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1.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360627

RESUMO

Fucosylation is involved in a wide range of biological processes from cellular adhesion to immune regulation. Although the upregulation of fucosylated glycans was reported in diseased corneas, its implication in ocular surface disorders remains largely unknown. In this study, we analyzed the expression of a fucosylated glycan on the ocular surface in two mouse models of dry eye disease (DED), the NOD.B10.H2b mouse model and the environmental desiccating stress model. We furthermore investigated the effects of aberrant fucosylation inhibition on the ocular surface and DED. Results demonstrated that the level of type 2 H antigen, an α(1,2)-fucosylated glycan, was highly increased in the cornea and conjunctiva both in NOD.B10.H2b mice and in BALB/c mice subjected to desiccating stress. Inhibition of α(1,2)-fucosylation by 2-deoxy-D-galactose (2-D-gal) reduced corneal epithelial defects and increased tear production in both DED models. Moreover, 2-D-gal treatment suppressed the levels of inflammatory cytokines in the ocular surface and the percentages of IFN-γ+CD4+ cells in draining lymph nodes, whereas it did not affect the number of conjunctival goblet cells, the MUC5AC level or the meibomian gland area. Together, the findings indicate that aberrant fucosylation underlies the pathogenesis of DED and may be a novel target for DED therapy.


Assuntos
Túnica Conjuntiva/metabolismo , Córnea/metabolismo , Síndromes do Olho Seco/etiologia , Galactose/análogos & derivados , Antígenos H-2/metabolismo , Animais , Túnica Conjuntiva/efeitos dos fármacos , Córnea/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/metabolismo , Fucose/metabolismo , Galactose/farmacologia , Galactose/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos/metabolismo
2.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201662

RESUMO

Gene expression and phytohormone contents were measured in response to elevating ascorbate in the absence of other confounding stimuli such as high light and abiotic stresses. Young Arabidopsis plants were treated with 25 mM solutions of l-galactose pathway intermediates l-galactose (l-gal) or l-galactono-1,4-lactone (l-galL), as well as L-ascorbic acid (AsA), with 25 mM glucose used as control. Feeding increased rosette AsA 2- to 4-fold but there was little change in AsA biosynthetic gene transcripts. Of the ascorbate recycling genes, only Dehydroascorbate reductase 1 expression was increased. Some known regulatory genes displayed increased expression and included ANAC019, ANAC072, ATHB12, ZAT10 and ZAT12. Investigation of the ANAC019/ANAC072/ATHB12 gene regulatory network revealed a high proportion of ABA regulated genes. Measurement of a subset of jasmonate, ABA, auxin (IAA) and salicylic acid compounds revealed consistent increases in ABA (up to 4.2-fold) and phaseic acid (PA; up to 5-fold), and less consistently certain jasmonates, IAA, but no change in salicylic acid levels. Increased ABA is likely due to increased transcripts for the ABA biosynthetic gene NCED3. There were also smaller increases in transcripts for transcription factors ATHB7, ERD1, and ABF3. These results provide insights into how increasing AsA content can mediate increased abiotic stress tolerance.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/fisiologia , Ácido Ascórbico/metabolismo , Glutationa Transferase/genética , Reguladores de Crescimento de Plantas/metabolismo , Estresse Fisiológico/fisiologia , Ácido Abscísico/metabolismo , Arabidopsis/efeitos dos fármacos , Proteínas de Arabidopsis/metabolismo , Ascorbato Oxidase/genética , Ascorbato Oxidase/metabolismo , Ácido Ascórbico/genética , Ciclopentanos/metabolismo , Galactose/farmacologia , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Glutationa Transferase/metabolismo , Ácidos Hexurônicos/metabolismo , Ácidos Indolacéticos/metabolismo , Oxilipinas/metabolismo , Reguladores de Crescimento de Plantas/genética , Sesquiterpenos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202112

RESUMO

D-galactose (D-gal) administration causes oxidative disorder and is widely utilized in aging animal models. Therefore, we subcutaneously injected D-gal at 200 mg/kg BW dose to assess the potential preventive effect of thymoquinone (TQ) and curcumin (Cur) against the oxidative alterations induced by D-gal. Other than the control, vehicle, and D-gal groups, the TQ and Cur treated groups were orally supplemented at 20 mg/kg BW of each alone or combined. TQ and Cur effectively suppressed the oxidative alterations induced by D-gal in brain and heart tissues. The TQ and Cur combination significantly decreased the elevated necrosis in the brain and heart by D-gal. It significantly reduced brain caspase 3, calbindin, and calcium-binding adapter molecule 1 (IBA1), heart caspase 3, and BCL2. Expression of mRNA of the brain and heart TP53, p21, Bax, and CASP-3 were significantly downregulated in the TQ and Cur combination group along with upregulation of BCL2 in comparison with the D-gal group. Data suggested that the TQ and Cur combination is a promising approach in aging prevention.


Assuntos
Benzoquinonas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Curcumina/farmacologia , Galactose/farmacologia , Miocárdio/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Benzoquinonas/química , Curcumina/química , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Especificidade de Órgãos , Ratos , Relação Estrutura-Atividade
4.
Int J Biol Macromol ; 183: 2074-2087, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34097961

RESUMO

Lycium barbarum polysaccharides (LBPs) are known for their beneficial effects on diabetes, NAFLD and related chronic metabolic diseases induced by high-fat diet (HFD). However, the relevant researches are mainly about the whole crude polysaccharides, the specific active ingredient of LBPs and its bioactivity have been rarely explored. Herein, a homogeneous polysaccharide (LBP-W) was isolated and purified from crude LBPs. Structure characterizations indicated that LBP-W contained a main chain consisting of a repeated unit of →6)-ß-Galp(1 â†’ residues with branches composed of α-Araf, ß-Galp and α-Rhap residues at position C-3. The objective of this study was to evaluate the anti-obesogenic effect of LBP-W and figure out the underlying mechanisms. In vivo efficacy trial illustrated that LBP-W supplements can alleviate HFD-induced mice obesity significantly. Gut microbiota analysis showed that LBP-W not only improved community diversity of intestinal flora, but also regulated their specific genera. Moreover, LBP-W can increase the content of short-chain fatty acids (SCFAs), a metabolite of the intestinal flora. In summary, all these results demonstrated that the homogeneous polysaccharide purified from L. barbarum could be used as a prebiotic agent to improve obesity by modulating the composition of intestinal flora and the metabolism of SCFAs.


Assuntos
Fármacos Antiobesidade/farmacologia , Bactérias/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Prebióticos , Animais , Fármacos Antiobesidade/química , Arabinose/química , Arabinose/farmacologia , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Disbiose , Ácidos Graxos/sangue , Galactose/química , Galactose/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Obesidade/sangue , Obesidade/microbiologia , Ramnose/química , Ramnose/farmacologia , Relação Estrutura-Atividade
5.
PLoS One ; 16(4): e0249487, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33857158

RESUMO

Erectile dysfunction (ED) is defined as the inability to achieve and/or maintain penile erection sufficient for satisfactory sexual relations, and aging is one of the main risk factors involved. The D-(+)-Galactose aging model is a consolidated methodology for studies of cardiovascular aging; however, its potential for use with ED remain unexplored. The present study proposed to characterize a new experimental model for ED, using the D-(+)-Galactose aging model. For the experiments, the animals were randomly divided into three groups receiving: vehicle (CTL), D-galactose 150 mg/kg (DGAL), and D-(+)-galactose 150 mg/Kg + sildenafil 1.5 mg/Kg (DGAL+SD1.5) being administered daily for a period of eight weeks. All of the experimental protocols were previously approved by the Ethics Committee on the Use of Animals at the Federal University of Paraíba n° 9706070319. During the treatment, we analyzed physical, molecular, and physiological aspects related to the aging process and implicated in the development of ED. Our findings demonstrate for the first time that D-(+)-Galactose-induced aging represents a suitable experimental model for ED assessment. This was evidenced by an observed hyper-contractility in corpora cavernosa, significant endothelial dysfunction, increased ROS levels, an increase in cavernous tissue senescence, and the loss of essential penile erectile components.


Assuntos
Envelhecimento , Disfunção Erétil/etiologia , Galactose/efeitos adversos , Envelhecimento/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Disfunção Erétil/metabolismo , Galactose/farmacologia , Masculino , Ereção Peniana , Pênis/patologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Citrato de Sildenafila/efeitos adversos , Citrato de Sildenafila/farmacologia
6.
Mar Drugs ; 19(4)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921308

RESUMO

Numerous health benefits of diets containing red seaweeds or agar-derived sugar mixtures produced by enzymatic or acid hydrolysis of agar have been reported. However, among various agar-derived sugars, the key components that confer health-beneficial effects, such as prebiotic and anti-colon cancer activities, remain unclear. Here, we prepared various agar-derived sugars by multiple enzymatic reactions using an endo-type and an exo-type of ß-agarase and a neoagarobiose hydrolase and tested their in vitro prebiotic and anti-colon cancer activities. Among various agar-derived sugars, agarotriose exhibited prebiotic activity that was verified based on the fermentability of agarotriose by probiotic bifidobacteria. Furthermore, we demonstrated the anti-colon cancer activity of 3,6-anhydro-l-galactose, which significantly inhibited the proliferation of human colon cancer cells and induced their apoptosis. Our results provide crucial information regarding the key compounds derived from red seaweeds that confer beneficial health effects, including prebiotic and anti-colon cancer activities, to the host.


Assuntos
Ágar/metabolismo , Antineoplásicos/farmacologia , Bifidobacterium/metabolismo , Neoplasias do Colo/tratamento farmacológico , Galactose/análogos & derivados , Prebióticos , Rodófitas/metabolismo , Alga Marinha/metabolismo , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Fermentação , Galactose/isolamento & purificação , Galactose/farmacologia , Células HCT116 , Humanos , Hidrólise
7.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800818

RESUMO

This work presents a semi-quantitative spectroscopic approach, including FTIR-ATR and Raman spectroscopies, for the biochemical analysis of red blood cells (RBCs) supported by the biochemical, morphological and rheological reference techniques. This multi-modal approach provided the description of the RBC alterations at the molecular level in a model of accelerated aging induced by administration of D-galactose (D-gal), in comparison to natural aging. Such an approach allowed to conclude that most age-related biochemical RBC membrane changes (a decrease in lipid unsaturation and the level of phospholipids, or an increase in acyl chain shortening) as well as alterations in the morphological parameters and RBC deformability are well reflected in the D-gal model of accelerated aging. Similarly, as in natural aging, a decrease in LDL level in blood plasma and no changes in the fraction of glucose, creatinine, total cholesterol, HDL, iron, or triglycerides were observed during the course of accelerated aging. Contrary to natural aging, the D-gal model led to an increase in cholesterol esters and the fraction of total esterified lipids in RBC membranes, and evoked significant changes in the secondary structure of the membrane proteins. Moreover, a significant decrease in the phosphorous level of blood plasma was specific for the D-gal model. On the other hand, natural aging induced stronger changes in the secondary structures of the proteins of the RBCs' interior. This work proves that research on the aging mechanism, especially in circulation-related diseases, should employ the D-gal model with caution. Nonetheless, the D-gal model enables to imitate age-related rheological alterations in RBCs, although they are partially derived from different changes observed in the RBC membrane at the molecular level.


Assuntos
Senilidade Prematura/induzido quimicamente , Envelhecimento/sangue , Modelos Animais de Doenças , Membrana Eritrocítica/química , Galactose/toxicidade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Senilidade Prematura/sangue , Animais , Citosol/química , Envelhecimento Eritrocítico/efeitos dos fármacos , Deformação Eritrocítica/efeitos dos fármacos , Índices de Eritrócitos/efeitos dos fármacos , Membrana Eritrocítica/efeitos dos fármacos , Radicais Livres/toxicidade , Galactose/farmacologia , Hemorreologia/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fósforo/sangue , Projetos de Pesquisa
8.
Biochem Biophys Res Commun ; 549: 187-193, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33676187

RESUMO

The cellular environment affects optimal viral replication because viruses cannot replicate without their host cells. In particular, metabolic resources such as carbohydrates, lipids, and ATP are crucial for viral replication, which is sensitive to cellular metabolism. Intriguingly, recent studies have demonstrated that human immunodeficiency virus type 1 (HIV-1) infection induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis in CD4+ T cells to produce the virus efficiently. However, the importance of aerobic glycolysis in maintaining the quality of viral components and viral infectivity has not yet been fully investigated. Here, we show that aerobic glycolysis is necessary not only to override the inhibitory effect of virion-incorporated glycolytic enzymes, but also to maintain the enzymatic activity of reverse transcriptase and the adequate packaging of envelope proteins into HIV-1 particles. To investigate the effect of metabolic remodeling on the phenotypic properties of HIV-1 produced by infected cells, we replaced glucose with galactose in the culture medium because the cells grown in galactose-containing medium are forced to carry out oxidative metabolism instead of aerobic glycolysis. We found that the packaging levels of glyceraldehyde 3-phosphate dehydrogenase, alpha-enolase and pyruvate kinase muscle type 2, which decrease HIV-1 infectivity by packaging into viral particles, are increased in progeny viruses produced by the cells grown in galactose-containing medium. Furthermore, we found that the entry and reverse transcription efficiency of the progeny viruses were reduced, which was caused by a decrease in the enzymatic activity of reverse transcriptase in the viral particles and a decrease in the packaging levels of envelope proteins and reverse transcriptase. These results indicate that the aerobic glycolysis environment in HIV-1-infected cells may contribute to the quality control of viruses.


Assuntos
Glucose/metabolismo , Glicólise , HIV-1/patogenicidade , Vírion/metabolismo , Aerobiose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Meios de Cultura , Proteínas de Ligação a DNA/metabolismo , Galactose/farmacologia , Produtos do Gene env/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Glicólise/efeitos dos fármacos , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Proteínas de Membrana/metabolismo , Fosfopiruvato Hidratase/metabolismo , Transcrição Reversa/efeitos dos fármacos , Transcrição Reversa/genética , Hormônios Tireóideos/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Empacotamento do Genoma Viral/efeitos dos fármacos
9.
Neurochem Res ; 46(5): 1058-1067, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33761044

RESUMO

Albicanol is a natural terpenoid derived from Dryopteris fragrans. Herein, we assessed the ability of Albicanol to protect against oxidative stress-induced senescence. Using a murine model of D-galactose (D-gal)-induced aging, we determined that Albicanol treatment can reverse D-gal-mediated learning impairments and behavioral changes, while also remediating brain tissue damage in treated mice. We found that serum SOD, CAT, GSH-Px, and T-AOC levels were significantly decreased in aging mice, and that Albicanol treatment significantly increased the serum levels of these antioxidant enzymes. We additionally evaluated the impact of Albicanol treatment on the Keap1/Nrf2/ARE signaling pathway, and found that it was able to decrease Keap1 expression while increasing the expression of Nrf2, thereby activating this signaling pathway, suppressing oxidative damage, and enhancing the expression of downstream target genes including SOD, GSH, GST, HO-1, and NQO1 in this murine aging model system. Albicanol treatment also inhibited the secretion of inflammatory TNF-a and IL-1b. Together, these data indicated that Albicanol can activate Nrf2 pathway-related genes, thereby inhibition of delayed aging by alleviating oxidative stress-induced damage.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/uso terapêutico , Galactose/farmacologia , Naftalenos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Expressão Gênica/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
10.
Metabolism ; 119: 154767, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33753088

RESUMO

BACKGROUND: Obesity and osteoporosis frequently coexist, and might have a causal relationship. Gut microbiota, associated with both lipid and bone metabolism, plays an important role in the pathogenesis of excessive fat accumulation and bone loss. The improvement of intestinal flora by prebiotics was a promising strategy for ameliorating obesity-related bone loss. METHODS: Obesity model was established by feeding mice with high fat diet (HFD) for 16 weeks. Fructooligosaccharides (FOS) and/or galactooligosaccharides (GOS) were daily gavaged to mice. Osteoblastic, adipocytic, and osteoclastic differentiation was performed on primary cells isolated from experimental mice. The composition of gut flora was evaluated by 16s rDNA sequencing. Expression of intestinal junction proteins was assessed by qPCR and immunohistochemistry. Cytokine levels were measured by qPCR. RESULTS: Long-term HFD caused decreased bone mass in mice, which was associated with decreased osteogenesis, increased osteoclastogenesis, and excessive adipogenesis. FOS/GOS treatment significantly alleviated HFD-induced bone loss and reversed the imbalanced differentiation of osteoblasts, adipocytes, and osteoclasts. In addition, our study showed that FOS/GOS administration ameliorated microbiota dysbiosis (manifested as enhanced Firmicutes:Bacteriodetes ratio and reduced biodiversity), downregulated expression of intestinal junction proteins (including Claudin1, Claudin15, ZO-1, and JAM-A), and increased inflammatory cytokines (including TNFα, IL6, and IL17) in HFD-fed mice. CONCLUSION: Long-term HFD led to decreased bone mass, with microbiota dysbiosis, leaky gut, and systemic inflammation. The administration of FOS/GOS could significantly increase biodiversity and SCFA concentrations of intestinal flora in HFD fed mice, then reverse high gut permeability and inflammatory cytokines, in the end protect against HFD induced osteopenia.


Assuntos
Doenças Ósseas Metabólicas/prevenção & controle , Disbiose/prevenção & controle , Inflamação/prevenção & controle , Mucosa Intestinal/efeitos dos fármacos , Oligossacarídeos/farmacologia , Animais , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/microbiologia , Células Cultivadas , Dieta Hiperlipídica , Disbiose/etiologia , Disbiose/metabolismo , Galactose/química , Galactose/farmacologia , Galactose/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/microbiologia , Oligossacarídeos/química , Oligossacarídeos/uso terapêutico , Permeabilidade/efeitos dos fármacos
11.
Phytomedicine ; 84: 153509, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33636579

RESUMO

BACKGROUND: Radix Astragali (RA) consists of the dried root of Astragalus membranaceus Bunge and is one of the most frequently used dietetic Chinese herbs to treat inflammation and neurodegenerative disease among other conditions. Radix Astragali preparata (RAP) is a medicinal form of RA. RA and RAP have been used as anti-aging agent, however, the mechanisms underlying their effects are still unclear. PURPOSE: Considering the wide application of RA and RAP in clinical practice, it is necessary to identify the better product between the two and elucidate the molecular mechanism responsible for their anti-aging effects. STUDY DESIGN: In this study, network pharmacology integrated with molecular biology techniques were employed to explore the possible mechanism of RA and RAP against aging. METHODS: Aging animal models were constructed by exposure to D-galactose (D-gal), and the anti-aging effect of RA and RAP were determined based on behavior tests and histomorphological observation. Network pharmacology was performed to construct the "compound-target-pathway" network. Gene and protein expression of possible targets were validated and analyzed using qRT-PCR and Western blotting. RESULTS: Treatment by RA and RAP could alleviate the symptoms of aging such as a decrease in body weight and organ indices, behavioral impairment, increased oxidative stress, weaken histopathological evaluation. The effect of RAP was more pronounced than that of RA in preventing aging process in a mouse model. The anti-aging effect of RA and RAP is associated with the balance of oxidative stress and activation of PI3K/Akt signaling pathway. CONCLUSION: Using an integrated strategy of network pharmacology and molecular biology we attempted to elucidate the mechanisms of action of RA and RAP.


Assuntos
Envelhecimento/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Envelhecimento/fisiologia , Animais , Astragalus propinquus/química , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Galactose/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Int J Mol Med ; 47(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33448313

RESUMO

Codonopsis pilosula is a type of traditional Chinese medicine that exerts an anti­aging effect and can regulate the gastrointestinal (GI) system. The aim of the present study was to investigate the underlying molecular mechanisms responsible for the anti­aging effects of Codonopsis pilosula in the GI tract of mice with D­galactose­induced aging. First, a successful mouse model of aging was established, and Codonopsis pilosula water extract was then used for treatment. The anti­aging effects of Codonopsis pilosula on the GI tract were then detected from the perspectives of tissue structure, physiological function and cell ultrastructure. Finally, in order to explore the underlying molecular mechanisms, the expression profiles of lncRNAs and mRNAs in the stomach and intestine were examined using microarray technology. A total of 117 (41 lncRNAs and 76 mRNAs) and 168 (85 lncRNA sand 83 mRNAs) differentially expressed genes associated with the anti­aging effects of Codonopsis pilosula were identified in the stomach and intestine, respectively. Through integrated analysis of the stomach and intestine, 4 hub RNAs, including 1 lncRNA (LOC105243318) and 3 mRNAs (Fam132a, Rorc and 1200016E24Rik) were identified, which may be associated with the anti­aging effects of Codonopsis pilosula in the GI tract of aging mice. The Kyoto Encyclopedia of Genes and Genomes analysis revealed that the metabolic pathway was an important pathway underlying the anti­aging effects of Codonopsis pilosula in the GI tract. On the whole, in the present study, 4 hub RNAs associated with these effects and their regulatory networks were found in the GI tract of aging mice. In addition, the metabolic pathway was found to play an important role in these anti­aging effects in the GI tract.


Assuntos
Envelhecimento/efeitos dos fármacos , Codonopsis/química , Galactose/farmacologia , Trato Gastrointestinal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Longo não Codificante/biossíntese , RNA Mensageiro/biossíntese , Envelhecimento/metabolismo , Animais , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Extratos Vegetais/química , RNA Longo não Codificante/genética , RNA Mensageiro/genética
13.
Clin Nutr ; 40(5): 3019-3031, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33509667

RESUMO

BACKGROUND & AIMS: Ageing is associated with an increased risk of frailty, intestinal microbiota perturbations, immunosenescence and oxidative stress. Prebiotics such as galacto-oligosaccharides (GOS) may ameliorate these ageing-related alterations. We aimed to compare the faecal microbiota composition, metabolite production, immune and oxidative stress markers in prefrail elderly and younger adults, and investigate the effects of GOS supplementation in both groups. METHODS: In a randomised controlled cross-over study, 20 prefrail elderly and 24 healthy adults received 21.6 g/day Biotis™ GOS (containing 15.0 g/day GOS) or placebo. Faecal 16S rRNA gene-based microbiota and short-chain fatty acids were analysed at 0, 1 and 4 weeks of intervention.Volatile organic compounds were analysed in breath, and stimulated cytokine production, CRP, malondialdehyde, trolox equivalent antioxidant capacity (TEAC) and uric acid (UA) in blood at 0 and 4 weeks. RESULTS: Principle coordinate analysis showed differences in microbial composition between elderly and adults (P≤0.05), with elderly having lower bifidobacteria (P≤0.033) at baseline. In both groups, GOS affected microbiota composition (P≤0.05), accompanied by increases in bifidobacteria (P<0.001) and decreased microbial diversity (P≤0.023). Faecal and breath metabolites, immune and oxidative stress markers neither differed between groups (P ≥ 0.125) nor were affected by GOS (P ≥ 0.236). TEAC values corrected for UA were higher in elderly versus adults (P<0.001), but not different between interventions (P ≥ 0.455). CONCLUSIONS: Elderly showed lower faecal bifidobacterial (relative) abundance than adults, which increased after GOS intake in both groups. Faecal and breath metabolites, parameters of immune function and oxidative stress were not different at baseline, and not impacted by GOS supplementation. CLINICALTRIALS. GOV WITH STUDY ID NUMBER: NCT03077529.


Assuntos
Bifidobacterium/isolamento & purificação , Suplementos Nutricionais , Fezes/microbiologia , Galactose/farmacologia , Imunidade/efeitos dos fármacos , Oligossacarídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prebióticos/administração & dosagem , Adulto Jovem
14.
Int J Mol Sci ; 22(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494388

RESUMO

Epidemiological studies associate milk consumption with an increased risk of Parkinson's disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic ß-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic ß-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic ß-cells linking the pathogenesis of PD and T2D.


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Exossomos/metabolismo , Galactose/metabolismo , Leite/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Autofagia , Transporte Biológico , Células Cultivadas , Diabetes Mellitus Tipo 2/patologia , Galactose/farmacologia , Humanos , Lisossomos/metabolismo , MicroRNAs/genética , Estresse Oxidativo , Doença de Parkinson/patologia , Transdução de Sinais , alfa-Sinucleína/efeitos adversos
15.
Am J Physiol Cell Physiol ; 320(5): C778-C793, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33439775

RESUMO

Tumor cell proliferation requires sufficient metabolic flux through the pentose phosphate pathway to meet the demand for biosynthetic precursors and to increase protection against oxidative stress which in turn requires an upregulation of substrate flow through glycolysis. This metabolic poise is often coupled with a shift in ATP production from mitochondrial OXPHOS to substrate-level phosphorylation. Despite major advances that were facilitated by using tumor-derived cell lines in research areas spanning from membrane to cytoskeletal biology, this distorted metabolic profile limits their impact as a model in physiology and toxicology. Substitution of glucose with galactose in the cell culture medium has been demonstrated to shift ATP production from substrate-level phosphorylation to mitochondrial OXPHOS. This increase in oxygen utilization is coupled to a global metabolic reorganization with potential impacts on macromolecule biosynthesis and cellular redox homeostasis, but a comprehensive analysis on the effects of sugar substitution in tumor-derived cells is still missing. To address this gap in knowledge we performed transcriptomic and metabolomic analyses on human hepatocellular carcinoma (HepG2) cells adapted to either glucose or galactose as the aldohexose source. We observed a shift toward oxidative metabolism in all primary metabolic pathways at both transcriptomic and metabolomic levels. We also observed a decrease in nicotinamide dinucleotide (NAD(P)) levels and subcellular NAD+-to-NADH ratios in cells cultured with galactose compared with glucose control cells. Our results suggest that galactose reduces both glycolytic and biosynthetic flux and restores a metabolic poise in HepG2 cells that closely reflects the metabolic state observed in primary hepatocytes.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Galactose/farmacologia , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Metabolismo Energético/genética , Regulação Neoplásica da Expressão Gênica , Glucose/farmacologia , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Metaboloma , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Oxirredução , Fenótipo , Fatores de Tempo , Transcriptoma
16.
Int J Biol Macromol ; 168: 130-142, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33278441

RESUMO

Iron oxide nanoparticles (IONPs) are employed as MRI contrast agents and as effective drug delivery vehicles. However, the limited solubility and biodegradability of these nanoparticles need to be improved for safer biomedical applications. In an attempt to improve the bottlenecks associated with IONPs, the current study focuses on the synthesis of folic acid conjugated, galactoxyloglucan-iron oxide nanoparticles (FAPIONPs), for the loading and controlled release of the encapsulated chemotherapeutic agent doxorubicin (DOX). The as-designed DOX@FAPIONPs induced a dose-dependent increase in cytotoxicity in folate receptor-positive cells through a caspase-mediated programmed cell death pathway while bare DOX demonstrated a non-targeted toxicity profile. Using LC-MS/MS analysis, several major biological processes altered in treated cells, from which, cell cycle, cellular function and maintenance were the most affected. Detailed toxicity studies in healthy mice indicated the absence of any major side effects while bare drugs created substantial organ pathology. Gadolinium-based contrast agents have a risk of adverse effects, including nephrogenic systemic fibrosis overcome by the administration of DOX@FAPIONPs in xenograft mice model. Tumor-targeted biodistribution pattern with a favorable DOX pharmacokinetics will be the driving factor behind the appealing tumor reduction capacity and increased survival benefits demonstrated on solid tumor-bearing mice.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Galactose/química , Glucanos/química , Nanopartículas Magnéticas de Óxido de Ferro/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida/métodos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Feminino , Ácido Fólico/química , Ácido Fólico/metabolismo , Ácido Fólico/farmacologia , Galactose/farmacologia , Glucanos/farmacologia , Humanos , Nanopartículas de Magnetita/uso terapêutico , Camundongos , Tamanho da Partícula , Polietilenoglicóis/farmacologia , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual/efeitos dos fármacos
17.
Chem Biodivers ; 18(1): e2000710, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33289247

RESUMO

In this study, the pine nut (Pinus yunnanensis Franch.) protein was hydrolyzed by alkaline protease and trypsin to prepare pine nut protein hydrolysate (PNPH). The chemical, intracellular and in vivo antioxidant capacity of PNPH were evaluated. PNPH owned the ability of scavenging free radicals, and it could protect the HepG2 cells from oxidative damage by preserving cell viability. Moreover, PNPH could reduce the malondialdehyde (MDA) content and improved the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in serum, heart and liver of aging mice induced by D-galactose. Further, the PNPH was stepwise purified and identified, and 15 peptides were identified from purified fraction in PNPH. The three-dimension structures of identified peptides were predicted. Among all identified peptides, peptide 3, 7, 8 and 11 were presumed to possess good antioxidant activity. Overall, PNPH and purified peptides isolated from PNPH have potential application prospects in the field of natural antioxidants and anti-aging functional foods.


Assuntos
Antioxidantes/química , Pinus/química , Substâncias Protetoras/química , Hidrolisados de Proteína/química , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Feminino , Galactose/farmacologia , Glutationa Peroxidase/metabolismo , Coração/efeitos dos fármacos , Células Hep G2 , Humanos , Peróxido de Hidrogênio/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Malondialdeído/metabolismo , Camundongos , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pinus/metabolismo , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , Hidrolisados de Proteína/isolamento & purificação , Hidrolisados de Proteína/farmacologia , Estrutura Terciária de Proteína , Superóxido Dismutase/metabolismo
18.
Int J Biol Macromol ; 168: 251-260, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33309662

RESUMO

In this research, a novel polysaccharide (PCP) was extracted from Pleurotus citrinopileatus and purified by Sephadex G-150 gel column, and its antitumor activity was investigated using the model H22 tumor-bearing mice. PCP was found to be composed of arabinose, galactose, glucose, xylose, mannose and glucuronic acid in a proportion of 0.66: 14.59: 10.77: 1: 0.69: 0.23 with average molecular weight of 7.30 × 105 Da. Further analysis suggested that PCP was a pyranose with α-type and ß-type glycosidic residues. The antitumor assays in vivo indicated that PCP could effectively suppress H22 solid tumor growth, protect immune organs and improve inflammation and anemia. Besides, Annexin V-FITC/PI double staining and JC-1 staining demonstrated that PCP could induce apoptosis of H22 hepatoma cells. The PI staining assay revealed that PCP induced H22 hepatoma cells apoptosis by arresting cell cycle in S phase. These results suggest that the polysaccharide from Pleurotus citrinopileatus possesses potential value in the treatment of liver cancer.


Assuntos
Pleurotus/metabolismo , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arabinose/farmacologia , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , China , Galactose/farmacologia , Ácido Glucurônico/farmacologia , Glicosídeos/farmacologia , Neoplasias Hepáticas/patologia , Masculino , Manose/farmacologia , Camundongos , Peso Molecular , Monossacarídeos/farmacologia , Polissacarídeos/farmacologia , Xilose/farmacologia
19.
Arch Gerontol Geriatr ; 92: 104288, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33147533

RESUMO

The present study aims to shed new light on anti-aging effect of DL-ß-hydroxybutyrate (ßOHB) against hepatic cellular senescence induced by d-galactose or γ-irradiation. The rats divided into 6 groups. Group 1, control, group 2, exposed to γ-ray (5 GY), group 3, injected by d-galactose (150 mg/kg) daily for consecutive 6 weeks, which regarded to induce the aging, group 4, injected intraperitoneal by ß-hydroxybutyrate (ßOHB) (72.8 mg/kg) daily for consecutive 14 days, group 5, exposed to γ-ray then treated with ßOHB daily for consecutive 14 days, group 6, injected daily with d-galactose for consecutive 6 weeks, then treated with ßOHB daily at the last two weeks of d-galactose. Aspartate amino transferase (AST), alanine amino transferase (ALT), Insulin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were estimated in serum. Moreover, protein expression of Microtubule-associated proteins 1A/1B light chain 3B (LC3-II/LC3-I) ratio, mechanistic target of rapamycin (mTOR), pAMPK, mRNA gene expression of 5' AMP-activated protein kinase (AMPK), Nucleoporin p62 (p62), cyclin-dependent kinase inhibitor 1(P21CIP1), cyclin-dependent kinase inhibitor 2A (p16INK4a) and DNA fragmentation percentage were measured in liver tissue as a biomarker of cellular senescence. The results confirmed that ßOHB modulated serum level of AST, ALT, insulin, IL-6 and TNF-α, protein expression of mTOR and LC3-II/LC3-I ratio, pAMPK and p62 in liver aging model induced by d-galactose or γ-irradiation. Histopathological examination results of liver tissue indicated coincidence with those recorded by molecular biochemical inspection. Taken together, these findings suggest that ßOHB may be useful in combating hepatic cellular senescence induced by d-galactose or γ-irradiation via autophagy dependent mechanisms.


Assuntos
Autofagia , Galactose , Ácido 3-Hidroxibutírico , Envelhecimento , Animais , Senescência Celular , Galactose/farmacologia , Humanos , Fígado , Masculino , Ratos
20.
Pak J Pharm Sci ; 33(3(Special)): 1413-1417, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-33361031

RESUMO

To investigate the effect and mechanism of galactose on cerulean-induced pancreatic acinar cell injury. Acute pancreatitis cell injury model was established by arbusin-induced pancreatic acinar cell AR42J injury; galactose (25, 50, 100 mmol / L) was used to treat the injured cells, and the optimal concentration was 50 mmol / L; cell counting kit (CCK-8), enzyme linked immunosorbent assay (ELISA) to detect cell survival rate and necrosis rate; flow cytometry and Western blotting (Western blot) to detect cell apoptosis and autologous phage-related gene (Beclin1) and microtubule-associated protein 1 light chain 3 (LC3), apoptosis-related protein B-cell lymphoma / leukemia-2 (Bcl-2), Bcl-2-related X gene (Bax), and fibroblasts Expression of growth factor 21 antibody (FGF21) and anti-aging gene Klotho. A pancreatic acinar cell injury model was successfully established with cerana (100 nmol / L); galactose (25, 50, 100 mmol/L) In a concentration-dependent manner, the inhibitory effect of ceriferin on AR42J injury was inhibited at an optimal concentration of 50 mmol / L. Compared with the ceriferin group, the apoptosis rate of AR42J cells in the galactose group was significantly reduced. table Significantly increased, Bcl-2, FGF21 and Klotho protein expression was significantly increased, Bax protein was significantly decreased; the FGF21 inhibitor can be significantly reduced on galactose these caerulein-induced AR42J cells. Galactose can inhibit the apoptosis and autophagy of pancreatic acinar cells induced by cerana, and its potential mechanism is to up-regulate FGF21 and Klotho, providing a new potential drug for the treatment of acute pancreatitis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismo , Galactose/farmacologia , Glucuronidase/metabolismo , Pâncreas Exócrino/efeitos dos fármacos , Pancreatite/prevenção & controle , Substâncias Protetoras/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Linhagem Celular , Ceruletídeo/toxicidade , Pâncreas Exócrino/metabolismo , Pâncreas Exócrino/patologia , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Pancreatite/patologia , Ratos , Transdução de Sinais
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