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1.
Zhen Ci Yan Jiu ; 45(9): 689-95, 2020 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-32959549

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture at "Baihui"(GV20) and "Shenshu"(BL23) on the expression of autophagy-related proteins in the hippocampus of rats with Alzheimer's disease (AD),so as to explore its underlying mechanisms on improvement of AD. METHODS: Forty-eight male SD rats were randomly divided into blank control group, model group, electroacupuncture group and sham electroacupuncture group, with 12 rats in each group. The AD rat model was establish by intraperitoneal injection of D-galactose for 6 weeks. Rats in the electroacupuncture group received electroacupuncture (50 Hz, 1 mA)at GV20 and BL23 for 20 min each time after daily intraperitoneal injection. Rats in the sham electroacupuncture group received acupuncture at the local skin of GV20 and BL23 without electricity. After the intervention, Morris water maze and open field test were used to evaluate the learning and cognitive ability of rats in each group. The transmission electron microscope was used to observe the numerical density of synaptic in hippocampus, and the immunohistochemical staining was used to observe the paired helical filament protein-1 (PHF-1) in the hippocampus. Western blot was used to detected the expression of autophagy-related proteins phosphoinositide-3-kinase (PI3K), protein kinase B (AKT), phosphorylated AKT (p-AKT), mammalian target of rapamycin (mTOR) in the hippocampus. RESULTS: Compared with the blank control group, the escape latency of the rats in the model group increased from day 2 to day 5 (P<0.01), and the ratio of the time through the quadrant of the original platform reduced (P<0.01), in the open field test the distance of exercise, the number of uprights and the rate of exercise time in the central area decreased (P<0.01), meanwhile the density of hippocampus synapses decreased (P<0.01), the positive expression of PHF-1 and the relative expression of PI3K, AKT, p-AKT, and mTOR all increased (P<0.01). Compared with the model group, the escape latency of rats in the electroacupuncture group was shortened from day 2 to day 5 (P<0.01), and the ratio of the time through the quadrant of the original platform meanwhile, the distance of the open field test, the number of uprights, and the rate of central area exercise time up-regulated (P<0.01), the numerical density of hippocampus synatic increased (P<0.01), the positive expression of PHF-1 and the relative expression of PI3K, AKT, p-AKT, and mTOR all down-regulated (P<0.01). Compared with the model group, the expression of PI3K in the sham electroacupuncture group decreased (P<0.05). CONCLUSION: Electroacupuncture can improve learning and memory and cognitive impairment in AD rats, which may be associated with its effects in regulation of hippocampal autophagy and removal of neurofibrillary tangles by suppressing PI3K/AKT/mTOR signaling pathway.


Assuntos
Doença de Alzheimer , Autofagia , Eletroacupuntura , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Cognição , Galactose , Hipocampo , Masculino , Fosfatidilinositol 3-Quinases , Ratos , Ratos Sprague-Dawley
2.
PLoS One ; 15(9): e0236611, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941446

RESUMO

Treatment of diseases that affect the CNS by gene therapy requires delivery of oligonucleotides to target cells within the brain. As the blood brain barrier prevents movement of large biomolecules, current approaches involve direct injection of the oligonucleotides, which is invasive and may have only a localised effect. The aim of this study was to investigate the potential of 2 nm galactose-coated gold nanoparticles (NP-Gal) as a delivery system of oligonucleotides across brain endothelium. DNA oligonucleotides of different types were attached to NP-Gal by the place exchange reaction and were characterised by EMSA (electrophoretic mobility shift assay). Several nanoparticle formulations were created, with single- or double-stranded (20nt or 40nt) DNA oligonucleotides, or with different amounts of DNA attached to the carriers. These nanocarriers were applied to transwell cultures of human brain endothelium in vitro (hCMEC/D3 cell-line) or to a 3D-hydrogel model of the blood-brain barrier including astrocytes. Transfer rates were measured by quantitative electron microscopy for the nanoparticles and qPCR for DNA. Despite the increase in nanoparticle size caused by attachment of oligonucleotides to the NP-Gal carrier, the rates of endocytosis and transcytosis of nanoparticles were both considerably increased when they carried an oligonucleotide cargo. Carriers with 40nt dsDNA were most efficient, accumulating in vesicles, in the cytosol and beneath the basal membrane of the endothelium. The oligonucleotide cargo remained attached to the nanocarriers during transcytosis and the transport rate across the endothelial cells was increased at least 50fold compared with free DNA. The nanoparticles entered the extracellular matrix and were taken up by the astrocytes in biologically functional amounts. Attachment of DNA confers a strong negative charge to the nanoparticles which may explain the enhanced binding to the endothelium and transcytosis by both vesicular transport and the transmembrane/cytosol pathway. These gold nanoparticles have the potential to transport therapeutic amounts of nucleic acids into the CNS.


Assuntos
Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Nanopartículas Metálicas/química , Oligodesoxirribonucleotídeos/metabolismo , Astrócitos/metabolismo , Linhagem Celular , Células Cultivadas , Galactose/química , Ouro/química , Humanos , Oligodesoxirribonucleotídeos/administração & dosagem
3.
Am J Chin Med ; 48(5): 1141-1157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668974

RESUMO

Oxidative stress is considered as a major factor in aging and exacerbates aging process through a variety of molecular mechanisms. D-galactose, a normal reducing sugar with high dose can cause the accumulation of reactive oxygen species (ROS) or stimulate free radical production indirectly by the formation of advanced glycation end products in tissues, finally resulting in oxidative stress. 20(R)-ginsenoside Rg3 (20(R)-Rg3), a major and representative component isolated from red ginseng (Panax ginseng C.A Meyer), has been shown to observably have an anti-oxidative effect. We thereby investigated the beneficial effects of 20(R)-Rg3 on D-galactose-induced oxidative stress injury and its underlying mechanisms. Our results showed that continuous injection of D-galactose with 800[Formula: see text]mg/kg/day for 8 weeks increased the levels of alanine aminotransferase (ALT) and blood urea nitrogen (BUN). However, such increases were attenuated by the treatment of 20(R)-Rg3 for 4 weeks. Meanwhile, 20(R)-Rg3 markedly inhibited D-galactose-caused oxidative stress in liver and kidney. The anti-oxidants, including catalase (CAT) and superoxide dismutase (SOD), were elevated in the mice from 20(R)-Rg3-treated group compared with that from D-galactose group. In contrast, a significant decrease in levels of cytochrome P450 E1 (CYP2E1) and the lipid peroxidation product malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were observed in the 20(R)-Rg3-treated group. These effects were associated with a significant increase of AGEs. More importantly, 20(R)-Rg3 effectively attenuated D-galactose induced apoptosis in liver and kidney via restoring the upstream PI3K/AKT signaling pathway. Taken together, our study suggests that 20(R)-Rg3 may be a novel and promising anti-oxidative therapeutic agent to prevent aging-related injuries in liver and kidney.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Galactose/efeitos adversos , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Panax/química , Fitoterapia , Animais , Antioxidantes , Modelos Animais de Doenças , Ginsenosídeos/isolamento & purificação , Produtos Finais de Glicação Avançada/metabolismo , Camundongos Endogâmicos ICR , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Life Sci ; 258: 118119, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682915

RESUMO

Ceftriaxone (CTX) is a third-generation cephalosporin antibiotic that has broad-spectrum antimicrobial activity. This agent also has anti-inflammatory and antioxidant characteristics. In the current study, the effects of CTX against hepatorenal damages in a D-galactose (DGL) induced aging model were investigated. We used twenty-eight male mice which equally and randomly were separated into four groups as follows: Control, DGL group (treated with 500 mg/kg/day DGL orally for six weeks), DGL + CTX group (treated with 500 mg/kg/day DGL orally plus 200 mg/kg/day CTX intraperitoneally for six weeks), and CTX group (treated with 200 mg/kg/day CTX intraperitoneally for six weeks). The liver and kidney function indices such as serum creatinine, blood urine nitrogen, alanine aminotransferase, and aspartate aminotransferase were measured. Also, levels of malondialdehyde, catalase, and glutathione peroxidase in hepatic and renal tissues were evaluated. Moreover, the expression profiles of interleukin 1 beta and tumor necrosis factor alpha were assessed. The liver and kidney tissues were assessed for histopathological lesions. The results showed that aging induced by DGL leads to abnormalities in functional indices of the liver and kidneys. DGL also induced significant oxidative stress and inflammation, as well as histopathological lesions, in these organs. CTX improved functional indices, as well as the parameters of oxidative stress and inflammation, compared with the DGL-treated animals. These results were also confirmed by histological evaluations of the liver and kidneys. These data provide evidence for the therapeutic value of CTX in clinical practice for mitigating the hepatorenal damages of aging.


Assuntos
Envelhecimento/patologia , Ceftriaxona/uso terapêutico , Síndrome Hepatorrenal/tratamento farmacológico , Animais , Ceftriaxona/farmacologia , Galactose , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos
5.
Allergol. immunopatol ; 48(3): 251-258, mayo-jun. 2020. tab
Artigo em Inglês | IBECS | ID: ibc-192027

RESUMO

INTRODUCTION AND OBJECTIVES: Allergy to galactose-α-1,3-galactose (alpha-gal) is a peculiar form of food allergy generally manifesting as an anaphylactic reaction hours after mammalian meat consumption, due to the presence of specific IgE against this oligosaccharide. In addition, immediate anaphylaxis may develop after exposure to other sources of alpha-gal, such as monoclonal antibody cetuximab, vaccines, plasma expanders or anti-snake venoms. Sensitization to alpha-gal has also been implicated in the rapid degeneration of biological valve implants, and recognized as a cause of occupational disease in cattle raisers. The implication of tick bites in this type of sensitization has been accepted by all the research groups dedicated to this disease. PATIENTS AND METHOD: The present study describes the clinical and sensitization characteristics of 39 patients diagnosed with alpha-gal allergy in the hospitals of our province (Lugo, Monforte de Lemos and Burela, Spain). RESULTS: Most patients were middle-age males. Of note, is the fact that the series includes the first pediatric patient reported in Spain to date. The predominant clinical manifestations were urticaria or delayed anaphylaxis after consumption of mammalian meat. Seventy-four percent of the patients reported having suffered a previous tick bite, and the clinical presentation of anaphylaxis was significantly more prevalent in those with a persistent local reaction following the bite than in those with no such reaction (p = 0.032). CONCLUSIONS: A review is also made of the disorder which, due to its variable clinical expression, is referred to as alpha-gal syndrome. The study concludes that a diagnosis of alpha-gal allergy should be considered in patients with urticaria-anaphylaxis of uncertain origin or manifesting after the administration of vaccines or products of bovine/porcine origin


No disponible


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Galactose/imunologia , Hipersensibilidade Alimentar/imunologia , Alérgenos/imunologia , Hipersensibilidade Alimentar/diagnóstico , Galactose/efeitos adversos , Hipersensibilidade Tardia/imunologia , Espanha , Imunoglobulina E/imunologia , Anafilaxia/imunologia , Testes Cutâneos , Anticorpos Monoclonais/imunologia
6.
J Dairy Sci ; 103(8): 6830-6842, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32475665

RESUMO

In this study, we purified and characterized exopolysaccharide (EPS) produced by a high-EPS-producing dairy starter bacterium, Streptococcus thermophilus ASCC 1275. Crude EPS was extracted from S. thermophilus ASCC 1275 and partially purified using dialysis. Further purification and fractionation of exopolysaccharide was conducted using HPLC on a Superose 6 column (Cytiva/Global Life Sciences Solutions, Marlborough, MA). Glycosyl composition analysis, linkage analysis along with 1-dimensional and 2-dimensional nuclear magnetic resonance spectroscopy were performed to deduce the structure of EPS. Three fractions (F) obtained from gel permeation chromatography were termed F1 (2.6%), F2 (45.8%), and F3 (51.6%) with average molecular weights of approximately 511, 40, and 5 kDa, respectively. Monosaccharide composition analysis revealed the dominance of glucose, galactose, and mannose in all 3 fractions. Major linkages observed in F3 were terminal galactopyranosyl (t-Gal), 3-linked glucopyranosyl (3-Glc), 3-linked galactofuranosyl (3-Galf), and 3,6-linked glucopyranosyl (3,6-Glc) and major linkages present in F2 were 4-Glc (48 mol%), followed by terminal mannopyranosyl (t-Man), 2- + 3-linked mannopyranosyl (2-Man+3-Man), and 2,6-linked mannopyranosyl (2,6-Man; total ∼28 mol%). The 1-dimensional and 2-dimensional nuclear magnetic resonance spectroscopy revealed that F2 comprised mannans linked by (1→2) linkages and F3 consisted of linear chains of α-d-glucopyranosyl (α-d-Glcp), ß-d-glucopyranosyl (ß-d-Glcp), and ß-d-galactofuranosyl (ß-d-Galf) connected by (1→3) linkages; branching was through (1→6) linkage in F3. A possible structure of EPS in F2 and F3 was proposed.


Assuntos
Polissacarídeos Bacterianos/química , Streptococcus thermophilus/química , Galactose/química , Glucose/química , Espectroscopia de Ressonância Magnética , Mananas/química , Peso Molecular , Polissacarídeos Bacterianos/isolamento & purificação , Conformação Proteica
7.
Nat Commun ; 11(1): 3259, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591509

RESUMO

Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome. In mice, hematogenous F. nucleatum can colonize CRC tissue using its lectin Fap2, which attaches to tumor-displayed Gal-GalNAc. Here, we show that Gal-GalNAc levels increase as human breast cancer progresses, and that occurrence of F. nucleatum gDNA in breast cancer samples correlates with high Gal-GalNAc levels. We demonstrate Fap2-dependent binding of the bacterium to breast cancer samples, which is inhibited by GalNAc. Intravascularly inoculated Fap2-expressing F. nucleatum ATCC 23726 specifically colonize mice mammary tumors, whereas Fap2-deficient bacteria are impaired in tumor colonization. Inoculation with F. nucleatum suppresses accumulation of tumor infiltrating T cells and promotes tumor growth and metastatic progression, the latter two of which can be counteracted by antibiotic treatment. Thus, targeting F. nucleatum or Fap2 might be beneficial during treatment of breast cancer.


Assuntos
Neoplasias da Mama/microbiologia , Neoplasias da Mama/patologia , Progressão da Doença , Fusobacterium nucleatum/crescimento & desenvolvimento , Animais , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Contagem de Colônia Microbiana , DNA Bacteriano/genética , Modelos Animais de Doenças , Feminino , Fusobacterium nucleatum/efeitos dos fármacos , Fusobacterium nucleatum/genética , Galactosamina/metabolismo , Galactose/metabolismo , Genoma Bacteriano/genética , Humanos , Imunidade/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Metástase Neoplásica
8.
Proc Natl Acad Sci U S A ; 117(25): 14243-14250, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32518113

RESUMO

Cells must couple cell-cycle progress to their growth rate to restrict the spread of cell sizes present throughout a population. Linear, rather than exponential, accumulation of Whi5, was proposed to provide this coordination by causing a higher Whi5 concentration in cells born at a smaller size. We tested this model using the inducible GAL1 promoter to make the Whi5 concentration independent of cell size. At an expression level that equalizes the mean cell size with that of wild-type cells, the size distributions of cells with galactose-induced Whi5 expression and wild-type cells are indistinguishable. Fluorescence microscopy confirms that the endogenous and GAL1 promoters produce different relationships between Whi5 concentration and cell volume without diminishing size control in the G1 phase. We also expressed Cln3 from the GAL1 promoter, finding that the spread in cell sizes for an asynchronous population is unaffected by this perturbation. Our findings indicate that size control in budding yeast does not fundamentally originate from the linear accumulation of Whi5, contradicting a previous claim and demonstrating the need for further models of cell-cycle regulation to explain how cell size controls passage through Start.


Assuntos
Tamanho Celular , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomycetales/fisiologia , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Fase G1 , Galactoquinase/genética , Galactoquinase/metabolismo , Galactose , Regulação Fúngica da Expressão Gênica , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
9.
Food Chem ; 329: 127042, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504916

RESUMO

Polysaccharides are a major active component of Porphyra haitanensis, which is an important food source in many countries. Four different molecular-weight fractions, namely PHPD-I (329 kDa), PHPD-II (203 kDa), PHPD-III (128 kDa), and PHPD-IV (10 kDa), were obtained from P. haitanensis polysaccharides by degradation using the H2O2/ascorbic acid system. PHPD-IV elicited the highest level of antioxidant and immunostimulatory activity among the four fractions. PHPD-IV was purified by DEAE-cellulose column and five fractions were obtained, designated PHPD-IV-1-PHPD-IV-5. PHPD-IV-4 displayed the greatest biological activity by up-regulating the phosphorylation of MAPK signalling molecules. PHPD-IV-4 was further purified, and its structure was characterized by monosaccharide composition and 1/2D-NMR analysis. The result revealed that PHPD-IV-4 was repeated units of â†’ 3) ß-d-galactose (1 â†’ 4) 3, 6-anhydro-α-l-galactose (1→, and â†’ 3) ß-d-galactose (1 â†’ 4) α-l-galactose-6-S (1→. This study provides a theoretical basis for the utilisation and structure-activity assessment of P. haitanensis polysaccharides.


Assuntos
Polissacarídeos/química , Porphyra/química , Antioxidantes/química , Ácido Ascórbico/química , Galactose/química , Peróxido de Hidrogênio/química , Espectroscopia de Ressonância Magnética , Peso Molecular
10.
Pol J Microbiol ; 69(2): 205-215, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32548989

RESUMO

Oxidative stress-induced series of related degenerative diseases have received widespread attention. To screen new lactic acid bacteria (LAB) strains to resist oxidative stress, traditional Chinese fermented vegetables were used as a resource library to screen of LAB. The Lactobacillus fermentum JX306 strain, which showed high scavenging activity of DPPH free radical and hydrogen radical, and a strong lipid peroxidation inhibition rate in vitro was selected. L. fermentum JX306 was also examined for its antioxidant capacity in D-galactose-induced aging mice. The results showed that L. fermentum JX306 could significantly decrease malondialdehyde (MDA) levels and improve the activity of glutathione peroxidase (GSH-Px), and total antioxygenic capacity (TOC) in the serum, kidney, and liver. Meanwhile, the strain could remarkably upregulate the transcriptional level of the antioxidant-related enzyme genes, such as peroxiredoxin1 (Prdx1), glutathione reductase (Gsr), glutathione peroxidase (Gpx1), and thioredoxin reductase (TR3) encoding genes in the liver. Besides, histopathological observation proves that this probiotic strain could effectively inhibit oxidative damage to the liver and kidney in aging mice. Therefore, this unique antioxidant strain may have a high application value in the functional food industry and medicine industry.Oxidative stress-induced series of related degenerative diseases have received widespread attention. To screen new lactic acid bacteria (LAB) strains to resist oxidative stress, traditional Chinese fermented vegetables were used as a resource library to screen of LAB. The Lactobacillus fermentum JX306 strain, which showed high scavenging activity of DPPH free radical and hydrogen radical, and a strong lipid peroxidation inhibition rate in vitro was selected. L. fermentum JX306 was also examined for its antioxidant capacity in D-galactose-induced aging mice. The results showed that L. fermentum JX306 could significantly decrease malondialdehyde (MDA) levels and improve the activity of glutathione peroxidase (GSH-Px), and total antioxygenic capacity (TOC) in the serum, kidney, and liver. Meanwhile, the strain could remarkably upregulate the transcriptional level of the antioxidant-related enzyme genes, such as peroxiredoxin1 (Prdx1), glutathione reductase (Gsr), glutathione peroxidase (Gpx1), and thioredoxin reductase (TR3) encoding genes in the liver. Besides, histopathological observation proves that this probiotic strain could effectively inhibit oxidative damage to the liver and kidney in aging mice. Therefore, this unique antioxidant strain may have a high application value in the functional food industry and medicine industry.


Assuntos
Microbiologia de Alimentos , Lactobacillus fermentum/metabolismo , Estresse Oxidativo/fisiologia , Oxirredutases/metabolismo , Envelhecimento , Animais , Alimentos e Bebidas Fermentados/microbiologia , Galactose/farmacologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos
11.
AAPS PharmSciTech ; 21(5): 174, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32548786

RESUMO

Hepatocellular carcinoma (HCC) is a foremost type of cancer problem in which asialoglycoprotein receptors are overexpressed. In this study, asialoglycoprotein receptor-targeted nanoformulation (galactose-conjugated TPGS micelles) loaded with docetaxel (DTX) was developed to achieve its site-specific delivery for HCC therapy. The pharmaceutical characteristics like shape morphology, average particle size and zeta potential, drug entrapment efficiency, and in vitro release kinetics of developed system were evaluated. DTX-loaded galactosylated TPGS (DTX-TPGS-Gal) micelles and TPGS micelles (DTX-TPGS) were having 58.76 ± 1.82% and 54.76 ± 1.42% entrapment of the DTX, respectively. In vitro drug release behavior from micelles was controlled release. Cytotoxicitiy (IC50) of DTX-TPGS-Gal formulation on HepG2 cell lines was significantly (p ≤ 0.01) lower (6.3 ± 0.86 µg/ml) than DTX-TPGS (9.06 ± 0.82 µg/ml) and plain DTX (16.06 ± 0.98 µg/ml) indicating higher efficacy of targeted formulation. Further, in vivo biodistribution studies in animal model showed maximum drug accumulation at target site, i.e., the liver in the case of DTX-TPGS-Gal as compared with non-targeted one. It is concluded from the findings that TPGS-Gal micelles can be utilized for targeted drug delivery of cytotoxic drugs towards HCC with minimized side effects. Graphical abstract.


Assuntos
Carcinoma Hepatocelular/metabolismo , Docetaxel/química , Sistemas de Liberação de Medicamentos/métodos , Galactose/química , Neoplasias Hepáticas/metabolismo , Vitamina E/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Desenvolvimento de Medicamentos/métodos , Feminino , Galactose/administração & dosagem , Galactose/farmacocinética , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Distribuição Aleatória , Ratos , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Vitamina E/administração & dosagem , Vitamina E/farmacocinética
12.
Chemistry ; 26(43): 9620-9631, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32368810

RESUMO

The synthesis of tailored bioactive carbohydrates usually comprises challenging (de)protection steps, which lowers synthetic yields and increases time demands. We present here a regioselective single-step introduction of benzylic substituents at 3-hydroxy groups of ß-d-galactopyranosyl-(1→1)-thio-ß-d-galactopyranoside (TDG) employing dibutyltin oxide in good yields. These glycomimetics act as inhibitors of galectins-human lectins, which are biomedically attractive targets for therapeutic inhibition in, for example, cancerogenesis. The affinity of the prepared glycomimetics to galectin-1 and galectin-3 was studied in enzyme-linked immunosorbent (ELISA)-type assays and their potential to inhibit galectin binding on the cell surface was shown. We used our original in vivo biotinylated galectin constructs for easy detection by flow cytometry. The results of the biological experiments were compared with data from molecular modeling with both galectins. The present work reveals a facile and elegant synthetic route for the preparation of TDG-derived glycomimetics that exhibit differing selectivity and affinity to galectins depending on the choice of 3-O-substitution.


Assuntos
Carboidratos/química , Galectina 1/química , Galectina 3/química , Galectinas/química , Tiogalactosídeos/química , Galactose , Galectina 1/metabolismo , Galectina 3/metabolismo , Galectinas/metabolismo , Humanos , Modelos Moleculares
13.
Microb Cell Fact ; 19(1): 104, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410635

RESUMO

BACKGROUND: Marine macroalgae Gelidium amansii is a promising feedstock for production of sustainable biochemicals to replace petroleum and edible biomass. Different from terrestrial lignocellulosic biomass, G. amansii is comprised of high carbohydrate content and has no lignin. In previous studies, G. amansii biomass has been exploited to obtain fermentable sugars along with suppressing 5-hydroxymethylfurfural (HMF) formation for bioethanol production. In this study, a different strategy was addressed and verified for dual production of D-galactose and HMF, which were subsequently oxidized to D-galactonic acid and 5-hydroxymethyl-2-furancarboxylic acid (HMFCA) respectively via Pseudomonas putida. RESULTS: G. amansii biomass was hydrolyzed by dilute acid to form D-galactose and HMF. The best result was attained after pretreatment with 2% (w/w) HCl at 120 °C for 40 min. Five different Pseudomonas sp. strains including P. putida ATCC 47054, P. fragi ATCC 4973, P. stutzeri CICC 10402, P. rhodesiae CICC 21960, and P. aeruginosa CGMCC 1.10712, were screened for highly selective oxidation of D-galactose and HMF. Among them, P. putida ATCC 47054 was the outstanding suitable biocatalyst converting D-galactose and HMF to the corresponding acids without reduced or over-oxidized products. It was plausible that the pyrroloquinoline quinone-dependent glucose dehydrogenase and undiscovered molybdate-dependent enzyme(s) in P. putida ATCC 47054 individually played pivotal role for D-galactose and HMF oxidation. Taking advantage of its excellent efficiency and high selectivity, a maximum of 55.30 g/L D-galactonic acid and 11.09 g/L HMFCA were obtained with yields of 91.1% and 98.7% using G. amansii hydrolysates as substrate. CONCLUSIONS: Valorization of G. amansii biomass for dual production of D-galactonic acid and HMFCA can enrich the product varieties and improve the economic benefits. This study also demonstrates the perspective of making full use of marine feedstocks to produce other value-added products.


Assuntos
Biomassa , Furaldeído/análogos & derivados , Rodófitas/química , Açúcares Ácidos/metabolismo , Ácidos/metabolismo , Fermentação , Furaldeído/metabolismo , Galactose/metabolismo , Hidrólise , Oxirredução , Pseudomonas putida/metabolismo
14.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(5): 473-477, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32434643

RESUMO

OBJECTIVE: To study the role of follicular helper T (Tfh) cells and galactose-deficient IgA1 (Gd-IgA1) in the pathogenesis of childhood Henoch-Schönlein purpura (HSP) and the correlation between them. METHODS: A total of 36 children with newly-diagnosed HSP were enrolled. They were divided into two groups: HSP nephritis (HSPN) group with 11 children and non-HSPN group with 25 children according to the presence or absence of HSPN. Another 15 children who underwent physical examination at the outpatient service were enrolled as the healthy control group. Flow cytometry was used to measure the proportion of Tfh cells (CD4+CXCR5+ICOS+) in peripheral blood. ELISA was used to measure the levels of interleukin-21 (IL-21) and interleukin-6 (IL-6) in peripheral blood and the serum levels of IgA1 and Gd-IgA1. A Pearson correlation analysis was used to investigate the correlation of serum Gd-IgA1 concentration with Tfh cells and related factors expression in the children with HSP. RESULTS: Both the HSPN and non-HSPN groups had significantly higher proportion of Tfh cells and expression levels of IL-21 and IL-6 in peripheral blood than the healthy control group (P<0.05). The HSPN group had significant increases in the above indices compared with the non-HSPN group (P<0.05). Both the HSPN and non-HSPN groups had significantly higher serum levels of IgA1 and Gd-IgA1 than the healthy control group (P<0.05). The HSPN group had significantly higher serum levels of IgA1 and Gd-IgA1 than the non-HSPN group (P<0.05). In the children with HSP, serum Gd-IgA1 level was positively correlated with Tfh cells proportion and IL-21 and IL-6 levels (P<0.05). CONCLUSIONS: Tfh cells and related cytokines and serum Gd-IgA1 are involved in the development of HSP/HSPN. Tfh cells may mediate the increased production of Gd-IgA1.


Assuntos
Púrpura de Schoenlein-Henoch , Linfócitos T Auxiliares-Indutores , Criança , Galactose , Humanos , Imunoglobulina A , Receptores CXCR5
15.
Life Sci ; 254: 117776, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437790

RESUMO

AIMS: Rg1 is the most active component of traditional Chinese medicine ginseng, having anti-aging and anti-oxidative stress features in multiple organs. Cellular senescence of hepatocytes is involved in the progression of a wide spectrum of chronic liver diseases. In this study, we investigated the potential benefits and mechanism of action of Rg1 on aging-driven chronic liver diseases. MATERIALS AND METHODS: A total of 40 male C57BL/6 mice were randomly divided into four groups: control group; Rg1 group; Rg1+d-gal group; and d-gal group. Blood and liver tissue samples were collected for determination of liver function, biochemical and molecular markers, as well as histopathological investigation. KEY FINDINGS: Rg1 played an anti-aging role in reversing d-galactose induced increase in senescence-associated SA-ß-gal staining and p53, p21 protein in hepatocytes of mice and sustained mitochondria homeostasis. Meanwhile, Rg1 protected livers from d-galactose caused abnormal elevation of ALT and AST in serum, hepatic steatosis, reduction in hepatic glucose production, hydrogenic degeneration, inflammatory phenomena including senescence-associated secretory phenotype (SASP) IL-1ß, IL-6, MCP-1 elevation and lymphocyte infiltration. Furthermore, Rg1 suppressed drastic elevation in FOXO1 phosphorylation resulting in maintaining FOXO1 protein level in the liver after d-galactose treatment, followed by FOXO1 targeted antioxidase SOD and CAT significant up-regulation concurrent with marked decrease in lipid peroxidation marker MDA. SIGNIFICANCE: Rg1 exerts pharmaceutic effects of maintaining FOXO1 activity in liver, which enhances anti-oxidation potential of Rg1 to ameliorate SASP and to inhibit inflammation, also promotes metabolic homeostasis, and thus protects livers from senescence induced fatty liver disease. The study provides a potential therapeutic strategy for alleviating chronic liver pathology.


Assuntos
Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Proteína Forkhead Box O1/metabolismo , Ginsenosídeos/farmacologia , Animais , Antioxidantes/farmacologia , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Galactose/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Fatores de Transcrição/metabolismo
16.
J Oleo Sci ; 69(5): 467-477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32378550

RESUMO

Esterases catalyze the hydrolysis of ester bonds in fatty acid esters with short-chain acyl groups. In the present study, thirty-seven bacterial isolates were isolated from soil contaminated with waste cooking oil, dairy waste etc. from Shimla and Solan district of H.P. Out of 37 isolates, the isolate RL-1, which gave maximum activity, was identified as Bacillus licheniformis MH061919. The optimization of various production parameters resulted in maximum activity at inoculum age of 24 h and inoculum size of 1.5% (v/v). Esterase gave considerable activity in production medium containing sodium chloride (0.5 % w/v), galactose (1%, w/v), coconut oil (2.0%, v/v) and beef extract (0.3%, w/v) at a temperature of 45℃ and pH 8.5.The enzyme production was enhanced by 3-fold after optimization of production parameters. Further, on optimizing reaction conditions, enzyme gave maximum activity at a temperature of 45℃ and pH 8.5. The para-nitrophenyl acetate (p-NPA) was found to be optimum substrate and metal ions and detergents have inhibitory effect on esterase activity.


Assuntos
Bacillus/enzimologia , Meios de Cultura/química , Técnicas de Cultura/métodos , Esterases/metabolismo , Bacillus/isolamento & purificação , Óleo de Coco , Galactose , Concentração de Íons de Hidrogênio , Nitrofenóis/metabolismo , Carne Vermelha , Cloreto de Sódio , Temperatura , Extratos de Tecidos
17.
Toxicol Appl Pharmacol ; 398: 115028, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360636

RESUMO

NADPH oxidase (NOX) has been identified as a crucial contender of oxidative damage in Alzheimer's disease (AD). However, the capability of diapocynin, a NOX inhibitor, to offer neuroprotection in AD models is still a matter of debate. Hence, the current work is dedicated to investigate the influence of diapocynin on cognitive impairment prompted by ovariectomy combined with D-galactose injection in rats (an AD animal model), and to elucidate the signaling mechanisms regulating diapocynin-induced effects. Female rats were exposed to ovariectomy or sham operation. Ovariectomized rats were injected intraperitoneally with D-galactose (150 mg/kg/day) for 70 days and, on day 43, they were orally treated with diapocynin (10 mg/kg/day) for 28 days. Diapocynin amended cognitive functions as confirmed using novel object recognition and Morris water maze tests along with histopathological improvement. It caused a prominent decrement in ß-secretase, p-tau, and amyloid ß, contrary to α-secretase elevation in hippocampus and hampered neuroinflammation and oxidative stress, manifested by declined levels of NOX1, tumor necrosis factor-α, and nuclear factor-kappa B p65. In addition, diapocynin augmented synaptophysin, brain-derived neurotrophic factor, and phospho-cAMP response element binding protein and enhanced protein expression of phosphorylated forms of phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3ß (GSK-3ß), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) 1/2, ERK kinase kinase (Raf-1), and ERK kinase (MEK) 1/2, while inhibiting those of c-Jun and c-Jun N-terminal kinase (JNK). In conclusion, diapocynin attenuated memory impairment and AD-like anomalies via activating Raf-1/MEK/ERK and PI3K/Akt/GSK-3ß, while inhibiting JNK/c-Jun signaling cascades.


Assuntos
Acetofenonas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Compostos de Bifenilo/farmacologia , Cognição/efeitos dos fármacos , Galactose/metabolismo , Nootrópicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Memória/efeitos dos fármacos , Ratos , Ratos Wistar
18.
Food Chem ; 328: 127135, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32473490

RESUMO

Watermelon seed, a watermelon processing industry by-product, is a good protein source for the preparation of antioxidant peptides due to its high protein content, low cost, special amino acid composition. Antioxidant hydrolysates obtained from watermelon seed protein (WSP) after slit divergent ultrasound (SDU) treatment were studied. The stepwise multiple linear regression model verified that the reducing power of watermelon seed protein hydrolysates (WSPHs) is positively related with -SH and ß-turn content of WSP (R2 = 0.931, p < 0.01). Using the degree of hydrolysis (DH) and reducing power as indicators, the WSPHs was prepared under the optimal conditions (ultrasound frequency: 20/28 kHz, time: 60 min, power density: 100 W/L) and divided into three components by ultrafiltration membrane (1 and 5 kDa). Compared with WSPHs and other fractions, WSPHs-I (Mw < 1 kDa) not only significantly protected HepG2 cells from H2O2-induced damage, but also greatly alleviated the liver injury caused by d-galactose in male SD rats.


Assuntos
Antioxidantes/farmacologia , Citrullus/química , Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Enzimas/metabolismo , Galactose/toxicidade , Células Hep G2 , Humanos , Peróxido de Hidrogênio/farmacologia , Hidrólise , Modelos Lineares , Masculino , Proteínas de Plantas/química , Proteínas de Plantas/farmacologia , Ratos Sprague-Dawley , Sementes/química , Ultrassom/instrumentação , Ultrassom/métodos
19.
Mol Cell ; 78(5): 915-925.e7, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32392469

RESUMO

Transcriptional memory of gene expression enables adaptation to repeated stimuli across many organisms. However, the regulation and heritability of transcriptional memory in single cells and through divisions remains poorly understood. Here, we combined microfluidics with single-cell live imaging to monitor Saccharomyces cerevisiae galactokinase 1 (GAL1) expression over multiple generations. By applying pedigree analysis, we dissected and quantified the maintenance and inheritance of transcriptional reinduction memory in individual cells through multiple divisions. We systematically screened for loss- and gain-of-memory knockouts to identify memory regulators in thousands of single cells. We identified new loss-of-memory mutants, which affect memory inheritance into progeny. We also unveiled a gain-of-memory mutant, elp6Δ, and suggest that this new phenotype can be mediated through decreased histone occupancy at the GAL1 promoter. Our work uncovers principles of maintenance and inheritance of gene expression states and their regulators at the single-cell level.


Assuntos
Galactoquinase/genética , Regulação Fúngica da Expressão Gênica/genética , Transcrição Genética/genética , Galactose/metabolismo , Expressão Gênica/genética , Genes Fúngicos/genética , Hereditariedade/genética , Histonas/metabolismo , Regiões Promotoras Genéticas/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Análise de Célula Única/métodos
20.
Am J Gastroenterol ; 115(6): 906-915, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32433273

RESUMO

INTRODUCTION: The low FODMAP diet (LFD) reduces symptoms and bifidobacteria in irritable bowel syndrome (IBS). ß-galactooligosaccharides (B-GOS) may reduce the symptoms and increase bifidobacteria in IBS. We investigated whether B-GOS supplementation alongside the LFD improves IBS symptoms while preventing the decline in bifidobacteria. METHODS: We performed a randomized, placebo-controlled, 3-arm trial of 69 Rome III adult patients with IBS from secondary care in the United Kingdom. Patients were randomized to a sham diet with placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.4 g/d B-GOS (LFD/B-GOS) for 4 weeks. Gastrointestinal symptoms, fecal microbiota (fluorescent in situ hybridization and 16S rRNA sequencing), fecal short-chain fatty acids (gas-liquid chromatography) and pH (probe), and urine metabolites (H NMR) were analyzed. RESULTS: At 4 weeks, adequate symptom relief was higher in the LFD/B-GOS group (16/24, 67%) than in the control group (7/23, 30%) (odds ratio 4.6, 95% confidence interval: 1.3-15.6; P = 0.015); Bifidobacterium concentrations (log10 cells/g dry weight) were not different between LFD and LFD/B-GOS but were lower in the LFD/B-GOS (9.49 [0.73]) than in the control (9.77 [0.41], P = 0.018). A proportion of Actinobacteria was lower in LFD (1.9%, P = 0.003) and LFD/B-GOS (1.8%, P < 0.001) groups than in the control group (4.2%). Fecal butyrate was lower in the LFD (387.3, P = 0.028) and LFD/B-GOS (346.0, P = 0.007) groups than in the control group (609.2). DISCUSSION: The LFD combined with B-GOS prebiotic produced a greater symptom response than the sham diet plus placebo, but addition of 1.4 g/d B-GOS did not prevent the reduction of bifidobacteria. The LFD reduces fecal Actinobacteria and butyrate thus strict long-term use should not be advised.


Assuntos
Bifidobacterium/genética , Dieta com Restrição de Carboidratos/métodos , Galactose/uso terapêutico , Microbioma Gastrointestinal/genética , Síndrome do Intestino Irritável/terapia , Oligossacarídeos/uso terapêutico , Prebióticos , Adulto , Terapia Combinada , Dietoterapia/métodos , Fezes/química , Feminino , Fermentação , Humanos , Hibridização in Situ Fluorescente , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/microbiologia , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S , Resultado do Tratamento , Urina/química , Adulto Jovem
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