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1.
FEMS Microbiol Ecol ; 100(7)2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38794902

RESUMEN

Mucin is a glycoprotein secreted throughout the mammalian gastrointestinal tract that can support endogenous microorganisms in the absence of complex polysaccharides. While several mucin-degrading bacteria have been identified, the interindividual differences in microbial communities capable of metabolizing this complex polymer are not well described. To determine whether community assembly on mucin is deterministic across individuals or whether taxonomically distinct but functionally similar mucin-degrading communities are selected across fecal inocula, we used a 10-day in vitro sequential batch culture fermentation from three human donors with mucin as the sole carbon source. For each donor, 16S rRNA gene amplicon sequencing was used to characterize microbial community succession, and the short-chain fatty acid profile was determined from the final community. All three communities reached a steady-state by day 7 in which the community composition stabilized. Taxonomic comparisons amongst communities revealed that one of the final communities had Desulfovibrio, another had Akkermansia, and all three shared other members, such as Bacteroides. Metabolic output differences were most notable for one of the donor's communities, with significantly less production of acetate and propionate than the other two communities. These findings demonstrate the feasibility of developing stable mucin-degrading communities with shared and unique taxa. Furthermore, the mechanisms and efficiencies of mucin degradation across individuals are important for understanding how this community-level process impacts human health.


Asunto(s)
Heces , Fermentación , Consorcios Microbianos , Mucinas , ARN Ribosómico 16S , Humanos , Mucinas/metabolismo , ARN Ribosómico 16S/genética , Heces/microbiología , Bacterias/metabolismo , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal , Akkermansia/metabolismo , Desulfovibrio/metabolismo , Desulfovibrio/genética , Desulfovibrio/clasificación , Bacteroides/metabolismo , Bacteroides/genética , Bacteroides/clasificación , Bacteroides/crecimiento & desarrollo
2.
ACS Cent Sci ; 10(3): 717-728, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38559297

RESUMEN

Direct inhibitor of tau aggregation has been extensively studied as potential therapeutic agents for Alzheimer's disease. However, the natively unfolded structure of tau complicates the structure-based ligand design, and the relatively large surface areas that mediate tau-tau interactions in aggregation limit the potential for identifying high-affinity ligand binding sites. Herein, a group of isatin-pyrrolidinylpyridine derivative isomers (IPP1-IPP4) were designed and synthesized. They are like different forms of molecular "transformers". These isatin isomers exhibit different inhibitory effects on tau self-aggregation or even possess a depolymerizing effect. Our results revealed for the first time that the direct inhibitor of tau protein aggregation is not only determined by the previously reported conjugated structure, substituent, hydrogen bond donor, etc. but also depends more importantly on the molecular shape. In combination with molecular docking and molecular dynamics simulations, a new inhibition mechanism was proposed: like a "molecular clip", IPP1 could noncovalently bind and fix a tau polypeptide chain at a multipoint to prevent the transition from the "natively unfolded conformation" to the "aggregation competent conformation" before nucleation. At the cellular and animal levels, the effectiveness of the inhibitor of the IPP1 has been confirmed, providing an innovative design strategy as well as a lead compound for Alzheimer's disease drug development.

3.
mSystems ; 9(4): e0029424, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38530054

RESUMEN

Maternal secretor status is one of the determinants of human milk oligosaccharides (HMOs) composition, which, in turn, influences the gut microbiota composition of infants. To understand if this change in gut microbiota impacts immune cell composition, intestinal morphology, and gene expression, 21-day-old germ-free C57BL/6 mice were transplanted with fecal microbiota from infants whose mothers were either secretors (SMM) or non-secretors (NSM) or from infants consuming dairy-based formula (MFM). For each group, one set of mice was supplemented with HMOs. HMO supplementation did not significantly impact the microbiota diversity; however, SMM mice had a higher abundance of genus Bacteroides, Bifidobacterium, and Blautia, whereas, in the NSM group, there was a higher abundance of Akkermansia, Enterocloster, and Klebsiella. In MFM, gut microbiota was represented mainly by Parabacteroides, Ruminococcaceae_unclassified, and Clostrodium_sensu_stricto. In mesenteric lymph node, Foxp3+ T cells and innate lymphoid cells type 2 were increased in MFM mice supplemented with HMOs, while in the spleen, they were increased in SMM + HMOs mice. Similarly, serum immunoglobulin A was also elevated in MFM + HMOs group. Distinct global gene expression of the gut was observed in each microbiota group, which was enhanced with HMOs supplementation. Overall, our data show that distinct infant gut microbiota due to maternal secretor status or consumption of dairy-based formula and HMO supplementation impacts immune cell composition, antibody response, and intestinal gene expression in a mouse model. IMPORTANCE: Early life factors like neonatal diet modulate gut microbiota, which is important for the optimal gut and immune function. One such factor, human milk oligosaccharides (HMOs), the composition of which is determined by maternal secretor status, has a profound effect on infant gut microbiota. However, how the infant gut microbiota composition determined by maternal secretor status or consumption of infant formula devoid of HMOs impacts infant intestinal ammorphology, gene expression, and immune signature is not well explored. This study provides insights into the differential establishment of infant microbiota derived from infants fed by secretor or non-secretor mothers milk or those consuming infant formula and demonstrates that the secretor status of mothers promotes Bifidobacteria and Bacteroides sps. establishment. This study also shows that supplementation of pooled HMOs in mice changed immune cell composition in the spleen and mesenteric lymph nodes and immunoglobulins in circulation. Hence, this study highlights that maternal secretor status has a role in infant gut microbiota composition, and this, in turn, can impact host gut and immune system.


Asunto(s)
Inmunidad Innata , Microbiota , Lactante , Femenino , Humanos , Animales , Ratones , Ratones Endogámicos C57BL , Linfocitos/metabolismo , Leche Humana/química , Sistema Inmunológico/metabolismo , Oligosacáridos/análisis , Bifidobacterium/genética
4.
Food Funct ; 15(6): 3186-3198, 2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38441170

RESUMEN

The modern diet delivers nearly equal amounts of carbohydrates and protein into the colon representing an important protein increase compared to past higher fiber diets. At the same time, plant-based protein foods have become increasingly popular, and these sources of protein are generally less digestible than animal protein sources. As a result, a significant amount of protein is expected to reach the colon and be available for fermentation by gut microbiota. While studies on diet-microbiota interventions have mainly focused on carbohydrate fermentation, limited attention has been given to the role of protein or protein-fiber mixtures as fermentation substrates for the colonic microbiota. In this study, we aimed to investigate: (1) how changing the ratio of protein to fiber substrates affects the types and quantities of gut microbial metabolites and bacteria; and (2) how the specific fermentation characteristics of different types of fiber might influence the utilization of protein by gut microbes to produce beneficial short chain fatty acids. Our results revealed that protein fermentation in the gut plays a crucial role in shaping the overall composition of microbiota communities and their metabolic outputs. Surprisingly, butyrate production was maintained or increased when fiber and protein were combined, and even when pure protein samples were used as substrates. These findings suggest that indigestible protein in fiber-rich substrates may promote the production of microbial butyrate perhaps including the later stages of fermentation in the large intestine.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Animales , Fibras de la Dieta/análisis , Butiratos/metabolismo , Fermentación , Ácidos Grasos Volátiles/metabolismo , Heces/microbiología
5.
J Sci Food Agric ; 104(5): 2897-2906, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38018273

RESUMEN

BACKGROUND: Highland hulless barley has garnered attention as a promising economic product and a potential healthy food ingredient. The present study aimed to comprehensively investigate the molecular structure of extractable fibers obtained from a specific highland hulless barley. Water-soluble fiber (WSF) and alkaline-soluble fiber (ASF) were extracted using enzymatic digestion and an alkaline method, respectively. The purified fibers underwent a thorough investigation for their structural characterization. RESULTS: The monosaccharide composition revealed that WSF primarily consisted of glucose (91.7%), whereas ASF was composed of arabinose (54.5%) and xylose (45.5%), indicating the presence of an arabinoxylan molecule with an A/X ratio of 1.2. The refined structural information was further confirmed through methylation, 1 H NMR and Fourier-transform infrared spectroscopy analyses. WSF fiber exclusively exhibited α-anomeric patterns, suggesting it was an α-glucan. It has a low molecular weight of 5 kDa, as determined by gel permeation chromatography. Conversely, ASF was identified as a heavily branched arabinoxylan with 41.55% of '→2,3,4)-Xylp-(1→' linkages. ASF and WSF exhibited notable differences in their morphology, water absorption capabilities and rheological properties. CONCLUSION: Based on these findings, molecular models of WSF and ASF were proposed. The deep characterization of these fiber structures provides valuable insights into their physicochemical and functional properties, thereby unlocking their potential applications in the food industry. © 2023 Society of Chemical Industry.


Asunto(s)
Hordeum , Hordeum/química , Glucanos/análisis , Monosacáridos , Industria de Alimentos , Industria de Procesamiento de Alimentos
6.
Foods ; 12(20)2023 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-37893765

RESUMEN

Polysaccharides and oligosaccharides are abundantly found in various foods [...].

7.
Foods ; 12(18)2023 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-37761090

RESUMEN

Young hulless barley leaves are gaining recognition for potential health benefits, and the method of extracting polysaccharides from them is critical for potential food industry applications. This study delves into a comparative analysis of six distinct fiber extraction techniques: hot water extraction; high-pressure steam extraction; alkaline extraction; xylanase extraction; cellulase extraction; and combined xylanase and cellulase extraction. This analysis included a thorough comparison of polysaccharide-monosaccharide composition, structural properties, antioxidant activities (DPPH, ABTS, and FRAP), and rheological properties among fibers extracted using these methods. The results underscore that the combined enzymatic extraction method yielded the highest extraction yield (22.63%), while the rest of the methods yielded reasonable yields (~20%), except for hot water extraction (4.11%). Monosaccharide composition exhibited divergence across methods; alkaline extraction yielded a high abundance of xylose residues, whereas the three enzymatic methods demonstrated elevated galactose components. The extracted crude polysaccharides exhibited relatively low molecular weights, ranging from 5.919 × 104 Da to 3.773 × 105 Da across different extraction methods. Regarding antioxidant activities, alkaline extraction yielded the highest value in the ABTS assay, whereas enzymatically extracted polysaccharides, despite higher yield, demonstrated lower antioxidant capacity. In addition, enzymatically extracted polysaccharides exerted stronger shear thinning behavior and higher initial viscosity.

8.
Carbohydr Polym ; 316: 121039, 2023 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-37321733

RESUMEN

Dietary fibers are known to modulate microbiome composition, but it is unclear to what extent minor fiber structural differences impact community assembly, microbial division of labor, and organismal metabolic responses. To test the hypothesis that fine linkage variations afford different ecological niches for distinct communities and metabolism, we employed a 7-day in vitro sequential batch fecal fermentation with four fecal inocula and measured responses using an integrated multi-omics approach. Two sorghum arabinoxylans (SAXs) were fermented, with one (RSAX) having slightly more complex branch linkages than the other (WSAX). Although there were minor glycoysl linkage differences, consortia on RSAX retained much higher species diversity (42 members) than on WSAX (18-23 members) with distinct species-level genomes and metabolic outcomes (e.g., higher short chain fatty acid production from RSAX and more lactic acid produced from WSAX). The major SAX-selected members were from genera of Bacteroides and Bifidobacterium and family Lachnospiraceae. Carbohydrate active enzyme (CAZyme) genes in metagenomes revealed broad AX-related hydrolytic potentials among key members; however, CAZyme genes enriched in different consortia displayed various catabolic domain fusions with diverse accessory motifs that differ among the two SAX types. These results suggest that fine polysaccharide structure exerts deterministic selection effect for distinct fermenting consortia.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Humanos , Microbioma Gastrointestinal/fisiología , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Heces/microbiología , Fibras de la Dieta , Fermentación
9.
Food Chem ; 425: 136471, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37269637

RESUMEN

Starch is an abundant and common food ingredient capable of complexing with various bioactive compounds (BCs), including polyphenols. However, little information is available about using native starch network arrangement for the starch-BCs inclusion. Herein, two BCs, curcumin, and resveratrol, were undertaken to delineate the role of different starch crystalline types on their encapsulation efficiency. Four starches with different crystalline types, botanical sources, and amylose content were examined. The results suggest that B-type hexagonal packing is necessary to encapsulate curcumin and resveratrol successfully. The increase in XRD crystallinity while maintaining the FTIR band at 1048/1016 cm-1 suggests that BCs are likely entrapped inside the starch granule than attaching to the granule surface. A significant change in starch digestion is seen only for the B-starch complexes. Embedding BCs in the starch network and controlling starch digestion could be a cost-effective and valuable approach to designing and developing novel starch-based functional food ingredients.


Asunto(s)
Curcumina , Almidón , Almidón/química , Curcumina/química , Resveratrol , Digestión , Amilosa/química
10.
Talanta ; 260: 124649, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37167677

RESUMEN

Amyloid-ß oligomers (AßO) have been identified as core biomarkers for early diagnosis of Alzheimer's disease (AD). For the first time, a "turn-on" unlabeled colorimetric aptasensor based on aptamer-polythymine (polyT)-polyadenine (polyA)-gold nanoparticles (pA-pT-apt@AuNPs) was developed for highly sensitive and specific detection of amyloid-ß1-40 oligomers (Aß40-O). In this system, polyA sequence could preferentially anchor onto AuNPs surface as well as reduce the non-specific adsorption, and the aptamer could form upright conformation for the specific recognition of Aß40-O. The aggregation of pA-pT-apt@AuNPs was induced by MgCl2. However, the addition of Aß40-O enabled the aptamer fold adaptively upon recognition and aptamer-Aß40-O complex formed surrounding AuNPs, effectively stabilizing pA-pT-apt@AuNPs against salt-induced aggregation, therefore the color of pA-pT-apt@AuNPs solution still retained red. Based on this principle, the proposed aptasensor exhibited high sensitivity with the limit of detection of 3.03 nM and a linear detectable range from 10.00 nM to 100.0 nM. The superb sensitivity was achieved via the optimization of the length of polyA and polyT spacer. This pA-pT-apt@AuNPs based colorimetric aptasensor provides a rapid, cost-effective, highly sensitive detection method for Aß40-O, which is valuable for the early diagnosis of AD.


Asunto(s)
Enfermedad de Alzheimer , Aptámeros de Nucleótidos , Técnicas Biosensibles , Nanopartículas del Metal , Humanos , Colorimetría/métodos , Péptidos beta-Amiloides , Oro , Enfermedad de Alzheimer/diagnóstico , Técnicas Biosensibles/métodos , Límite de Detección
11.
Nat Microbiol ; 7(4): 556-569, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35365790

RESUMEN

Processed foods often include food additives such as xanthan gum, a complex polysaccharide with unique rheological properties, that has established widespread use as a stabilizer and thickening agent. Xanthan gum's chemical structure is distinct from those of host and dietary polysaccharides that are more commonly expected to transit the gastrointestinal tract, and little is known about its direct interaction with the gut microbiota, which plays a central role in digestion of other dietary fibre polysaccharides. Here we show that the ability to digest xanthan gum is common in human gut microbiomes from industrialized countries and appears contingent on a single uncultured bacterium in the family Ruminococcaceae. Our data reveal that this primary degrader cleaves the xanthan gum backbone before processing the released oligosaccharides using additional enzymes. Some individuals harbour Bacteroides intestinalis that is incapable of consuming polymeric xanthan gum but grows on oligosaccharide products generated by the Ruminococcaceae. Feeding xanthan gum to germfree mice colonized with a human microbiota containing the uncultured Ruminococcaceae supports the idea that the additive xanthan gum can drive expansion of the primary degrader Ruminococcaceae, along with exogenously introduced B. intestinalis. Our work demonstrates the existence of a potential xanthan gum food chain involving at least two members of different phyla of gut bacteria and provides an initial framework for understanding how widespread consumption of a recently introduced food additive influences human microbiomes.


Asunto(s)
Microbioma Gastrointestinal , Animales , Fibras de la Dieta , Aditivos Alimentarios , Humanos , Ratones , Polisacáridos Bacterianos
12.
RSC Adv ; 12(3): 1451-1459, 2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-35425202

RESUMEN

Attached microalgae production in wastewater is a promising method to further develop biofilm reactors by reducing economic costs associated with biomass separation and harvesting. However, the reliability of materials to support such adherence needs further investigation. Five common microfiltration membranes were evaluated in this study to assess their influence on the efficacy of harvesting Chlorella pyrenoidosa. The material-to-material, algae-to-algae, and algae-to-material interactions were studied based on the Extended Derjaguin, Landau, Verwey, Overbeek (XDLVO) theory. The results showed that Chlorella pyrenoidosa was hydrophobic and that the algae particles derived from this algae type tended to agglomerate. Furthermore, the algae-membrane adhesion free energy further validated the accumulation of biomass in the experiments - the cellulose acetate nitrate (CACN) membrane and the cellulose acetate (CA) membrane obtained an optical biomass production of 59.93 and 51.27 g m-2. The presence of these interactions promoted the adhesion of more microalgae particles to the membrane. Moreover, the relationship between the algae-membrane and the distance at which the microalgae approached the membrane surface was simulated. The study indicated that the XDLVO theory could be successfully applied to the mechanism for the adhesion of the attached culture of Chlorella pyrenoidosa to the membrane material.

13.
Food Chem ; 366: 130609, 2022 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-34311231

RESUMEN

Several grains such as wheat, rice, corn, oat, barley and rye are cultivated throughout the world. They are converted to variety of food products using a multitude of processing technologies to quench the growing organoleptic demands and consumers' preferences. Among them, corn, ranking third in wide consumption, is cost-effective and has long-term storability. Herein, ready-to-eat corn flours with variable starch digestion have been developed by processing at high temperature with shear using a twin screw continuous processor. The influence of processing temperature (121, 145 and 160°C) and moisture (25, 30 and 35%) has been studied. Results suggest both processing temperature and moisture modulate the rapidly digestible starch (RDS), slowly digestible starch (SDS) and resistant starch (RS) amounts of the flours. The presence or absence of oil in the flour further controls the starch digestion. The outcome is deemed to be helpful to design and develop healthy and palatable functional food products in addition to furthering the current market share for corn and other grains.


Asunto(s)
Harina , Oryza , Digestión , Almidón , Zea mays
14.
ACS Chem Neurosci ; 12(21): 4162-4174, 2021 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-34649422

RESUMEN

A molecular inhibitor of tau protein aggregation offers an attractive therapeutic possibility as disease-modifying treatment of Alzheimer's disease. However, the ineffectiveness as well as adjoint toxicity due to superficial understanding of the inhibition mechanism has hindered drug development. Conventional approaches for screening drug ligands rely on compatible docking with the well-defined structure of a protein receptor. Therefore, the design of tau aggregation inhibitors has been inevitably hindered by the unstructured, highly dynamic nature of the tau protein. This paper suggested a new strategy for reducing tau aggregation through a dynamic process of conformational isomerization. A group of glucose gallate derivatives were selected as tau aggregation inhibitors. These star-shaped molecules have a biocompatible glucose core surrounded by several gallic acid polyphenol arms, which can bind to peptide chains at different sites, probably through hydrogen bonds and π-π stacking. Theoretically, by elevating the saddle point on the potential energy surfaces (PES) of proteins, the barrier in the dynamic pathway of peptide isomerization, glucose gallates effectively inhibit tau aggregation through a dynamic mechanism. A tau cell model based on human neurons was constructed. For the first time, we confirmed that the moderate thermodynamic binding of the molecular ligand to the tau peptide chain can not only prevent the isomerization of the peptide chain leading to aggregation but also avoid toxicity resulting from the dissociation of tau from microtubules.


Asunto(s)
Enfermedad de Alzheimer , Proteínas tau , Glucosa , Humanos , Ligandos , Neuronas
15.
Small ; 17(47): e2103919, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34623753

RESUMEN

Given that traditional anticancer therapies fail to significantly improve the prognoses of triple negative breast cancer (TNBC), new modalities with high efficiency are urgently needed. Herein, by mixing the metal-phenolic network formed by tannic acid (TA), bleomycin (BLM), and Fe3+ with glutathione peroxidase 4 (GPX4) inhibitor (ML210) loaded hollow mesoporous Prussian blue (HMPB) nanocubes, the HMPB/ML210@TA-BLM-Fe3+ (HMTBF) nanocomplex is prepared to favor the ferroptosis/apoptosis synergism in TNBC. During the intracellular degradation, Fe3+ /Fe2+ conversion mediated by TA can initiate the Fenton reaction to drastically upregulate the reactive oxygen species level in cells, subsequently induce the accumulation of lipid peroxidation, and thereby cause ferroptotic cell death; meanwhile, the released ML210 efficiently represses the activity of GPX4 to activate ferroptosis pathway. Besides, the chelation of Fe2+ with BLM leads to in situ BLM toxification at tumor site, then triggers an effective apoptosis to synergize with ferroptosis for tumor therapy. As a result, the superior in vivo antitumor efficacy of HMTBF is corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression, indicating that the nanoformulations can serve as efficient ferroptosis and apoptosis inducers for use in combinatorial TNBC therapy.


Asunto(s)
Ferroptosis , Nanopartículas , Neoplasias de la Mama Triple Negativas , Animales , Apoptosis , Bleomicina , Línea Celular Tumoral , Ferrocianuros , Humanos , Ratones , Polifenoles , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico
16.
Nutrients ; 13(9)2021 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-34578800

RESUMEN

Increased dietary fiber consumption has been shown to increase human gut microbial diversity, but the mechanisms driving this effect remain unclear. One possible explanation is that microbes are able to divide metabolic labor in consumption of complex carbohydrates, which are composed of diverse glycosidic linkages that require specific cognate enzymes for degradation. However, as naturally derived fibers vary in both sugar composition and linkage structure, it is challenging to separate out the impact of each of these variables. We hypothesized that fine differences in carbohydrate linkage structure would govern microbial community structure and function independently of variation in glycosyl residue composition. To test this hypothesis, we fermented commercially available soluble resistant glucans, which are uniformly composed of glucose linked in different structural arrangements, in vitro with fecal inocula from each of three individuals. We measured metabolic outputs (pH, gas, and short-chain fatty acid production) and community structure via 16S rRNA amplicon sequencing. We determined that community metabolic outputs from identical glucans were highly individual, emerging from divergent initial microbiome structures. However, specific operational taxonomic units (OTUs) responded similarly in growth responses across individuals' microbiota, though in context-dependent ways; these data suggested that certain taxa were more efficient in competing for some structures than others. Together, these data support the hypothesis that variation in linkage structure, independent of sugar composition, governs compositional and functional responses of microbiota.


Asunto(s)
Microbioma Gastrointestinal , Glucanos/química , Glucanos/metabolismo , Adulto , Dieta , Carbohidratos de la Dieta/análisis , Fibras de la Dieta/análisis , Ácidos Grasos Volátiles/metabolismo , Heces/microbiología , Fermentación , Glucosa/química , Glucosa/metabolismo , Glicósidos/química , Humanos , Masculino , ARN Ribosómico 16S/genética , Adulto Joven
17.
J Nanobiotechnology ; 19(1): 261, 2021 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-34481495

RESUMEN

BACKGROUND: Chemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H2O2) into toxic hydroxyl radicals (·OH) to kill cancer cells, holds great promise in tumor therapy due to its high selectivity. However, the therapeutic effect is significantly limited by insufficient intracellular H2O2 level in tumor cells. Fortunately, ß-Lapachone (Lapa) that can exert H2O2-supplementing functionality under the catalysis of nicotinamide adenine dinucleotide (phosphate) NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme offers a new idea to solve this problem. However, extensive DNA damage caused by high levels of reactive oxygen species can trigger the "hyperactivation" of poly(ADP-ribose) polymerase (PARP), which results in the severe interruption of H2O2 supply and further the reduced efficacy of CDT. Herein, we report a self-amplified nanocatalytic system (ZIF67/Ola/Lapa) to co-deliver the PARP inhibitor Olaparib (Ola) and NQO1-bioactivatable drug Lapa for sustainable H2O2 production and augmented CDT ("1 + 1 + 1 > 3"). RESULTS: The effective inhibition of PARP by Ola can synergize Lapa to enhance H2O2 formation due to the continuous NQO1 redox cycling. In turn, the high levels of H2O2 further react with Co2+ to produce the highly toxic ·OH by Fenton-like reaction, dramatically improving CDT. Both in vitro and in vivo studies demonstrate the excellent antitumor activity of ZIF67/Ola/Lapa in NQO1 overexpressed MDA-MB-231 tumor cells. Importantly, the nanocomposite presents minimal systemic toxicity in normal tissues due to the low NQO1 expression. CONCLUSIONS: This design of nanocatalytic system offers a new paradigm for combing PARP inhibitor, NQO1-bioactivatable drug and Fenton-reagents to obtain sustained H2O2 generation for tumor-specific self-amplified CDT.


Asunto(s)
Antineoplásicos/farmacología , Nanoestructuras/química , Nanoestructuras/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Apoptosis , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Ratones , NAD(P)H Deshidrogenasa (Quinona) , Nanopartículas , Naftoquinonas , Poli(ADP-Ribosa) Polimerasa-1 , Especies Reactivas de Oxígeno/metabolismo
18.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(7): 871-875, 2021 Jul.
Artículo en Chino | MEDLINE | ID: mdl-34412760

RESUMEN

OBJECTIVE: To evaluate the intestinal function in rats with exertional heat stroke (EHS) and explore the protective role of Ruifuping pectin (RFP) against heat related intestinal mucosal injury. METHODS: One hundred and twenty healthy special pathogen free (SPF) male Sprague-Dawley (SD) rats were randomly divided into normothermic control group, EHS model group, hyperthermic plus drinking water group (H2O+EHS group) and hyperthermic plus pectin group (RFP+EHS group) with 30 rats in each group. The rats in the H2O+EHS group and RFP+EHS group were given water 20 mL/kg or RFP 20 mL/kg orally for 5 days during adaptive training period. After 1 week, the temperature control range was adjusted to (37±1) centigrade using the temperature control treadmill, and the rat model of EHS was reproduced by one-time high temperature exhaustive exercise. No rehydration intervention was given during the training adaptation period in the EHS model group. The rats in the normothermic control group were maintained to room temperature (25±2) centigrade and humidity (55±5)% without other treatment. Behavior tests including withdraw response, righting, and muscle strength were performed immediately after onset of EHS. Blood of inferior vena cava was collected, and the serum inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukins (IL-6, IL-1ß, IL-10)] and activity of diamine oxidase (DAO) were detected by enzyme linked immunosorbent assay (ELISA). The intestinal mucosa was collected, after hematoxylin-eosin (HE) staining, and Chiu score was performed to assess EHS induced pathological changes under light microscope. RESULTS: The rats in the EHS model group had behavioral, inflammatory and pathological changes, such as delayed withdraw response and righting, decreased forelimb pulling, increased inflammatory index, and obvious intestinal mucosal injury, which indicated that the reproduction of the EHS model was successful. There was no significant difference in above parameters between the H2O+EHS group and the EHS model group except that the inflammatory index in the RFP+EHS group was improved. Compared with the EHS model group, the withdraw reflex to pain and righting after RFP pretreatment in the RFP+EHS group were significantly improved (righting score: 1.4±0.2 vs. 0.3±0.2, withdraw reflex to pain score: 1.0±0.1 vs. 0.2±0.1, both P < 0.05), the muscle strength was significantly increased (N: 13.0±0.5 vs. 8.2±0.6, P < 0.01). The levels of pro-inflammatory factors in the RFP+EHS group were significantly lower than those in the EHS model group [TNF-α (ng/L): 67.5±9.2 vs. 194.3±13.7, IL-6 (ng/L): 360.0±54.1 vs. 981.2±84.4, IL-1ß (ng/L): 33.7±9.0 vs. 88.7±6.1, all P < 0.01], while the level of anti-inflammatory factor IL-10 was higher than that in the EHS model group (ng/L: 208.7±10.5 vs. 103.7±7.0, P < 0.01). The degree of intestinal mucosal injury in the RFP+EHS group was less severe than that in the EHS model group, and the Chiu score and DAO were significantly lower than those in the EHS model group [Chiu score: 1.5±0.2 vs. 3.8±0.0, DAO (U/L): 83.7±6.7 vs. 128.7±10.5, both P < 0.05]. CONCLUSIONS: High temperature training can damage the intestinal barrier function, and induce endotoxemia and systemic inflammatory response syndrome (SIRS) in rats. Oral prophylactic RFP can protect the intestinal barrier function, alleviate SIRS, and promote the recovery of basic nerve reflex and muscle strength after the occurrence of EHS in rats.


Asunto(s)
Golpe de Calor , Pectinas , Animales , Mucosa Intestinal , Masculino , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa
19.
Chem Commun (Camb) ; 57(34): 4158-4161, 2021 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-33908477
20.
Carbohydr Polym ; 257: 117667, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33541670

RESUMEN

While gut bacteria have different abilities to utilize dietary fibers, the degree of fiber structural alignment to bacteria species is not well understood. Corn bran arabinoxylan (CAX) was used to investigate how minor polymer fine structural differences at the genotype × environment level influences the human gut microbiota. CAXs were extracted from 4 corn genotypes × 3 growing years and used in in vitro fecal fermentations. CAXs from different genotypes had varied contents of arabinose/xylose ratio (0.46-0.54), galactose (58-101 mg/g), glucuronic acid (18-32 mg/g). There was genotype- but not environment-specific differences in fine structures. After 24 h fermentation, CAX showed different acetate (71-86 mM), propionate (35-44 mM), butyrate (7-10 mM), and total short chain fatty acid (SCFA) (117-137 mM) production. SCFA profiles and gut microbiota both shifted in a genotype-specific way. In conclusion, the study reveals a very high specificity of fiber structure to gut bacteria use and SCFA production.


Asunto(s)
Microbioma Gastrointestinal/efectos de los fármacos , Xilanos/química , Zea mays/genética , Acetatos/química , Arabinosa/química , Butiratos/química , Fibras de la Dieta/análisis , Ácidos Grasos Volátiles/química , Heces , Fermentación , Galactosa/química , Genotipo , Ácido Glucurónico/química , Humanos , Polímeros/química , Propionatos/química , Xilosa/química
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