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1.
Int J Occup Environ Med ; 11(3): 140-147, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32683426

RESUMO

BACKGROUND: The major portion of lead in the body resides in skeletal system. The bone turnover affects the release of lead into the circulation from bones. The bone turnover biomarkers (BTM) in lead-battery workers with long-term exposure to lead have not been explored yet. OBJECTIVE: To evaluate the BTM (formation and resorption) in lead-battery workers with long-term exposure to lead in lead-battery manufacturing plant. METHODS: 176 male lead-exposed workers and 80 matched comparison group were studied. All participants were examined for blood lead levels (BLLs), bone formation biomarkers- serum osteocalcin (OC), alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP)-and bone resorption biomarkers-serum pyridinoline (PYD), deoxypyridinoline (DPYD), tartarate-resistant acid phosphatase-5b (TRACP-5b), and urinary hydroxyproline (UHYP). RESULTS: We found a significantly higher bone formation biomarkers such as BALP (p=0.007) and bone resorption biomarkers, eg, PYD (p=0.048), TRCAP-5b (p=0.001), and UHYP (p=0.001) in lead-exposed workers. A significant (p=0.041) negative correlation (ρ ­0.128) was noted between BLLs and OC. A significant positive correlation was noted between BLLs and TRACP-5b (ρ 0.176, p=0.005) and UHYP (ρ 0.258, p=0.004). Serum OC (p=0.040) and UHYP (p=0.015) levels changed significantly with BLL level. Bone resorption biomarkers levels- PYD, TRACP-5b, and BALP-were higher among those with higher BLLs levels. The duration of exposure was significantly associated with BALP (p=0.037), DPYD (p=0.016), TRACP-5b (p=0.001), and UHYP (p=0.002) levels. CONCLUSION: Long-term lead exposure affects the bone turnover.


Assuntos
Biomarcadores/sangue , Remodelação Óssea/fisiologia , Fontes de Energia Elétrica , Chumbo/toxicidade , Exposição Ocupacional/análise , Fosfatase Ácida/sangue , Fosfatase Ácida/metabolismo , Adulto , Fosfatase Alcalina/sangue , Biomarcadores/análise , Reabsorção Óssea/sangue , Estudos de Casos e Controles , Estudos Transversais , Fontes de Energia Elétrica/efeitos adversos , Humanos , Isoenzimas/sangue , Isoenzimas/metabolismo , Chumbo/química , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/diagnóstico , Masculino , Instalações Industriais e de Manufatura , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/estatística & dados numéricos , Osteocalcina/sangue , Local de Trabalho
2.
Ecotoxicol Environ Saf ; 192: 110264, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035397

RESUMO

Copper (Cu) mining has to address a critical environmental issue related to the disposal of heavy metals and metalloids (HMs). Due to their deleterious effects on living organisms, Cu and arsenic (As) have gained global attention, and thus their monitoring in the environment is an important task. The aims of this study were: 1) to evaluate the alteration of soil enzyme activities (EAs) and soil microbial functional diversity with Cu/As contamination, and 2) to select the most reliable biochemical indicators of Cu/As contamination. A twelve-week soil experiment was performed with four increasing levels of Cu, As, and Cu/As from 150/15 to 1000/100 mg Cu/As kg-1. Soil enzyme activities and soil community-level physiological profile (CLPP) using MicroResp™ were measured during the experiment. Results showed reduced EAs over time with increasing Cu and Cu/As levels. The most Cu-sensitive EAs were dehydrogenase, acid phosphatase, and arylsulfatase, while arginine ammonification might be related to the resilience of soil microbial communities due to its increased activity in the last experimental times. There was no consistent response to As contamination with reduced individual EAs at specific sampling times, being urease the only EA negatively affected by As. MicroResp™ showed reduced carbon (C) substrate utilization with increasing Cu levels indicating a community shift in C acquisition. These results support the use of specific EAs to assess the environmental impact of specific HMs, being also the first assessment of EAs and the use of CLPP (MicroResp™) to study the environmental impact in Cu/As contaminated soils.


Assuntos
Arsênico/farmacologia , Cobre/farmacologia , Microbiologia do Solo , Poluentes do Solo/farmacologia , Fosfatase Ácida/metabolismo , Arilsulfatases/metabolismo , Oxirredutases/metabolismo , Solo/química , Urease/metabolismo
3.
Cancer Immunol Immunother ; 69(4): 641-651, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32016503

RESUMO

Prostate cancer is a candidate for immunotherapy because cancer cells express tissue-specific proteins that can be therapeutic targets. However, immune checkpoint inhibitors and active immunization have performed poorly in clinical trials. We developed a novel virus-like particle (VLP) vaccine composed of bovine papillomavirus L1 protein engineered to display surface docking sites. We decorated VLPs with peptides encoding T cell epitopes from two prostate cancer-associated tumor antigens, prostate stem cell antigen (PSCA), and prostatic acid phosphatase (PAP-1 and PAP-2), and a neo-antigen, stimulator of prostatic adenocarcinoma-specific T cells (SPAS-1). The VLP vaccines induced a mean frequency of antigen-specific IFN-γ secreting CD8 + T cells of 2.9% to PSCA, 9.5% to SPAS-1, 0.03% to PAP-1, and 0.03% to PAP-2 in tumor-bearing TRAMP mice. We treated TRAMP mice at 19-20 weeks of age, when mice have advanced stages of carcinogenesis, with either VLP vaccine, anti-PD1 antibody, or combination immunotherapy. The VLP vaccine alone or in combination with anti-PD1 antibody significantly reduced tumor burden, while anti-PD1 antibody had a modest non-significant therapeutic effect. All treatments significantly increased CD3 + and CD8 + T cell infiltration into tumor tissue compared to control mice, and combination therapy resulted in significantly greater CD3 + and CD8 + T cell infiltration than monotherapy. Reduction in tumor burden in vaccine-treated mice was inversely correlated with CD8 + T cell numbers in tumor tissue. No other immunotherapy has shown efficacy in this animal model of advanced prostate cancer, making bovine papillomavirus VLPs an attractive vaccine technology to test in patients with metastatic prostate cancer.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Proteínas do Capsídeo/imunologia , Proteínas de Neoplasias/imunologia , Antígeno Prostático Específico/imunologia , Neoplasias da Próstata/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Fosfatase Ácida/imunologia , Fosfatase Ácida/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Proteínas Ligadas por GPI/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Camundongos Transgênicos , Neoplasias da Próstata/terapia , Resultado do Tratamento , Vacinação
4.
Org Biomol Chem ; 18(6): 1148-1154, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31971197

RESUMO

Fluorescent probes for the detection of acid phosphatases (ACP) are important in the investigation of the pathology and diagnosis of diseases. We reported a lysosome-targeted near-infrared (NIR) fluorescent probe SHCy-P based on a novel NIR-emitting thioxanthene-indolium dye for the detection of ACP. The probe showed a long wavelength fluorescence emission at λem = 765 nm. Due to the ACP-catalyzed cleavage of the phosphate group in SHCy-P, the probe exhibited high selectivity and sensitivity for the 'turn-on' detection of ACP with a limit of detection as low as 0.48 U L-1. The probe SHCy-P could also be used to detect and image endogenous ACP in lysosomes. In light of these prominent properties, we envision that SHCy-P will be an efficient optical imaging approach for investigating the ACP activity in disease diagnosis.


Assuntos
Fosfatase Ácida/análise , Corantes Fluorescentes/química , Lisossomos/enzimologia , Imagem Óptica , Fosfatase Ácida/metabolismo , Biocatálise , Células HeLa , Humanos , Indóis/química , Raios Infravermelhos , Estrutura Molecular , Tioxantenos/química
5.
Artigo em Inglês | MEDLINE | ID: mdl-31629812

RESUMO

The present report describes a comprehensive study on comparative biochemical characterization of two lysosomal enzymes, acid phosphatase and ß-hexosaminidase in three different strains of Hydra; Hydra vulgaris Ind-Pune, H. vulgaris Naukuchiatal and H. magnipapillata sf-1 (self-feeder-1). Since morphology and habitat of Hydra effect lysosomal enzymes and their response to environmental pollutants, it would be interesting to identify them in different Hydra strains so as to use them as toxicity testing. Preliminary studies revealed a differential expression of acid phosphatase, ß-hexosaminidase and ß-glucuronidase in three Hydra strains. Expression of all three lysosomal enzymes in H. vulgaris Ind-Pune was low in comparison to H. vulgaris Naukuchiatal and H. magnipapillata sf-1, while their expression is comparable in H. vulgaris Naukuchiatal and H. magnipapillata sf-1. The Michaelis-Menten (KM) values for lysosomal ß-hexosaminidase using 4-nitrophenyl N-acetyl-ß-D-glucosaminide as substrate were found to be 1.3 mM, 1.1 mM and 0.8 mM, respectively for H. vulgaris Ind-Pune, H. vulgaris Naukuchiatal and H. magnipapillata sf-1. For acid phosphatase using 4-nitrophenyl-phosphate as substrate, the KM values were 0.38 mM, 1.2 mM and 0.52 mM respectively, for H. vulgaris Ind-Pune, H. vulgaris Naukuchiatal and sf-1 strains. The optimum temperature for ß-hexosaminidase was 60 °C for H. vulgaris Ind-Pune, while 50 °C was observed for H. vulgaris Naukuchiatal and sf-1 strains. The optimum pH for ß-hexosaminidase was found to be 6.0 for H. vulgaris Ind-Pune and H. vulgaris Naukuchiatal, and 5.0 for sf-1. The optimum temperature and pH of acid phosphatase was similar in all three strains, viz., 40 °C and 3.0, respectively. Preliminary localization studies using whole mount in situ hybridization revealed predominant endodermal expression of three enzymes in H. vulgaris Ind-Pune. Our results thus support the conservation of lysosomal hydrolases in Hydra.


Assuntos
Fosfatase Ácida/metabolismo , Hydra/enzimologia , Lisossomos/enzimologia , beta-N-Acetil-Hexosaminidases/metabolismo , Animais , Especificidade da Espécie
6.
Chemosphere ; 239: 124668, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31494325

RESUMO

Nitrite is one of major environmental pollutants that can impact immunological parameters in aquatic organisms. In the present study, we investigated the effects of nitrite exposure on oxidative stress, DNA damage and apoptosis in mud crab (Scylla paramamosain). Mud crab were exposed to 0, 5, 10 and 15 mg L-1 nitrite for 72 h. These data showed that acid phosphatase (ACP) and alkaline phosphatase (ALP) activity significantly decreased in treatments with various concentrations of nitrite (5, 10 and 15 mg L-1) after 24 and 48 h, while the levels of nitric oxide (NO) significantly increased in these treatments. Nitrite exposure could suppress superoxide dismutase (SOD) and catalase (CAT) activity, and increase the formation of malondialdehyde (MDA) after 48 and 72 h of exposure. In addition, nitrite exposure decreased total haemocyte counts after 48 and 72 h of exposure. Cytological damage, DNA damage and apoptosis was observed obviously at 72 h after nitrite exposure. Moreover, nitrite exposure significantly induced the mRNA levels of phosphorylated Jun N-terminal kinases (JNK), and eventually activated p53 signaling and caspase-3. These results indicated that nitrite exposure could induce oxidative stress, which further caused DNA damage and apoptosis in mud crab. Our results will be helpful to understand the mechanism of nitrite toxicity on crustaceans.


Assuntos
Apoptose/efeitos dos fármacos , Braquiúros/efeitos dos fármacos , Dano ao DNA/genética , Nitritos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Braquiúros/genética , Catalase/metabolismo , Hemócitos , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo
7.
J Therm Biol ; 85: 102404, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31657746

RESUMO

The red claw crayfish, Cherax quadricarinatus, is an economically important freshwater crustacean that cannot tolerate low temperature, which diminishes survival via unknown mechanisms. Herein, physiological regulation of C. quadricarinatus was investigated following exposure to low temperature stress at 9 ±â€¯2 °C for 4 weeks. Hepatopancreas tissue was tested for nonspecific enzyme activity, histological structure, and transcriptome sequencing analyses. The results showed that the activities of nonspecific enzymes were inhibited following low temperature stress. Ultrastructural observation revealed that the hepatopancreas structure was oxidatively damaged at low temperature, with numerous autophagic vesicles visible. Apoptosis in the hepatopancreas was significantly increased in the cold stress group, indicating diminished function. Transcriptome sequencing identified 2615 differentially expressed genes (DEGs) following low temperature stress, of which 1147 and 1468 were up- and down-regulated, respectively. Functional analysis of DEGs indicated involvement in substance metabolism, antioxidant defences, signal transduction, and immune responses. Therefore, chronic cold stress can suppress metabolism and cause oxidative damage and immune deficiency in crayfish. The findings provide fundamental molecular information for further study of the regulatory mechanisms of cold tolerance in red claw crayfish.


Assuntos
Astacoidea/genética , Temperatura Baixa/efeitos adversos , Hepatopâncreas/metabolismo , Estresse Fisiológico/genética , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Astacoidea/fisiologia , Perfilação da Expressão Gênica , Hepatopâncreas/ultraestrutura , Microscopia Eletrônica de Transmissão , Monofenol Mono-Oxigenase/metabolismo , Muramidase/metabolismo
8.
PLoS Negl Trop Dis ; 13(10): e0007740, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31603908

RESUMO

Schistosomiasis is a serious worldwide parasitic disease. One of the best ways to control schistosomiasis is to control the population of Oncomelania hupensis snails. We sought to identify a high-efficiency biogenic molluscicide against Oncomelania with low toxicity, to avoid chemical molluscicide contamination and toxicity in aquatic organisms. We extracted quaternary benzo[c]phenanthridine alkaloids (QBAs) from Macleaya cordata fruits. Molluscicidal activity of the QBAs against Oncomelania was determined using bioassay. Our results showed that the extracted QBAs had a strong molluscicidal effect. In treatment of O. hupensis with QBAs for 48 h and 72 h, the lethal concentration (LC50) was 2.89 mg/L and 1.29 mg/L, respectively. The molluscicidal activity of QBAs was close to that of niclosamide (ethanolamine salt), indicating that QBAs have potential development value as novel biogenic molluscicides. We also analyzed physiological toxicity mechanisms by examining the activity of several important detoxification enzymes. We measured the effect of the extracted QBAs on the activities of glutathione S-transferase (GST), carboxylesterase (CarE), acid phosphatase (ACP), and alkaline phosphatase (AKP) in the liver of O. hupensis. We found that the effects of QBAs on detoxification metabolism in O. hupensis were time and concentration dependent. The activities of GST, CarE, AKP, and ACP in the liver of snails increased significantly in the early stage of treatment (24 h), but decreased sharply in later stages (120 h), compared with these activities in controls. GST, CarE, AKP, and ACP activity in the liver of snails treated with LC50 QBAs for 120 h decreased by 62.3%, 78.1%, 59.2%, and 68.6%, respectively. Our results indicate that these enzymes were seriously inhibited by the extracted QBAs and the detoxification and metabolic functions of the liver gradually weakened, leading to poisoning, which could be the main cause of death in O. hupensis snails.


Assuntos
Alcaloides/toxicidade , Frutas/química , Gastrópodes/efeitos dos fármacos , Moluscocidas/toxicidade , Papaveraceae/química , Fenantridinas/toxicidade , Extratos Vegetais/toxicidade , Fosfatase Ácida/efeitos dos fármacos , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Carboxilesterase/efeitos dos fármacos , Carboxilesterase/metabolismo , China , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Inativação Metabólica/efeitos dos fármacos , Fígado/metabolismo , Esquistossomose/prevenção & controle , Esquistossomose/transmissão
9.
Environ Pollut ; 255(Pt 2): 113321, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31610515

RESUMO

Ionic liquids (ILs) are extensively used in several chemistry fields. And research about the effects of ILs on soil microbes is needed. In this study, brown soil was exposed to 1-butyl-3-methylimidazolium bromide ([C4mim]Br), 1-hexyl-3-methylimidazolium bromide ([C6mim]Br) and 1-decyl-3-methylimidazolium bromide ([C10mim]Br). The toxicities of the three ILs are evaluated by measuring the soil culturable microbial number, enzyme activity, microbial diversity and, abundance of the ammonia monooxygenase (amoA) genes of ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA). Results showed that all tested ILs caused a decrease in culturable microbial abundance. Tested ILs exposure inhibit urease activity and promote acid phosphatase and ß-glucosidase activities. Tested ILs reduced soil microbial diversity and the abundances of AOB-amoA and AOA-amoA genes significantly. After a comparison of the integrated biomarker response (IBR) index, the toxicities of tested ILs to soil microorganisms were as follows: [C10mim]Br > [C6mim]Br > [C4mim]Br. Among all collected biomarkers, the abundance of the AOA-amoA gene was the most sensitive one and was easily affected after ILs exposure.


Assuntos
Archaea/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Boratos/toxicidade , Brometos/toxicidade , Imidazóis/toxicidade , Líquidos Iônicos/toxicidade , Fosfatase Ácida/metabolismo , Amônia/metabolismo , Glucosidases/metabolismo , Oxirredução , Oxirredutases/genética , Filogenia , Solo/química , Microbiologia do Solo , Urease/antagonistas & inibidores
10.
Molecules ; 24(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590284

RESUMO

The thiazolidinedione 49 (TD49) is an effective algaecide against harmful algae; however, its potential effects on the immune function of the edible bay scallop are unclear. Therefore, the present work studied the effects of TD49 on the immune response in bay scallop by evaluating activities of acid phosphatase (ACP), alkaline phosphatase (ALP), and superoxide dismutase (SOD), as well as nitric oxide (NO) levels, total protein content, and expression of immune genes (CTL-6, PGRP, PrxV, MT, and Cu/Zn-SOD) at 3-48 h post-exposure (hpe) to TD49. The activities of ACP and ALP significantly increased in TD49-treated groups at 3-24 hpe, whereas NO levels decreased significantly in 0.58 and 0.68 µM of TD49 at 6-24 hpe, after which the level was similar to that in the untreated control. Moreover, SOD activity significantly increased in all three concentration groups at 3-6 hpe, while it decreased at 12 hpe in the 0.68 µM TD49 treatment group. Notably, total protein content increased with TD49 treatment at each time interval. The results revealed that variable effects on the expression of immune-related genes were observed after treatment with TD49. The findings demonstrate that exposure of scallops to TD49 changes immune responses and expression of immune-related genes. We hypothesize that TD49 may disrupt immune system in bay scallop. The current investigation highlights the potential negative effects of using TD49 as an algaecide on marine economic bivalves to control harmful algal blooms in marine environments.


Assuntos
Herbicidas/efeitos adversos , Pectinidae/imunologia , Tiazolidinedionas/efeitos adversos , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Herbicidas/química , Imunidade/efeitos dos fármacos , Pectinidae/efeitos dos fármacos , Pectinidae/metabolismo , Frutos do Mar , Superóxido Dismutase/metabolismo , Tiazolidinedionas/química
11.
PLoS One ; 14(9): e0222234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509576

RESUMO

Prostatic acid phosphatase (PAP), which is secreted by prostate, increases in some diseases such as prostate cancer. PAP is also present in the central nervous system. In this study we reveal that α-synuclein (Snca) gene is co-deleted/mutated in PAP null mouse. It is indicated that mice deficient in transmembrane PAP display neurological alterations. By using immunohistochemistry, cerebellar cortical neurons and zone and stripes pattern were studied in Pap-/- ;Snca-/- mouse cerebellum. We show that the Pap-/- ;Snca-/- cerebellar cortex development appears to be normal. Compartmentation genes expression such as zebrin II, HSP25, and P75NTR show the zone and stripe phenotype characteristic of the normal cerebellum. These data indicate that although aggregation of PAP and SNCA causes severe neurodegenerative diseases, PAP -/- with absence of the Snca does not appear to interrupt the cerebellar architecture development and zone and stripe pattern formation. These findings question the physiological and pathological role of SNCA and PAP during cerebellar development or suggest existence of the possible compensatory mechanisms in the absence of these genes.


Assuntos
Fosfatase Ácida/metabolismo , Córtex Cerebelar/metabolismo , alfa-Sinucleína/metabolismo , Fosfatase Ácida/genética , Fosfatase Ácida/fisiologia , Animais , Cerebelo/metabolismo , Expressão Gênica/genética , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/genética , Atividade Motora/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Transcriptoma/genética , alfa-Sinucleína/genética , alfa-Sinucleína/fisiologia
12.
Food Funct ; 10(9): 5616-5625, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31432856

RESUMO

A novel osteogenic dodecapeptide peptide (PIE), IEELEEELEAER, was purified from the protein hydrolysate of blue mussels (Mytilus edulis). PIE was identified using a capillary electrophoresis electrospray ionization-quadrupole-time of flight mass spectrometer. PIE showed a good reduction in the bone loss in ovariectomized mice, and it also increased the bone mineral density of the ovariectomized mice. PIE has a high affinity with integrins (PDB: , ). There are 8 and 12 amino acid residues from PIE that interact with integrins and , respectively. PIE accelerates the transformation of G0/G1 phase cells into G2 M phase cells, which promotes the growth of osteoblasts. PIE (100 µg mL-1) can enhance alkaline phosphatase (ALP) activity by 26.48% compared with the control, and it also inhibits the growth of osteoclasts and tartrate resistant acid phosphatase (TRAP) activity. Therefore, PIE may contribute to preventing osteoporosis both in vitro and in vivo.


Assuntos
Mytilus edulis/química , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Peptídeos/administração & dosagem , Fosfatase Ácida/genética , Fosfatase Ácida/metabolismo , Animais , Densidade Óssea , Feminino , Humanos , Integrinas/genética , Integrinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoporose Pós-Menopausa/genética , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/fisiopatologia , Ovariectomia , Peptídeos/química , Hidrolisados de Proteína/química , Fosfatase Ácida Resistente a Tartarato/genética , Fosfatase Ácida Resistente a Tartarato/metabolismo
13.
Eur J Med Chem ; 182: 111611, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445230

RESUMO

Purple acid phosphatases (PAPs) are binuclear hydrolases that catalyze the hydrolysis of phosphorylated substrates under acidic to neutral conditions. Elevated serum concentrations of PAP are observed in patients suffering from osteoporosis, identifying this enzyme as a potential target for the development of novel therapeutic agents to treat this disease. α-Alkoxy-substituted naphthylmethylphosphonic acid derivatives have been identified previously as molecules that bind with high affinity to PAPs, and docking studies suggest that longer alkyl chains may increase the binding affinities of such compounds. Here, we synthesized several derivatives and tested their inhibitory effect against pig and red kidney bean PAPs. The most potent inhibitor within this series is the octadecyl derivative, which has a Ki value of ∼200 nM. Crystal structures of the dodecyl and octadecyl derivatives bound to red kidney bean PAP show that the length of the alkyl chain influences the ability of the phosphonate group to interact directly with the bimetallic center. These structures represent the first examples of potent inhibitors bound to a PAP that have drug-like properties. This study provides a starting point for the development of much needed new treatments for osteoporosis.


Assuntos
Fosfatase Ácida/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Osteoporose/tratamento farmacológico , Fosfatase Ácida/metabolismo , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Osteoporose/metabolismo , Phaseolus/enzimologia , Relação Estrutura-Atividade , Suínos
14.
Am J Physiol Heart Circ Physiol ; 317(5): H1013-H1027, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469290

RESUMO

Insufficient autophagy has been proposed as a mechanism of cellular aging, as this leads to the accumulation of dysfunctional macromolecules and organelles. Premature vascular aging occurs in hypertension. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in clinical and experimental hypertension. Previously, we have reported decreased autophagy in arteries from spontaneously hypertensive rats (SHRs); however, the effects of restoring autophagic activity on blood pressure and vascular function are currently unknown. We hypothesized that reconstitution of arterial autophagy in SHRs would decrease blood pressure and improve endothelium-dependent relaxation. We treated 14- to 18-wk-old Wistar rats (n = 7 vehicle and n = 8 trehalose) and SHRs (n = 7/group) with autophagy activator trehalose (2% in drinking water) for 28 days. Blood pressure was measured by radiotelemetry, and vascular function and structure were measured in isolated mesenteric resistance arteries (MRAs) using wire and pressure myographs, respectively. Treatment with trehalose had no effect on blood pressure in SHRs; however, isolated MRAs presented enhanced relaxation to acetylcholine, in a cyclooxygenase- and reactive oxygen species-dependent manner. Similarly, trehalose treatment shifted the relaxation to the Rho kinase (ROCK) inhibitor Y-27632 to the right, indicating reduced ROCK activity. Finally, trehalose treatment decreased arterial stiffness as indicated by the slope of the stress-strain curve. Overall these data indicate that reconstitution of arterial autophagy in SHRs improves endothelial and vascular smooth muscle function, which could synergize to prevent stiffening. As a result, restoration of autophagic activity could be a novel therapeutic for premature vascular aging in hypertension.NEW & NOTEWORTHY This work supports the concept that diminished arterial autophagy contributes to premature vascular aging in hypertension and that therapeutic reconstitution of autophagic activity can ameliorate this phenotype. As vascular age is a new clinically used index for cardiovascular risk, understanding this mechanism may assist in the development of new drugs to prevent premature vascular aging in hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Artérias Mesentéricas/efeitos dos fármacos , Trealose/farmacologia , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Fosfatase Ácida/metabolismo , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Modelos Animais de Doenças , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , Artérias Mesentéricas/fisiopatologia , Ratos Endogâmicos SHR , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Quinases Associadas a rho/metabolismo
15.
Nucleic Acids Res ; 47(16): 8452-8469, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31276588

RESUMO

Fission yeast phosphate acquisition genes pho1, pho84, and tgp1 are repressed in phosphate-rich medium by transcription of upstream lncRNAs. Here, we show that phosphate homeostasis is subject to metabolite control by inositol pyrophosphates (IPPs), exerted through the 3'-processing/termination machinery and the Pol2 CTD code. Increasing IP8 (via Asp1 IPP pyrophosphatase mutation) de-represses the PHO regulon and leads to precocious termination of prt lncRNA synthesis. pho1 de-repression by IP8 depends on cleavage-polyadenylation factor (CPF) subunits, termination factor Rhn1, and the Thr4 letter of the CTD code. pho1 de-repression by mutation of the Ser7 CTD letter depends on IP8. Simultaneous inactivation of the Asp1 and Aps1 IPP pyrophosphatases is lethal, but this lethality is suppressed by mutations of CPF subunits Ppn1, Swd22, Ssu72, and Ctf1 and CTD mutation T4A. Failure to synthesize IP8 (via Asp1 IPP kinase mutation) results in pho1 hyper-repression. Synthetic lethality of asp1Δ with Ppn1, Swd22, and Ssu72 mutations argues that IP8 plays an important role in essential 3'-processing/termination events, albeit in a manner genetically redundant to CPF. Transcriptional profiling delineates an IPP-responsive regulon composed of genes overexpressed when IP8 levels are increased. Our results establish a novel role for IPPs in cell physiology.


Assuntos
Fosfatase Ácida/genética , Regulação Fúngica da Expressão Gênica , Fosfatos de Inositol/metabolismo , Regulon , Proteínas de Schizosaccharomyces pombe/genética , Schizosaccharomyces/genética , Terminação da Transcrição Genética , Fosfatase Ácida/metabolismo , Fator de Especificidade de Clivagem e Poliadenilação/genética , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Deleção de Genes , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Pirofosfatases/deficiência , Pirofosfatases/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo
16.
Georgian Med News ; (290): 12-16, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31322506

RESUMO

Aim - study of marker enzymes, hormonal and carbohydrate-protein indicators of the state of reparative osteogenesis in patients with complicated and uncomplicated course of injuries of facial cranium. The study included 81 patients with injuries of facial cranium, which were divided into 2 groups, depending on the presence of complications. The following enzyme indicators were studied: the level of excretion of hydroxyproline in daily urine; alkaline and acid phosphatase activity; the percentage of bone isoenzymes of alkaline phosphatase. To assess the mineral metabolism, the level of total and ionized calcium and inorganic phosphorus in the blood serum, as well as their excretion in the urine, were determined. To assess the state of metabolism, the concentration of glycosaminoglycans and their fractions in the blood serum were studied. To study the structural and functional state of the bone tissue the densitometry was performed. In patients with complicated course of injuries of facial cranium assosiated with traumatic brain injury there was revealed the increase (р<0,05) of: excretion of phosphorus, uronic acids and oxyproline, while the excretion of calcium was not disturbed (р>0,05), and excretion of magnesium was decreased (р<0,05). It was found out that the level of calcium of blood serum in patients with complicated course is significantly (р<0,05) lower than in the control group and does not depend on the presence of craniocerebral injury (р>0,05). The decrease of the level of ionized calcium content in blood serum can be the confirmation of lower metabolic activity of reparative osteogenesis processes, first of all at the expense of damage of central mechanisms. When studying the content of carbohydrate-protein metabolites by complicated course of injuries of facial cranium, the absolute increase (р<0,05) of concentration of chondroitin-6-sulfates was revealed, and during the analysis of results it was found out that in absolute values, as well as in structural indexes, the specific weight of various fractions changes, that can be the evidence of instability of mechanisms of osteogenesis and of damage of physiological mechanisms of reparative osteogenesis. Densitometric equivalents of forming of complicated course of injuries of facial cranium are the increase of broadband ultrasonic attenuation and the decrease of its spreading speed on the background of low levels of chondroitin-6-sulfates.


Assuntos
Cálcio/sangue , Traumatismos Craniocerebrais , Traumatismos Faciais , Osteogênese/fisiologia , Fósforo/sangue , Crânio/lesões , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Cálcio/urina , Traumatismos Craniocerebrais/epidemiologia , Traumatismos Craniocerebrais/metabolismo , Traumatismos Faciais/enzimologia , Traumatismos Faciais/metabolismo , Glicosaminoglicanos/metabolismo , Humanos , Hidroxiprolina/urina , Minerais/metabolismo , Fósforo/urina
17.
Food Funct ; 10(7): 4134-4142, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31241125

RESUMO

This study aimed to investigate the effect of putrescine on the immune function and intestinal bacteria of weaning piglets. Twenty-four male castrated weaning piglets on their 21st day were randomly assigned into four groups: control (basal diet) and treatment groups given basal diets supplemented with 0.05%, 0.1%, and 0.15% putrescine for 11 days. Results were as follows: (1) Dietary putrescine increased the villus height, width, height/crypt depth and surface area, and decreased the diarrhea index (P < 0.05). (2) Dietary putrescine increased the lysozyme and acid phosphatase activities and the amount of immunoglobulin M, antibacterial peptides, and transforming growth factor ß1, but decreased the mRNA levels of tumor necrosis factor α, interleukin-6, interleukin-8 and inducible nitric oxide synthase (P < 0.05). (3) Dietary putrescine increased the mRNA expression of the mammalian target of rapamycin, signal transducer and activator of transcription, and Janus kinase 2 but decreased the mRNA expression of nuclear factor-kappa B P65 (P < 0.05). (4) Dietary putrescine increased the population of total bacteria, Lactobacillus, and Bifidobacterium and decreased that of Escherichia coli in the colon and cecum (P < 0.05). (5) Finally, dietary putrescine increased the concentrations of butyrate and total volatile fatty acids in the colon and those of acetate, propionate, and total volatile fatty acids in the cecum (P < 0.05). Overall, putrescine can enhance intestinal development, improve immune functions, and regulate the population of intestinal bacteria in weaning piglets.


Assuntos
Suplementos Nutricionais , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/microbiologia , Putrescina/farmacologia , Desmame , Fosfatase Ácida/metabolismo , Animais , Bifidobacterium/efeitos dos fármacos , Bifidobacterium/crescimento & desenvolvimento , Butiratos/metabolismo , Ceco/metabolismo , Ceco/microbiologia , Colo/metabolismo , Colo/microbiologia , Diarreia/prevenção & controle , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Ácidos Graxos Voláteis/metabolismo , Imunoglobulina M , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Janus Quinase 2/metabolismo , Lactobacillus/efeitos dos fármacos , Lactobacillus/crescimento & desenvolvimento , Masculino , Muramidase/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Suínos
18.
Int J Biol Macromol ; 137: 504-511, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229542

RESUMO

This work aims to analyze the immunomodulatory effect of pomegranate peel polysaccharides (PPP) on the immunosuppressed mice induced by cyclophosphamide (CTX). All the mice were divided into 6 groups randomly and the immunoprophylaxis mice were administrated with PPP [100, 200, 400 mg/(kg·d)] by gavage for consecutive 28 days. The results showed that PPP can slow down the decline of body weight and increase the immune organ index of the immunosuppressed mice. Compared to the model mice, the enzymatic activity of LDH (lactate dehydrogenase) and ACP (acid phosphatase) of the mice spleen administrated with PPP by gavage was enhanced significantly. PPP stimulated proliferation and secretion of splenic lymphocytes and markedly increased the immunoglobulin (Ig-A, Ig-G and Ig-M) expression and the release of cytokines (TNF-α, IL-2 and INF-γ) in cyclophosphamide-induced immunosuppressed mice. Hepatic antioxidant enzymatic activities of T-AOC (total antioxidant capacity), T-SOD (total superoxide dismutase), GSH-PX (glutathione peroxidase) and CAT (catalase) were markedly increased when the mice were administrated with high dosage of PPP. So it can be concluded that PPP could be used as an efficacious adjacent immunopotentiating therapy or an alternative means in lessening chemotherapy-induced immunosuppression, and also can be utilized as immunostimulants for food and pharmaceutical industries.


Assuntos
Antioxidantes/farmacologia , Fatores Imunológicos/farmacologia , Imunossupressão , Polissacarídeos/farmacologia , Romã (Fruta)/química , Fosfatase Ácida/metabolismo , Animais , Antioxidantes/química , Contagem de Células Sanguíneas , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Fenômenos Químicos , Glutationa/metabolismo , Fatores Imunológicos/química , L-Lactato Desidrogenase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Polissacarídeos/química , Superóxido Dismutase/metabolismo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
19.
Fish Physiol Biochem ; 45(4): 1367-1376, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31209688

RESUMO

The main purpose of this study was to investigate the distribution of acid phosphatase (ACP), alkaline phosphatase (ALP), non-specific esterase (NSE), peroxidase (POD), and mucous cells in the intestine of the koi carp Cyprinus carpio var. koi. ACP activity was located in the striated border, enterocytes, and lamina propria of the anterior and middle intestines. The ACP activity in the anterior intestine was higher than that in the middle and posterior intestines. ALP existed in the striated border of enterocytes and lamina propria, serosa, muscular layer, and the junction between muscular layer and submucosa layer of the intestine. The ALP activity in the anterior intestine was higher than that in the middle and posterior intestines. NSE activity was localized in the cytoplasm of enterocytes in the whole intestine, and the middle intestine showed the lower NSE activity than the anterior and posterior intestines. POD activity was localized in the blood cells of the lamina propria and cytoplasm of enterocytes in all intestinal segments. The POD activity among the anterior, middle, and posterior intestines was non-significantly different. Alcian blue periodic acid-Schiff histochemical results revealed three types of mucous cells in the intestine. The total number of mucous cells and percentage of type I cells among the anterior, middle, and posterior intestines were non-significantly different. The percentage of the type II cells was the highest in the posterior intestine, while the lowest in the anterior intestine. The percentage of the type III cells was the highest in the anterior intestine, while the lowest in the posterior intestine.


Assuntos
Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Carboxilesterase/metabolismo , Carpas/metabolismo , Mucosa Intestinal/enzimologia , Peroxidase/metabolismo , Animais , Muco/citologia , Muco/enzimologia
20.
Plant Sci ; 285: 110-121, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203875

RESUMO

In agricultural soil, the bioavailability of iron (Fe) and phosphorus (P) is often below the plant's requirement causing nutritional deficiency in crops. Under P-limiting conditions, white lupin (Lupinus albus L.) activates mechanisms that promote P solubility in the soil through morphological, physiological and molecular adaptations. Similar changes occur also in Fe-deficient white lupin roots; however, no information is available on the molecular bases of the response. In the present work, responses to Fe and P deficiency and their reciprocal interactions were studied. Transcriptomic analyses indicated that white lupin roots upregulated Fe-responsive genes ascribable to Strategy-I response, this behaviour was mainly evident in cluster roots. The upregulation of some components of Fe-acquisition mechanism occurred also in P-deficient cluster roots. Concerning P acquisition, some P-responsive genes (as phosphate transporters and transcription factors) were upregulated by P deficiency as well by Fe deficiency. These data indicate a strong cross-connection between the responses activated under Fe or P deficiency in white lupin. The activation of Fe- and P-acquisition mechanisms might play a crucial role to enhance the plant's capability to mobilize both nutrients in the rhizosphere, especially P from its associated metal cations.


Assuntos
Ferro/metabolismo , Lupinus/metabolismo , Fósforo/metabolismo , Raízes de Plantas/metabolismo , Fosfatase Ácida/metabolismo , FMN Redutase/metabolismo , Genes de Plantas/fisiologia , Ferro/deficiência , Lupinus/genética , Lupinus/fisiologia , Fósforo/deficiência , Raízes de Plantas/fisiologia , Rizosfera , Análise de Sequência de RNA , Transcriptoma
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