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1.
Adv Mater ; : e1904762, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566289

RESUMO

Wrinkled hydrogels from biomass sources are potential structural biomaterials. However, for biorelated applications, engineering scalable, structure-customized, robust, and biocompatible wrinkled hydrogels with highly oriented nanostructures and controllable intervals is still a challenge. A scalable biomass material, namely cellulose, is reported for customizing anisotropic, all-cellulose, wrinkle-patterned hydrogels (AWHs) through an ultrafast, auxiliary force, acid-induced gradient dual-crosslinking strategy. Direct immersion of a prestretched cellulose alkaline gel in acid and relaxation within seconds allow quick buildup of a consecutive through-thickness modulus gradient with acid-penetration-directed dual-crosslinking, confirmed by visual 3D Raman microscopy imaging, which drives the formation of self-wrinkling structures. Moreover, guided by quantitative mechanics simulations, the structure of AWHs is found to exhibit programmable intervals and aligned nanostructures that differ between ridge and valley regions and can be controlled by tuning the prestretching strain and acid treatment time, and these AWHs successfully induce cell alignment. Thus, a new avenue is opened to fabricate polysaccharide-derived, programmable, anisotropic, wrinkled hydrogels for use as biomedical materials via a bottom-up method.

2.
Neurosci Lett ; 714: 134502, 2019 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-31639423

RESUMO

The aim of this study was to investigate the relationship of dopamine D1 receptor (D1R) and its downstream factors with morphine withdrawal symptoms in rats. Rats were injected intraperitoneally with morphine in a dose-escalating manner. The midbrain periaqueductal gray (PAG) area was microinjected with D1R antagonist SCH23390 or D1R agonist SKF38393. Rats were intraperitoneally injected with naloxone (4 mg/kg) after the last morphine injection, and the withdrawal response was observed. The D1R antagonist reduced the withdrawal response in morphine-exposed rats and decreased the expression of Ca2+/calmodulin-dependent protein kinase II (CaMKII), phosphorylated extracellular signal-regulated kinase (p-ERK) and cAMP response element-binding protein (CREB) in the PAG. However, the ability of SKF38393 to increase the withdrawal response was weak and limited. Taken together, the results suggest that D1R antagonist decreased the withdrawal response in morphine-exposed rats by downregulating the downstream factors, CaMKII, p-ERK and CREB.

3.
Nanoscale ; 11(34): 15971-15983, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31424067

RESUMO

We explore the cellular uptake process of PEGylated liposomes and bicelles by investigating their membrane wrapping process using large-scale molecular dynamics simulations. We find that due to the mobility of ligands on the liposome/bicelle, the membrane wrapping process of a PEGylated liposome/bicelle can be divided into two stages, whose transition is determined by a critical wrapping fraction fc; it is reached when all the ligands are exhausted and bound to receptors within the cell membrane. Before this critical scenario is approached, the grafted polyethylene glycol (PEG) polymers aggregate together within the membrane-wrapped region of the liposome/bicelle, driven by ligand-receptor binding. For wrapping fractions f > fc, membrane wrapping cannot proceed unless a compressive membrane tension is provided. By systematically varying the membrane tension and PEG molar ratio, we establish phase diagrams about wrapping states for both PEGylated liposomes and bicelles. According to these diagrams, we find that the absolute value of the compressive membrane tension required by a fully wrapped PEGylated bicelle is smaller than that of the PEGylated liposome, indicating that the PEGylated bicelle is easily internalized by cells. Further theoretical analysis reveals that compared to a liposome, the flatter surface at the top of a bicelle makes it energetically more favored beyond the critical wrapping fraction fc. Our simulations confirm that the interplay between ligand mobility and NP geometry can significantly change the understanding about the influence of NP geometry on the membrane wrapping process. It can help us to better understand the cellular uptake process of the PEGylated liposome/bicelle and to improve the design of lipid-like NPs for drug delivery.

4.
Phys Chem Chem Phys ; 21(30): 16804-16817, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31332402

RESUMO

We present an improved Dreiding force field for single layer black phosphorus (SLBP) obtained by first-principle calculations in conjunction with the particle swarm optimization algorithm and molecular dynamics (MD) simulations. The proposed Dreiding force field can describe material properties of the SLBP very well in comparison with first-principle calculations and the Stillinger-Weber potential, including Young's modulus, Poisson's ratio, shear modulus, bending stiffness and phonon spectrum. Through the improved Dreiding force field, the wetting of a water nanodroplet and the adsorption of a villin headpiece on SLBP under compressive deformation are also studied by MD simulations. The simulation results show that the microscopic contact angle increases with the level of compressive strain on the SLBP. Meanwhile, the compressive strain reduces disruption caused by SLBP to the structure of the villin headpiece. The proposed Dreiding force field shows great potential to describe the interaction between SLBP and water molecules. It can be further used to simulate the transport of water on SLBP, especially under mechanical deformation, and interactions between SLBP and biological systems.

5.
Plant Cell Physiol ; 60(7): 1556-1566, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31073607

RESUMO

Oil crop Brassica napus is subjected to environmental stresses such as drought, cold and salt. Phospholipase Ds (PLDs) have vital roles in regulation of plant growth, development and stress tolerance. In this study, 32 BnaPLD genes were identified and classified into six subgroups depending on the conserved protein structures. High similarity in gene and protein structures exists between BnaPLDs and AtPLDs. Gene expression analysis showed that BnaPLDα1s and BnaPLDδs had higher expression than other PLDs. BnaPLDα1 and BnaPLDδ were significantly induced by abiotic stresses including dehydration, NaCl, abscisic acid (ABA) and 4�C. Lipidomic analysis showed that the content of main membrane phospholipids decreased gradually under stresses, except phosphatidylglycerol increased under the treatment of ABA and phosphatidylethanolamine increased under 4�C. Correspondingly, their product of phosphatidic acid increased often with a transient peak at 8 h. The plant height of mutants of PLDα1 was significantly reduced. Agronomic traits such as yield, seed number, silique number and branches were significantly impaired in PLDα1 mutants. These results indicate that there is a large family of PLD genes in B. napus, especially BnaPLDα1s and BnaPLDδs may play important roles in membrane lipids remodeling and maintaining of the growth and stress tolerance of B. napus.


Assuntos
Brassica napus/genética , Genes de Plantas/genética , Fosfolipase D/genética , Fosfolipídeos/metabolismo , Brassica napus/enzimologia , Brassica napus/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas/fisiologia , Estudo de Associação Genômica Ampla , Metabolismo dos Lipídeos , Lipídeos/fisiologia , Fosfolipase D/metabolismo , Fosfolipídeos/fisiologia , Filogenia , Folhas de Planta/metabolismo , Estresse Fisiológico , Transcriptoma
6.
Int J Mol Sci ; 20(10)2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31109005

RESUMO

Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat "browning". This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway.

7.
J Am Chem Soc ; 141(18): 7554-7561, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31017407

RESUMO

Metal-ligand cooperation (MLC) by dearomatization/aromatization provides a unique way for bond activation, which has led to the discovery of various acceptorless dehydrogenative coupling reactions. However, most of the studies are based on pincer complexes with a central nitrogen donor. Aiming at exploration of the possibility of MLC by PCP-type pincer complexes, we report herein the synthesis, characterization, structure, and reactivity of pyridine-based PCP-Ru complexes. X-ray structures and DFT calculations indicate a carbenoid character of quaternized pyridine-based PCP-Ru complexes. These complexes undergo dearomatization by direct deprotonation, and the dearomatized complex can react with hydrogen, alcohols, or nitriles to regain aromatization via MLC.

8.
Chemistry ; 25(19): 4931-4934, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30768816

RESUMO

An in situ generated oxidation species of nickel quinolinylpropioamide intermediate was produced. Characterization by X-ray absorption near edge structure (XANES) and EPR provides complementary insights into this oxidized nickel species. With aliphatic amides and isocyanides as substrates, a nickel-catalyzed facile synthesis of structurally diverse five-membered lactams could be achieved.

9.
Nat Commun ; 10(1): 639, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30733447

RESUMO

Oxidative C-H/N-H cross-coupling is one of the most atom-economical methods for the construction of C-N bonds. However, traditional oxidative C-H/N-H cross-coupling either required the use of strong oxidants or high reaction temperature, which makes it difficult to tolerate redox active functional groups. Herein we describe an external chemical oxidant-free electrooxidative C-H/N-H cross-coupling between electron-rich arenes and diarylamine derivatives. Under undivided electrolytic conditions, a series of triarylamine derivatives are produced from electron-rich arenes and diarylamine derivatives with high functional group tolerance. Both of the coupling partners are redox active in oxidative C-H/N-H cross-coupling, which enables high regioselectivity in C-N bond formation. Exclusive para-selectivity is observed for the coupling with anilines.

10.
Neurology ; 92(11): e1238-e1249, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30737342

RESUMO

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

11.
Nucleic Acids Res ; 47(5): 2349-2364, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30649550

RESUMO

Hippo pathway is involved in tumorigenesis, and its regulation in cytosol has been extensively studied, but its regulatory mechanisms in the nuclear are not clear. In the current study, using a FBS-inducing model following serum starvation, we identified KDM3A, a demethylase of histone H3K9me1/2, as a positive regulator for hippo target genes. KDM3A promotes gene expression through two mechanisms, one is to upregulate YAP1 expression, and the other is to facilitate H3K27ac on the enhancers of hippo target genes. H3K27ac upregulation is more relevant with gene activation, but not H3K4me3; and KDM3A depletion caused H3K9me2 upregulation mainly on TEAD1-binding enhancers rather than gene bodies, further resulting in H3K27ac decrease, less TEAD1 binding on enhancers and impaired transcription. Moreover, KDM3A is associated with p300 and required for p300 recruitment to enhancers. KDM3A deficiency delayed cancer cell growth and migration, which was rescued by YAP1 expression. KDM3A expression is correlated with YAP1 and hippo target genes in colorectal cancer patient tissues, and may serve as a potential prognosis mark. Taken together, our study reveals novel mechanisms for hippo signaling and enhancer activation, which is critical for tumorigenesis of colorectal cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais/genética , Histona Desmetilases com o Domínio Jumonji/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Humanos , Proteínas Nucleares/genética , Prognóstico , Regiões Promotoras Genéticas/genética , Transdução de Sinais , Fatores de Transcrição/genética
12.
J Agric Food Chem ; 67(5): 1392-1401, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30644744

RESUMO

Our previous study has confirmed that maltol can attenuate alcohol-induced acute hepatic damage and prevent oxidative stress in mice. Therefore, maltol might have the capacity to improve thioacetamide (TAA)-induced liver fibrosis. The purpose of this work was to explore the antifibrotic efficacy and underlying mechanisms of maltol for TAA-treated mice. Progressive liver fibrosis was established with a dose-escalating protocol in which the mice received TAA intraperitoneal three times a week for a total duration of 9 weeks. The injection doses of TAA were 50 mg/kg for the first week, 100 mg/kg for the second and third weeks, and 150 mg/kg for the rest of the injections. Maltol with doses of 50 and 100 mg/kg was given by gavage after 4 weeks of intraperitoneal injection of TAA, respectively, once daily for 5 weeks. Results indicated that TAA intraperitoneal injection significantly increased serum activities of alanine aminotransferase (ALT) (52.93 ± 13.21 U/L vs 10.22 ± 3.36 U/L) and aspartate aminotransferase (AST) (67.58 ± 25.84 U/L vs 39.34 ± 3.89 U/L); these elevations were significantly diminished by pretreatment with maltol. Additionally, maltol ameliorated TAA-induced oxidative stress with attenuation in MDA ( p < 0.05 or p < 0.01) content; evident elevation in the GSH levels, GSH/GSSG ratio ( p < 0.05 or p < 0.01), and superoxide dismutase (SOD) ( p < 0.01); and restored liver histology accompanied by a decrease of α-smooth muscle actin (α-SMA) expression. Furthermore, maltol significantly suppressed the transforming growth factor-ß1 (TGF-ß1) expression and the PI3K/Akt pathway. This study suggested that maltol alleviated experimental liver fibrosis by suppressing the activation of HSCs and inducing apoptosis of activated HSCs through TGF-ß1-mediated PI3K/Akt signaling pathway. These findings further clearly suggested that maltol is a potent therapeutic candidate for the alleviation of liver fibrosis.


Assuntos
Cirrose Hepática/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pironas/administração & dosagem , Fator de Crescimento Transformador beta1/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Tioacetamida/efeitos adversos , Fator de Crescimento Transformador beta1/genética
13.
J Sep Sci ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30488565

RESUMO

The chloramphenicol was chosen as the imprinted molecule and the methacrylic acid was chosen as the functional monomer to prepare molecularly imprinted polymers. The ethylene glycol dimethacrylate, pentaerythritol triacrylate, and trimethylolpropane trimethylacrylate were used as the cross-linking agents, respectively. The interaction processes between chloramphenicol and methacrylic acid were simulated basing on the ωB97XD/6-31G (d,p) method. The self-assembled configuration, bonding sites, binding number, binding energy, and interaction principle of stable complex formed by chloramphenicol and methacrylic acid with different molar ratios have been studied. The selectivity of the most stable complex formed from chloramphenicol and methacrylic acid was discussed with the thiamphenicol and florfenicol as the analogues of chloramphenicol. The results showed that chloramphenicol and methacrylic acid were interacted through the hydrogen bonds. When the molar ratio was 1: 10 and pentaerythritol triacrylate as the cross-linking agent, the ordered complex formed by chloramphenicol and methacrylic acid has the largest amount of hydrogen bonds and the lowest binding energy. The Scatchard showed that the maximum apparent adsorption capacity was 173.3 mg/g (0.536 mol/g), and the selection factor of florfenicol was the largest. This study provides a reliable theoretical and experimental basis for the design, preparation and characterization of chloramphenicol molecularly imprinted polymers. This article is protected by copyright. All rights reserved.

14.
Mol Inform ; 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30307134

RESUMO

Protein kinase CK2 is considered as an emerging target in cancer therapy, and recent efforts have been made to develop its ATP-competitive inhibitors, but achieving selectivity with respect to related kinases remains challenging because of the highly conserved ATP-binding pocket of kinases. Non-ATP competitive inhibitors might solve this challenge; one such strategy is to identify compounds that target the CK2α/CK2ß interface as CK2 holoenzyme antagonists. Here we improved the binding affinity to CK2α and cell-based anti-cancer activity of a CK2ß-derived cyclic peptide (Pc) by combining structure-based computational design with experimental evaluation. By analyzing molecular dynamics simulations of Pc bound to CK2α, a series of Pc-derived peptides was rationally designed and synthesized to evaluate their binding affinity to CK2α, as well as anti-proliferative and pro-apoptotic effects against HepG2 cancer cell line. One amino acid substitutions on Pc, I192F, exhibited over 10-fold improvement in the predicted binding affinity to CK2α when compared to Pc, and a cell-permeable version, I192F-Tat, also demonstrated more potent anti-proliferative and pro-apoptotic effects against HepG2 compared to Pc. A second modification of Pc, H193W, also led to more potent cell-based activity, despite having weaker binding affinity (∼5×) to CK2α. The discovery of the I192F and H193W peptides provides new insights for further optimization of CK2 antagonist candidates as anti-cancer leads.

15.
J Am Chem Soc ; 140(41): 13128-13135, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30260638

RESUMO

Oxidative R1-H/R2-H cross-coupling with hydrogen evolution serves as one of the most atom-economical methods for constructing new chemical bonds. This reaction strategy avoids substrate prefunctionalization steps in traditional cross-coupling reactions. Besides, hydrogen gas, which is recognized as a source of green energy, is the only byproduct during the reaction process. The major challenge in this reaction strategy is to achieve selective bond formation and hydrogen evolution at the same time. Over the past few years, novel synthetic techniques especially photochemistry and electrochemistry have provided possibilities for oxidative cross-coupling with H2 liberation. Both C-C and C-X bonds can be constructed without the use of any sacrificial reagents. In this perspective, we will discuss the concept of this reaction strategy and give an overview of its recent development.

16.
Sci Rep ; 8(1): 13859, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217990

RESUMO

Tree leaves are commonly composed of thin mesophyll, carrying out photosynthesis under sunlight, and thick veins. Although the role of leaf veins in water transportation has been known for a long time, their role in providing structural support and guaranteeing large sunlighted area was rarely studied and remains elusive. Here, with use of a novel inverse optimization approach, we aim for uncovering the material design principle behind the unique pattern of venation. It is intriguing to observe that an almost Golden Ratio (GR) distribution of leaf veins always provides optimized structural behavior. Specifically, our research reveals, for the first time, that this unique GR distribution of relatively strong vein material is helpful for maximizing the bending stiffness and leading to a large sunlighted area which is vital for the photosynthesis process of a leaf. Moreover, the GR distribution of leaf veins is also observed in a wide class of plant leaf geometries (i.e., shape, thickness), where experimental evidence is provided for the optimized results. Therefore, our findings can not only serve to explain the mystery of veins GR distribution but also provide widely applicable guidelines on designing soft structures with exceptional mechanical performances.

17.
Cell Death Differ ; 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237511

RESUMO

SPOP is one of the important subunits for CUL3/SPOP/RBX1 complex tightly connected with tumorigenesis. However, its exact roles in different cancers remain debatable. Here, we identify CYCLIN E1, as a novel substrate for SPOP. SPOP directly interacts with CYCLIN E1 and specific regulates its stability in prostate cancer cell lines. SPOP/CUL3/RBX1 complex regulates CYCLIN E1 stability through poly-ubiquitination. CDK2 competes with SPOP for CYCLIN E1 interaction, suggesting that SPOP probably regulates the stability of CDK2-free CYCLIN E1. CYCLIN E1 expression rescued proliferation, migration, and tumor formation of prostate cancer cell suppressed by SPOP. Furthermore, we found SPOP selectively regulates the substrates' stability and signaling pathways in prostate cancer and CCRC cell lines, suggesting that complicated mechanisms exist for SPOP to regulate substrate specificity. Altogether, we have revealed a novel mechanism for SPOP in suppressing prostate cancer and provided evidence to show SPOP has dual functions in prostate cancer and CCRC.

18.
Sci Adv ; 4(8): eaat5312, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30083610

RESUMO

Difunctionalization of alkenes is a valuable and versatile chemical transformation that could quickly build complex molecules. Extensive efforts have been made, and great achievement, such as Sharpless aminohydroxylation and dihydroxylation, has been reached. However, in marked contrast to the extensive research of aminohydroxylation and dihydroxylation, directly using thiophenols/thiols and O/N-nucleophiles to perform the difunctionalization of alkenes that form the C-S and C-O/N bonds together is still underexplored. The main issue is that thiophenols/thiols are often easily overoxidized to sulfoxides or sulphones under such essential oxidation conditions. We demonstrate an electrochemical oxidative oxysulfenylation and aminosulfenylation of alkenes. A critical feature of this transformation is that neither external chemical oxidants nor metal catalysts are required. This electrochemical oxidative synthetic strategy could also be applied for the hydroxysulfenylation and acyloxysulfenylation of alkenes.

19.
J Endocrinol ; 238(3): 231-244, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29941502

RESUMO

Endotoxemia has been recognized to be closely accompanied with type 2 diabetes mellitus (T2DM) and is responsible for many diabetic complications. Recent study suggests the potential role of butyrate, a short-chain fatty acid (SCFA) from microbiota metabolite, on T2DM. Gut-leak is a key event in diabetic-endotoxemia. To investigate if butyrate could ameliorate diabetic-endotoxemia, both in vivo and in vitro experiments were carried out in the present study. The effect of butyrate supplementation on blood HbA1c and inflammatory cytokines were determined in db/db mice; gut barrier integrity and expression of tight junction proteins were investigated both in vivo and in vitro Oral butyrate administration significantly decreased blood HbA1c, inflammatory cytokines and LPS in db/db mice; inflammatory cell infiltration was reduced, and gut integrity and intercellular adhesion molecules were increased as detected by HE staining, immunohistochemistry and Western blot. By gut microbiota assay, ratio of Firmicutes:Bacteroidetes for gut microbiota was reduced by butyrate. In Caco-2 cells, butyrate significantly promoted cell proliferation, decreased inflammatory cytokines' secretion, enhanced cell anti-oxidative stress ability and preserved the epithelial monocellular integrity, which was damaged by LPS. The present findings demonstrated that butyrate supplementation could ameliorate diabetic-endotoxemia in db/db mice via restoring composition of gut microbiota and preserving gut epithelial barrier integrity.

20.
J Nutr Biochem ; 58: 138-149, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29933196

RESUMO

Hepatic fibrosis is a common pathological basis of liver cirrhosis and hepatocellular carcinomas. So, prevention and treatment of liver fibrosis is one of the crucial therapeutic goals in hepatology. Organic selenium, glutathione or probiotics supplementation could ameliorate hepatic fibrosis, respectively. The purpose of this study is to develop a novel selenium-glutathione-enriched probiotics (SGP) and to investigate its protective effect on CCl4-induced liver fibrosis in rats. Yeast strains with the high-yield glutathione were isolated and identified by analysis of 26S ribosomal DNA sequences. The fermentation parameters of SGP were optimized through single-factor, Plackett-Burman (PB) design and response surface methodology (RSM). The final SGP contained 38.4 µg/g of organic selenium, 34.1 mg/g of intracellular glutathione, approximately 1×1010 CFU/g live Saccharomyces cerevisiae and 1×1012 CFU/g live Lactobacillus acidophilus. SGP had better protective effects on liver fibrosis than selenium, glutathione or probiotics, respectively. The hepatic silent information regulator 1 (SIRT1) level was down-regulated and oxidative stress, endoplasmic reticulum (ER) stress, inflammation and phosphorylated MAPK was increased in CCl4-treated rats. However, SGP can significantly reverse these changes caused by CCl4. Our findings suggest that SGP was effective in attenuating liver fibrosis by the activation of SIRT1 signaling and attenuating hepatic oxidative stress, ER stress, inflammation and MAPK signaling.

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