (2-3 nm), stronger SMZ adsorption ability (higher than 2 times). The maximum BET surface area was 1342 m2/g for the ACs prepared from the mixture of walnut shell and oily sludge by one-step activation and it had the maximum SMZ adsorption capacity up to 361.9 mg/g, which is higher than previous reported values. The capacity of SMZ adsorption of ACs was mainly attributed to pore size distribution, specific surface area and functional groups. Among them, the appropriate content of CO and CO functional groups, larger specific area and more pores range from 2 to 3 nm lead to higher adsorption capacity.


Assuntos
Modelos Químicos , Sulfametoxazol/química , Adsorção , Biomassa , Carbono/química , Carvão Vegetal/química , Cinética , Óleos , Porosidade , Pirólise
2.
Hypertension ; 74(2): 313-322, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31230549

RESUMO

Human blood pressure salt sensitivity is associated with changes in urinary metabolites related to fumarase (Fh) and nitric oxide (NO) metabolism, and fumarase promotes NO production through an arginine regeneration pathway. We examined the role of the fumarase-NO pathway in the development of hypertension using genetically engineered rat models. Dahl salt-sensitive (SS) rats with heterozygous mutation of eNOS (endothelial NO synthase or Nos3; SS-Nos3+/-) were bred with SS rats with a hemizygous Fh transgene. SS-Nos3+/- rats without the Fh transgene (SS-Nos3+/-/Fh0/0) developed substantial hypertension with a mean arterial pressure of 134.2±3.7 mm Hg on a 0.4% NaCl diet and 178.0±3.5 mm Hg after 14 days on a 4% NaCl diet. Mean arterial pressure decreased remarkably to 123.1±1.4 mm Hg on 0.4% NaCl, and 143.3±1.5 mm Hg on 4% NaCl in SS-Nos3+/- rats with a Fh transgene (SS-Nos3+/-/Fh0/1), and proteinuria, renal fibrosis, and tubular casts were attenuated in SS-Nos3+/-/Fh0/1 rats compared with SS-Nos3+/-/Fh0/0 rats. eNOS protein abundance decreased in rats with the Nos3 heterozygous mutation, which was not influenced by Fh overexpression in rats on the 0.4% NaCl diet. However, the decrease in NO metabolite in the renal outer medulla of SS-Nos3+/-/Fh0/0 rats on the 0.4% NaCl diet was reversed in SS-Nos3+/-/Fh0/1 rats, and levels of L-arginine, but not the other 12 amino acids analyzed, were significantly higher in SS-Nos3+/-/Fh0/1 rats than in SS-Nos3+/+/Fh0/0 rats. In conclusion, fumarase has potent effects in restoring NO production and blunting the development of hypertension attributable to eNOS haploinsufficiency.


Assuntos
Progressão da Doença , Fumarato Hidratase/genética , Haploinsuficiência/genética , Hipertensão/genética , Óxido Nítrico Sintase Tipo III/genética , Análise de Variância , Animais , Arginina/metabolismo , Biópsia por Agulha , Western Blotting/métodos , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipertensão/fisiopatologia , Imuno-Histoquímica , Masculino , Mutação/genética , Distribuição Aleatória , Ratos , Ratos Endogâmicos Dahl , Ratos Transgênicos , Urinálise/métodos
3.
Hypertens Res ; 42(11): 1672-1682, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31235845

RESUMO

Fumarase insufficiencies can increase reactive oxygen species (ROS). This study will further dissect the imbalance of redox metabolism and the mechanism of ROS production using proteomic technology in fumarase knockdown HK-2 cells. The contribution of fumarase was further confirmed by supplementation of fumarate and malate in Dahl salt-sensitive rats. Proteomic analysis indicated that fumarase knockdown in HK-2 cells changed the expression or activity of NADPH oxidase (NOX), mitochondrial respiratory chain Complex I and III, ATP synthase subunits, and α-oxoglutarate dehydrogenase (OGDH). Meanwhile, the activities of key antioxidant enzymes, including glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, increased significantly. The apparent activation of antioxidant defense appeared insufficient as the glutathione and GSH/GSSG ratio were decreased significantly. Dahl salt-sensitive rats exhibited changes in redox metabolism similar to HK-2 cells with fumarase knockdown. Supplementation with fumarate and malate increased and decreased, respectively, blood pressure and H2O2 and malondialdehyde in salt-sensitive rats. These results indicated that insufficient fumarase activity increased ROS by regulating NOX, Complex I and III, ATPase alpha, and OGDH and the imbalance of glutathione metabolism, which may be one of the main reasons for salt-sensitive hypertension. Malate may be a potentially effective drug for the prevention and treatment of salt-sensitive hypertension.

4.
Food Funct ; 10(2): 849-858, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30681096

RESUMO

In the present study, the renal-protective effect of hawthorn fruit extract (HW) on high-salt hypertension and its effect on metabolic patterns are determined. High salt causes hypertension in Dahl salt sensitive (SS) rats, while HW can effectively attenuate high-salt induced hypertension, and, various antihypertensive ingredients of HW have also been successfully identified using GC/MS. Of note, the biochemical assay indicates that HW significantly increases the concentration of nitric oxide (NO) and decreases the concentration of H2O2 and malonaldehyde. Especially, HW increases the activities of NO synthase and catalase in the renal medulla. Simultaneously, the renal cortex and medulla, harvested from SS rats, are used to perform the metabolomics analysis, and then, 11 and 8 differential metabolites are identified in the renal medulla and cortex with the HW gavage, respectively. All differential metabolites are then used to perform the pathway enrichment analysis. The results show that many metabolic pathways are enriched in both the renal medulla and cortex, especially those in the medulla including 23 enriched pathways. Therefore, it provides evidence that HW confers an antioxidant effect on high-salt induced hypertension and dramatically alters the metabolic patterns of SS rats, and the antihypertensive ingredients of HW also further indicate that it may be used as a nutritional supplemental therapeutic drug to protect against high-salt induced hypertension in the renal medulla.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Crataegus/química , Frutas/química , Extratos Vegetais/farmacologia , Animais , Catalase/genética , Catalase/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Medula Renal/efeitos dos fármacos , Medula Renal/enzimologia , Masculino , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo , Extratos Vegetais/química , Distribuição Aleatória , Ratos , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta/toxicidade
5.
Int J Mol Sci ; 19(10)2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30274177

RESUMO

Nanocarriers encapsulating multiple chemotherapeutics are a promising strategy to achieve combinational chemotherapy for cancer therapy; however, they generally use exotic new carriers without therapeutic effect, which usually suffer from carrier-related toxicity issues, as well as having to pass extensive clinical trials to be drug excipients before any clinical applications. Cargo-free nanomedicines, which are fabricated by drugs themselves without new excipients and possess nanoscale characteristics to realize favorable pharmacokinetics and intracellular delivery, have been rapidly developed and drawn much attention to cancer treatment. Herein, we discuss recent advances of cargo-free nanomedicines for cancer treatment. After a brief introduction to the major types of carrier-free nanomedicine, some representative applications of these cargo-free nanomedicines are discussed, including combination therapy, immunotherapy, as well as self-monitoring of drug release. More importantly, this review draws a brief conclusion and discusses the future challenges of cargo-free nanomedicines from our perspective.


Assuntos
Excipientes/química , Nanomedicina , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Imunoterapia
6.
Theranostics ; 8(15): 4097-4115, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30128039

RESUMO

Chemo-photothermal therapy shows great potential for inhibiting tumor growth. However, achieving maximal chemo-photothermal synergistic efficacy is challenging because of the low efficiency of controllable chemo-drug release in response to external or internal triggers. Thus, a nano-delivery system that could effectively achieve photothermal therapy and dual stimuli-responsive (heat and pH) drug release to inhibit both primary breast tumor growth and metastases is required. Methods: Herein, a thermo- and pH-responsive polymer (mPEG-PAAV) with an upper critical solution temperature (UCST) was synthesized to fabricate a DOX- and IR780-loaded micellar system. After systematic studies of the photothermal performance and controllable drug release of mPEG-PAAV micelles/IR780+DOX under NIR irradiation at different pH values, their chemo-photothermal synergetic therapy efficacies were also estimated both in in vitro and in vivo. Results: Because of the photothermal conversion of mPEG-PAAV micelle/IR780+DOX (~200 nm, 3.82 mV), high local temperature could be induced at the tumor site under NIR laser irradiation. This hyperthermia not only produced an enhanced tumor necrosis, but also broke down the micelles under the decreased pH environment, resulting in rapid DOX release and enhanced intracellular drug accumulation after NIR laser irradiation. In addition, photoacoustic imaging (PAI) of mPEG-PAAV/IR780+DOX micelle was adopted to monitor the morphology and micro-vascular distribution of the tumor tissue, which could also guide the chemo-photothermal therapy. Most importantly, the systemic administration of mPEG-PAAV micelles/IR780+DOX combined with NIR laser irradiation could simultaneously eliminate the 4T1 breast tumor and thoroughly suppress lung metastasis without any obvious adverse effects. Conclusion: Herein, a pH- and thermo-dual responsive UCST micelle system was developed for delivering IR780 and DOX, which could achieve NIR laser-controlled drug release and PA imaging guidance for chemo-photothermal synergistic therapy of both primary breast tumors and their metastases.


Assuntos
Neoplasias da Mama/terapia , Portadores de Fármacos/administração & dosagem , Tratamento Farmacológico/métodos , Hipertermia Induzida/métodos , Nanoestruturas/administração & dosagem , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Animais , Neoplasias da Mama/secundário , Terapia Combinada/métodos , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Portadores de Fármacos/efeitos da radiação , Concentração de Íons de Hidrogênio , Indóis/administração & dosagem , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Micelas , Nanoestruturas/efeitos da radiação , Polímeros/administração & dosagem , Polímeros/efeitos da radiação , Temperatura
7.
Amino Acids ; 50(10): 1407-1414, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30009324

RESUMO

Genetic background and high-salt diet are considered key factors contributing to the development of hypertension and its associated metabolic disorders. Metabolomics is an emerging powerful tool to analyze the low-molecular weight metabolites in plasma and tissue. This study integrated metabolomics and correlation network analysis to investigate the metabolic profiles of plasma and muscle of Dahl salt-sensitive (SS) rats and SS.13BN rats (control) under normal and high-salt diet. The hub metabolites, which could play important roles in the metabolic changes, were identified by correlation network analysis. The results of the network analysis were further confirmed by pathway analysis and enzyme activity analysis. The results indicated a higher amino acid levels in both plasma and muscle of SS rats fed with high-salt diet. Alanine was found as a hub metabolite with the highest score of three centrality indices and also as the significant differential metabolite in plasma of SS rats after high-salt diet. Valine and lysine were found as hub metabolites and differential metabolites in muscle of SS rats after high-salt diet. Amino acid levels increased in both plasma and muscle of SS rats fed with a high salt diet. Moreover, alanine in plasma and valine and lysine in muscle as hub metabolites could play important roles in the response to high-salt diet.


Assuntos
Aminoácidos/metabolismo , Hipertensão/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Aminoácidos/sangue , Animais , Humanos , Hipertensão/sangue , Masculino , Músculos/metabolismo , Ratos , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta/sangue
8.
Mol Pharm ; 15(8): 3343-3355, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-29923726

RESUMO

As a result of their ability to transform into bulk cancer cells and their resistance to radiotherapy and chemotherapy, cancer stem cells (CSCs) are currently considered as a major obstacle for cancer treatment. Application of multiple drugs using nanocarriers is a promising approach to simultaneously eliminate noncancer stem cells (non-CSCs) and CSCs. Herein, to employ the advantages of nanomedicine while avoiding new excipients, pH-responsive prodrug (PEG-CH═N-DOX) was employed as the surfactant to fabricate cargo-free nanomedicine for codelivery of DOX conjugated prodrug with SN38 to synergistically eradicate breast cancer stem cells (bCSCs) and non-bCSCs. Through the intermolecular interaction between DOX and SN38, PEG-CH═N-DOX and SN38 were assembled together to form a stable nanomedicine. This nanomedicine not only dramatically enhanced drug accumulation efficiency at the tumor site but also effectively eliminated bCSCs and non-bCSCs, which resulted in achieving a superior in vivo tumor inhibition activity. Additionally, the biosafety of this nanomedicine was systematically studied through immunohistochemistry, blood biochemistry assay, blood routine examination, and metabolomics. The results revealed that this nanomedicine significantly reduced the adverse effects of DOX and SN38. Therefore, this simple yet efficient nanomedicine provided a promising strategy for future clinical applications.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Irinotecano/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Combinação de Medicamentos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Feminino , Humanos , Concentração de Íons de Hidrogênio , Irinotecano/farmacocinética , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Nanomedicina Teranóstica/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Molecules ; 23(4)2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29617302

RESUMO

Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics.


Assuntos
Antineoplásicos/uso terapêutico , Nanotecnologia/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Humanos
10.
Theranostics ; 8(6): 1468-1480, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29556335

RESUMO

Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood, and it is difficult to assess blood pressure salt-sensitivity clinically. Methods: We examined urinary levels of metabolites in 103 participants of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial after nearly 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol per day). Targeted chromatography/mass spectrometry analysis was performed in 24 h urine samples for 47 amino metabolites and 10 metabolites related to the tricarboxylic acid cycle. The effect of an identified metabolite on blood pressure was examined in Dahl salt-sensitive rats. Results: Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations of 24 h excretions of ß-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine with systolic blood pressure and cystine with diastolic blood pressure. The differences in homocysteine levels between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with ß-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. Conclusion: These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries, which could be developed as markers or therapeutic targets for salt-sensitive hypertension.


Assuntos
Aminoácidos/urina , Ácidos Aminoisobutíricos/farmacologia , Aminas Biogênicas/urina , Hipertensão/urina , Cloreto de Sódio na Dieta/urina , Adulto , Ácidos Aminoisobutíricos/urina , Animais , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Dieta/métodos , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Masculino , Metaboloma/efeitos dos fármacos , Pessoa de Meia-Idade , Ratos , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta/administração & dosagem , Cloreto de Sódio na Dieta/antagonistas & inibidores
11.
Biomed Chromatogr ; 32(4)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29130499

RESUMO

Fumarase catalyzes the interconversion of fumarate and l-malate in the tricarboxylic acid cycle. Fumarase insufficiencies were associated with increased levels of fumarate, decreased levels of malate and exacerbated salt-induced hypertension. To gain insights into the metabolism profiles induced by fumarase insufficiency and identify key regulatory metabolites, we applied a GC-MS based metabolomics platform coupled with a network approach to analyze fumarase insufficient human umbilical vein endothelial cells (HUVEC) and negative controls. A total of 24 altered metabolites involved in seven metabolic pathways were identified as significantly altered, and enriched for the biological module of amino acids metabolism. In addition, Pearson correlation network analysis revealed that fumaric acid, l-malic acid, l-aspartic acid, glycine and l-glutamic acid were hub metabolites according to Pagerank based on their three centrality indices. Alanine aminotransferase and glutamate dehydrogenase activities increased significantly in fumarase deficiency HUVEC. These results confirmed that fumarase insufficiency altered amino acid metabolism. The combination of metabolomics and network methods would provide another perspective on expounding the molecular mechanism at metabolomics level.


Assuntos
Aminoácidos/metabolismo , Fumarato Hidratase/deficiência , Fumarato Hidratase/metabolismo , Metaboloma/fisiologia , Metabolômica/métodos , Aminoácidos/análise , Biomarcadores/análise , Biomarcadores/metabolismo , Ciclo do Ácido Cítrico/fisiologia , Cromatografia Gasosa-Espectrometria de Massas , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/fisiologia , Metaboloma/efeitos dos fármacos , Reprodutibilidade dos Testes , Cloreto de Sódio/farmacologia
12.
Biomaterials ; 147: 53-67, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28930649

RESUMO

Several studies have demonstrated that cancer stem cells (CSCs) are responsible for replenishing bulk tumor cells, generating new tumors and causing metastasis and relapse. Although combination therapy with multiple chemotherapeutics is considered to be a promising approach for simultaneously eliminating non-CSCs and CSCs, it is difficult to deliver drugs into the inner region of a solid tumor where the CSCs are located due to a lack of capillaries. Here, we synthesized a pH-sensitive polymer, poly(ethylene glycol)-benzoic imine-poly(γ-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer (PPBV), to develop a pH multistage responsive micellar system for co-delivering paclitaxel and curcumin and synergistically eliminating breast cancer stem cells (bCSCs) and non-bCSCs. This pH multistage responsive micellar system could intelligently switch its surface charge from neutral to positive, de-shield its PEG layer and reduce its size after long-circulation and extravasation from leaky blood vessels at tumor sites, thus facilitating their cellular uptake and deep tumor penetration. These advantages were also beneficial for the combinational therapy efficacy of PTX and CUR to reach the maximum level and achieve superior tumor inhibition activity and effective bCSCs-killing capacity in vivo. Consequently, this pH multistage responsive micellar system is a powerful platform for collaborative therapy with PTX and CUR to simultaneously eliminate bCSCs and non-CSCs.


Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Paclitaxel/farmacologia , Polietilenoglicóis/química , Animais , Antineoplásicos/química , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Neoplasias da Mama , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Portadores de Fármacos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Feminino , Humanos , Concentração de Íons de Hidrogênio , Imidazóis/química , Camundongos Endogâmicos BALB C , Micelas , Nanopartículas/química , Células-Tronco Neoplásicas/patologia , Paclitaxel/química , Tamanho da Partícula , Polivinil/química , Propriedades de Superfície
13.
Kidney Blood Press Res ; 42(3): 587-597, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28922660

RESUMO

BACKGROUND/AIMS: The kidney plays a critical role in the control of blood pressure and its elevation in salt-induced hypertension. Mitochondrial dysfunction, especially in energy metabolism, has been associated with hypertension. Here, we aimed to investigate mitochondrial function and metabolic features in renal mitochondria of Dahl salt-sensitive (SS) rats to gain further insight into the relationship between mitochondrial metabolism and predisposition to hypertension. METHODS: In this study, SS rats fed low-salt (LS) or high-salt (HS) diets were used to investigate mitochondrial function and metabolism including mitochondrial enzyme activities, pyridine nucleotides, metabolites, and oxidative stress by biochemical analysis and gas chromatography-mass spectrometer (GC-MS). RESULTS: Significantly lower activity levels of fumarase, isocitrate dehydrogenase and succinyl-CoA synthetase were observed in renal mitochondria of SS rats compared with SS.13BN control rats fed LS diets. Intra-mitochondrial pyridine nucleotide content and mitochondrial metabolism were adversely affected in SS rats. In accordance with this, reduced ATP production, Δψm, and superoxide dismutase (SOD) activity were also observed in mitochondria of the renal medulla and cortex of SS rats. Moreover, ATP production was further impaired and oxidative stress was increased, confirming that the mitochondria of SS rats fed HS diets were dysfunctional compared to those of rats fed LS diets. CONCLUSIONS: Our data demonstrated that the renal mitochondria of SS rats exhibited complicated metabolic alteration and dysfunction in low-salt diets, and high-salt diets aggravated these dysfunctions. Thus, these results may be associated with renal dysfunction, which, in turn, would help in understanding the development of salt-sensitive hypertension.


Assuntos
Dieta Hipossódica/efeitos adversos , Hipertensão/induzido quimicamente , Rim/metabolismo , Mitocôndrias/metabolismo , Cloreto de Sódio/farmacologia , Animais , Hipertensão/fisiopatologia , Rim/fisiopatologia , Rim/ultraestrutura , Ratos Endogâmicos Dahl
14.
Physiol Genomics ; 49(9): 496-504, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28754823

RESUMO

The activity of fumarase, an enzyme in the tricarboxylic acid cycle, is lower in Dahl salt-sensitive SS rats compared with SS.13BN rats. SS.13BN rats have a Brown Norway (BN) allele of fumarase and exhibit attenuated hypertension. The SS allele of fumarase differs from the BN allele by a K481E sequence variation. It remains unknown whether higher fumarase activities can attenuate hypertension and whether the mechanism is relevant without the K481E variation. We developed SS-TgFh1 transgenic rats overexpressing fumarase on the background of the SS rat. Hypertension was attenuated in SS-TgFh1 rats. Mean arterial pressure in SS-TgFh1 rats was 20 mmHg lower than transgene-negative SS littermates after 12 days on a 4% NaCl diet. Fumarase overexpression decreased H2O2, while fumarase knockdown increased H2O2 Ectopically expressed BN form of fumarase had higher specific activity than the SS form. However, sequencing of more than a dozen rat strains indicated most rat strains including salt-insensitive Sprague-Dawley (SD) rats had the SS allele of fumarase. Despite that, total fumarase enzyme activity in the renal medulla was still higher in SD rats than in SS rats, which was associated with higher expression of fumarase in SD. H2O2 can suppress the expression of fumarase. Renal medullary interstitial administration of fumarase siRNA in SD rats resulted in higher blood pressure on the high-salt diet. These findings indicate elevation of total fumarase activity attenuates the development of hypertension and can result from a nonsynonymous sequence variation in some rat strains and higher expression in other rat strains.


Assuntos
Fumarato Hidratase/genética , Fumarato Hidratase/metabolismo , Variação Genética , Hipertensão/enzimologia , Hipertensão/genética , Animais , Sequência de Bases , Células HEK293 , Humanos , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Ratos Transgênicos , Análise de Sequência de DNA , Regulação para Cima/genética
15.
Mol Nutr Food Res ; 61(10)2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28654221

RESUMO

SCOPE: A high salt (HS) diet is detrimental to cognitive function, in addition to having a role in cardiovascular disorders. However, the method by which an HS diet impairs cognitive functions such as learning and memory remains open. METHODS AND RESULTS: In this study, we found that mice on a 7 week HS diet demonstrated disturbed short-term memory in an object-place recognition task, and both 4 week and 7 week HS treatments impaired long-term memory, as evidenced in a fear conditioning test. Mechanistically, the HS diet inhibited memory-related long-term potentiation (LTP) in the hippocampus, while also increasing the levels of reactive oxygen species (ROS) in hippocampal cells and downregulating the expression of synapsin I, synaptophysin, and brain-derived neurotrophic factor in specific encephalic region. CONCLUSION: This suggests that oxidative stress or synaptic protein/neurotrophin deregulation was involved in the HS diet-induced memory impairment. Thus, the present study provides novel insights into the mechanisms of memory impairment caused by excessive dietary salt, and underlined the importance of controlling to salt absorb quantity.


Assuntos
Memória , Plasticidade Neuronal , Estresse Oxidativo , Cloreto de Sódio na Dieta/efeitos adversos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colesterol/sangue , Cognição , Dieta , Regulação para Baixo , Hipocampo/citologia , Hipocampo/metabolismo , Aprendizagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sinapsinas/genética , Sinapsinas/metabolismo , Triglicerídeos/sangue
16.
Cell Rep ; 19(8): 1631-1639, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28538181

RESUMO

Fumarase catalyzes the interconversion of fumarate and L-malate in the tricarboxylic acid cycle. The Dahl salt-sensitive (SS) rat, a model of salt-sensitive hypertension, exhibits fumarase insufficiencies. To investigate the mechanism mediating the effect of fumarase-related metabolites on hypertension, we considered the pathway in which L-malate can be converted to oxaloacetate, aspartate, argininosuccinate, and L-arginine, the substrate of nitric oxide (NO) synthase. The levels of aspartate, citrulline, L-arginine, and NO were significantly decreased in the kidneys of SS rats compared to salt-insensitive consomic SS.13BN rats. Knockdown of fumarase in human kidney cells and vascular endothelial cells resulted in decreased levels of malate, aspartate, L-arginine, and NO. Supplementation of aspartate or malate increased renal levels of L-arginine and NO and attenuated hypertension in SS rats. These findings reveal a multi-step metabolic pathway important for hypertension in which malate and aspartate may modulate blood pressure by altering levels of L-arginine and NO.


Assuntos
Arginina/metabolismo , Ácido Aspártico/metabolismo , Hipertensão/metabolismo , Malatos/metabolismo , Óxido Nítrico/metabolismo , Animais , Regulação para Baixo , Fumarato Hidratase/metabolismo , Técnicas de Silenciamento de Genes , Rim/metabolismo , Ratos Endogâmicos Dahl
17.
Anal Chim Acta ; 854: 95-105, 2015 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-25479872

RESUMO

The awareness, treatment, and control rates of hypertension for young adults are much lower than average. It is urgently needed to explore the variances of metabolic profiles for early diagnosis and treatment of hypertension. In current study, we applied a GC-MS based metabolomics platform coupled with a network approach to analyze plasma samples from young hypertensive men and age-matched healthy controls. Our findings confirmed distinct metabolic footprints of young hypertensive men. The significantly altered metabolites between two groups were enriched for the biological module of amino acids biosynthesis. The correlations of GC-MS metabolomics data were then visualized as networks based on Pearson correlation coefficient (threshold=0.6). The plasma metabolites identified by GC-MS and the significantly altered metabolites (P<0.05) between patients and controls were respectively included as nodes of a network. Statistical and topological characteristics of the networks were studied in detail. A few amino acids, glycine, lysine, and cystine, were screened as hub metabolites with higher values of degree (k), and also obtained highest scores of three centrality indices. The short average path lengths and high clustering coefficients of the networks revealed a small-world property, indicating that variances of these amino acids have a major impact on the metabolic change in young hypertensive men. These results suggested that disorders of amino acid metabolism might play an important role in predisposing young men to developing hypertension. The combination of metabolomics and network methods would provide another perspective on expounding the molecular mechanism underlying complex diseases.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Hipertensão/metabolismo , Metabolômica , Adolescente , Adulto , Aminoácidos/metabolismo , Humanos , Masculino , Adulto Jovem
18.
Biochimie ; 109: 27-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25497182

RESUMO

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is importantly involved in the regulation of development, DNA damage response, and several human diseases. The molecular mechanisms that control the expression of hnRNP K are largely unknown. In the present study, we investigated the detailed mechanism of the transcriptional regulation of human hnRNP K gene. Two activating and one repressive elements located in the proximal segment of the transcriptional initiation site were identified in hnRNP K gene. A 19 bp-region was responsible for the inhibitory activities of the repressor element. Twenty proteins were identified by DNA-affinity purification and mass spectrometry analyses as binding partners of the primary activating element in the hnRNP K promoter. Chromatin immunoprecipitation and EMSA analysis confirmed the binding of Sp1 with hnRNP K promoter. Sp1 enhanced the promoter activity, increased the expression of hnRNP K, and reduced the mRNA level of angiotensinogen, a gene known to be negatively regulated by hnRNP K. In summary, the current study characterized the promoter elements that regulate the transcription of human hnRNP K gene, identified 20 proteins that bind to the primary activating element of hnRNP K promoter, and demonstrated a functional effect of Sp1 on hnRNP K transcription.


Assuntos
Regulação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Regiões Promotoras Genéticas/genética , Elementos de Resposta/genética , Sequência de Bases , Sítios de Ligação/genética , Western Blotting , Linhagem Celular , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Células HEK293 , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Humanos , Células MCF-7 , Dados de Sequência Molecular , Ligação Proteica , Proteoma/metabolismo , Proteômica/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Espectrometria de Massas por Ionização por Electrospray
19.
Biochem Biophys Res Commun ; 450(1): 863-9, 2014 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-24971531

RESUMO

Salt-sensitive hypertension is a major risk factor for cardiovascular disorders. Our previous proteomic study revealed substantial differences in several proteins between Dahl salt-sensitive (SS) rats and salt-insensitive consomic SS.13(BN) rats. Subsequent experiments indicated a role of fumarase insufficiency in the development of hypertension in SS rats. In the present study, a global metabolic profiling study was performed using gas chromatography/mass spectrometry (GC/MS) in plasma of SS rats (n=9) and SS.13(BN) rats (n=8) on 0.4% NaCl diet, designed to gain further insights into the relationship between alterations in cellular intermediary metabolism and predisposition to hypertension. Principal component analysis of the data sets revealed a clear clustering and separation of metabolic profiles between SS rats and SS.13(BN) rats. 23 differential metabolites were identified (P<0.05). Higher levels of five TCA cycle metabolites, fumarate, cis-aconitate, isocitrate, citrate and succinate, were observed in SS rats. Pyruvate, which connects TCA cycle and glycolysis, was also increased in SS rats. Moreover, lower activity levels of fumarase, aconitase, α-ketoglutarate dehydrogenase and succinyl-CoA synthetase were detected in the heart, liver or skeletal muscles of SS rats. The distinct metabolic features in SS and SS.13(BN) rats indicate abnormalities of TCA cycle in SS rats, which may play a role in predisposing SS rats to developing salt-sensitive hypertension.


Assuntos
Proteínas Sanguíneas/metabolismo , Hipertensão/sangue , Proteoma/metabolismo , Ratos Endogâmicos BN/sangue , Ratos Endogâmicos Dahl/sangue , Cloreto de Sódio na Dieta/sangue , Animais , Pressão Sanguínea/genética , Predisposição Genética para Doença/genética , Hipertensão/genética , Endogamia , Ratos , Ratos Endogâmicos BN/genética , Ratos Endogâmicos Dahl/genética , Tolerância ao Sal/genética
20.
Am J Physiol Renal Physiol ; 306(10): F1190-7, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24694587

RESUMO

Metabolic and functional abnormalities in the kidney precede or coincide with the initiation of overt hypertension in the Dahl salt-sensitive (SS) rat. However, renal histological injury in SS rats is mild before the development of overt hypertension. We performed electron microscopy analysis in 7-wk-old SS rats and salt-insensitive consomic SS.13(BN) rats and Sprague-Dawley (SD) rats fed a 4% NaCl diet for 7 days. Long mitochondria (>2 µm) accounted for a significantly smaller fraction of mitochondria in medullary thick ascending limbs in SS rats (4% ± 1%) than in SS.13(BN) rats (8% ± 1%, P < 0.05 vs. SS rats) and SD rats (9% ± 1%, P < 0.01 vs. SS rats), consistent with previous findings of mitochondrial functional insufficiency in the medulla of SS rats. Long mitochondria in proximal tubules, however, were more abundant in SS rats than in SS.13(BN) and SD rats. The width of the endoplasmic reticulum, an index of endoplasmic reticulum stress, was significantly greater in medullary thick ascending limbs of SS rats (107 ± 1 nm) than in SS.13(BN) rats (95 ± 2 nm, P < 0.001 vs. SS rats) and SD rats (74 ± 3 nm, P < 0.01 vs. SS or SS.13(BN) rats). The tubules examined were indistinguishable between rat strains under light microscopy. These data indicate that ultrastructural abnormalities occur in the medullary thick ascending limbs of SS rats before the development of histological injury in renal tubules, providing a potential structural basis contributing to the subsequent development of overt hypertension.


Assuntos
Retículo Endoplasmático/ultraestrutura , Hipertensão/patologia , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/ultraestrutura , Mitocôndrias/ultraestrutura , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Masculino , Microscopia Eletrônica , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Cloreto de Sódio na Dieta/farmacologia
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