RESUMEN
Developing carbon dioxide (CO2) photocatalysts from transition metal carbides (TMCs) with abundant active sites, modulable electron cloud density, as well as low cost and high stability is of great significance for artificial photosynthesis. Building an efficient electron transfer channel between the photo-excitation site and the reaction-active site to extract and steer photo-induced electron flow is necessary but challenging for the highly selective conversion of CO2. In this study, we achieved an oxygen-bridged Schottky junction between ZnO and Ni3ZnC0.7 (denoted as Znoxide-O-ZnTMC) through a ligand-vacancy strategy of MOF. The ZnO-Ni3ZnC0.7 heterostructure integrates the photo-exciter (ZnO), high-speed electron transport channel (Znoxide-O-ZnTMC), and reaction-active species (Ni3ZnC0.7), where Znoxide-O-ZnTMC facilitates the transfer of excited electrons in ZnO to Ni3ZnC0.7. The Zn atoms in Ni3ZnC0.7 serve as electron-rich active sites, regulating the CO2 adsorption energy, promoting the transformation of *COOH to CO, and inhibiting H2 production. The ZnO-Ni3ZnC0.7 shows a high CO yield of 2674.80 µmol g-1h-1 with a selectivity of 93.40 % and an apparent quantum yield of 18.30 % (λ = 420 nm) with triethanolamine as a sacrificial agent. The CO production rate remains at 96.40 % after 18 h. Notably, ZnO-Ni3ZnC0.7 exhibits a high CO yield of 873.60 µmol g-1h-1 with a selectivity of 90.20 % in seawater.
RESUMEN
The intestine and liver are thought to metabolize dietary nutrients and regulate host nutrient homeostasis. Here, we find that the gut microbiota also reshapes the host amino acid (aa) landscape via efficiently metabolizing intestinal aa. To identify the responsible microbes/genes, we developed a metabolomics-based assay to screen 104 commensals and identified candidates that efficiently utilize aa. Using genetics, we identified multiple responsible metabolic genes in phylogenetically diverse microbes. By colonizing germ-free mice with the wild-type strain and their isogenic mutant deficient in individual aa-metabolizing genes, we found that these genes regulate the availability of gut and circulatory aa. Notably, microbiota genes for branched-chain amino acids (BCAAs) and tryptophan metabolism indirectly affect host glucose homeostasis via peripheral serotonin. Collectively, at single-gene level, this work characterizes a microbiota-encoded metabolic activity that affects host nutrient homeostasis and provides a roadmap to interrogate microbiota-dependent activity to improve human health.
Asunto(s)
Aminoácidos de Cadena Ramificada , Aminoácidos , Microbioma Gastrointestinal , Homeostasis , Triptófano , Animales , Microbioma Gastrointestinal/fisiología , Ratones , Aminoácidos/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Triptófano/metabolismo , Ratones Endogámicos C57BL , Nutrientes/metabolismo , Intestinos/microbiología , Humanos , Metabolómica , Glucosa/metabolismo , Serotonina/metabolismo , Vida Libre de Gérmenes , Bacterias/metabolismo , Bacterias/genética , Bacterias/clasificación , MasculinoRESUMEN
A strong correlation between gut microbes and host health has been observed in numerous gut metagenomic cohort studies. However, the underlying mechanisms governing host-microbe interactions in the gut remain largely unknown. Here we report that the gut commensal Christensenella minuta modulates host metabolism by generating a previously undescribed class of secondary bile acids with 3-O-acylation substitution that inhibit the intestinal farnesoid X receptor. Administration of C. minuta alleviated features of metabolic disease in high fat diet-induced obese mice associated with a significant increase in these acylated bile acids, which we refer to as 3-O-acyl-cholic acids. Specific knockout of intestinal farnesoid X receptor in mice counteracted the beneficial effects observed in their wild-type counterparts. Finally, we showed that 3-O-acyl-CAs were prevalent in healthy humans but significantly depleted in patients with type 2 diabetes. Our findings indicate a role for C. minuta and acylated bile acids in metabolic diseases.
Asunto(s)
Ácidos y Sales Biliares , Diabetes Mellitus Tipo 2 , Humanos , Animales , Ratones , Clostridiales , Dieta Alta en GrasaRESUMEN
Subphthalocyanines (SubPcs) are a kind of tripyrrolic macrocycle with a boron atom at their core. Incorporating different units onto the SubPc periphery can endow them with various unique properties. Herein, a series of novel fluorinated low-symmetry SubPc derivatives containing chlorine groups (F8-Cl4-SubPc, F4-Cl8-SubPc) and methoxy groups (F8-(OCH3)2-SubPc) were synthesized and characterized by spectral methods (MS, FT-IR, 1H, 13C, 11B, and 19F NMR spectroscopy), and the effect of the peripheral substituents on their electronic structure of low-symmetry macrocycle was investigated by cyclic voltammetry, theoretical calculation, electronic absorption, and emission spectroscopy. In contrast to perfluorinated SubPcs, these low-symmetry SubPcs revealed non-degenerate LUMO and LUMO + 1 orbitals, especially F8-(OCH3)2-SubPc, which was consistent with the split Q-band absorptions. The cyclic voltammetry revealed that these SubPcs exhibited two or three reduction waves and one oxidation wave, which is consistent with the reported SubPcs. Finally, an intracellular fluorescence imaging study of these compounds revealed that these compounds could enter cancer cells and be entrapped in the lysosomes, which provides a possibility of future applications in lysosome fluorescence imaging and targeting.
RESUMEN
Obesity, dyslipidemia and gut dysbiosis are all linked to cardiovascular diseases. A Ganoderma meroterpene derivative (GMD) has been shown to alleviate obesity and hyperlipidemia through modulating the gut microbiota in obese mice. Here we show that GMD protects against obesity-associated atherosclerosis by increasing the abundance of Parabacteroides merdae in the gut and enhancing branched-chain amino acid (BCAA) catabolism. Administration of live P. merdae to high-fat-diet-fed ApoE-null male mice reduces atherosclerotic lesions and enhances intestinal BCAA degradation. The degradation of BCAAs is mediated by the porA gene expressed in P. merdae. Deletion of porA from P. merdae blunts its capacity to degrade BCAAs and leads to inefficacy in fighting against atherosclerosis. We further show that P. merdae inhibits the mTORC1 pathway in atherosclerotic plaques. In support of our preclinical findings, an in silico analysis of human gut metagenomic studies indicates that P. merdae and porA genes are depleted in the gut microbiomes of individuals with atherosclerosis. Our results provide mechanistic insights into the therapeutic potential of GMD through P. merdae in treating obesity-associated cardiovascular diseases.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Humanos , Ratones , Animales , Masculino , Aminoácidos de Cadena Ramificada/metabolismo , Bacteroides/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Ratones Obesos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Aterosclerosis/prevención & control , Apolipoproteínas ERESUMEN
Flexible solid-state zinc-air batteries (ZABs) with low cost, excellent safety, and high energy density has been considered as one of ideal power sources for portable and wearable electronic devices, while their practical applications are still hindered by the kinetically sluggish cathodic oxygen reduction and oxygen evolution reactions (ORR/OER). Herein, a Janus-structured flexible free-standing bifunctional oxygen electrocatalyst, with OER-active O, N co-coordinated Ni single atoms and ORR-active Co3O4@Co1-xS nanosheet arrays being separately integrated at the inner and outer walls of flexible hollow carbon nanofibers (Ni-SAs/HCNFs/Co-NAs), is reported. Benefiting from the sophisticated topological structure and atomic-level-designed chemical compositions, Ni-SAs/HCNFs/Co-NAs exhibits outstanding bifunctional catalytic activity with the ΔE index of 0.65 V, representing the current state-of-the-art flexible free-standing bifunctional ORR/OER electrocatalyst. Impressively, the Ni-SAs/HCNFs/Co-NAs-based liquid ZAB show a high open-circuit potential (1.45 V), high capacity (808 mAh g-1 Zn), and extremely long life (over 200 h at 10 mA cm-2), and the assembled flexible all-solid-state ZABs have excellent cycle stability (over 80 h). This work provides an efficient strategy for developing high-performance bifunctional ORR/OER electrocatalysts for commercial applications.
RESUMEN
Polysaccharides are known to confer protection against obesity via modulation of gut microbiota. To expand our knowledge of mushroom-derived prebiotics, we investigated the structural characteristics and anti-obesity effects of Lyophyllum decastes polysaccharides. Two heteroglycans were purified and characterized. The isolated polysaccharides effectively reduced obesity and the related disorders in the diet-induced obese (DIO) mice. An altered gut microbiota with enrichments of Bacteroides intestinalis and Lactobacillus johnsonii and an increase of secondary bile acids were detected in the polysaccharide-treated mice. Supplementation of B. intestinalis and L. johnsonii prevented the obesity and hyperlipidemia in DIO mice, demonstrating their causal linkage to the efficacy of polysaccharides. An enhancement of energy expenditure in the brown adipose tissues due to up-regulation of the secondary bile acids-activated TGR5 pathway was deduced to be one of the mechanisms underlying the effect of polysaccharides. These results confirmed Lyophyllum decastes-derived polysaccharides as new prebiotics for preventing and treating obesity.
Asunto(s)
Agaricales , Microbioma Gastrointestinal , Animales , Ácidos y Sales Biliares , Dieta Alta en Grasa , Metabolismo Energético , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/prevención & control , Polisacáridos/química , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , PrebióticosRESUMEN
Background and Objective: White matter hyperintensities (WMH) are magnetic resonance imaging manifestations of brain white matter lesions, which are common in the elderly. There is a correlation between WMH and cognitive impairment, but its imaging features lack heterogeneity, which makes early diagnosis difficult. Studies have found that cognitive impairment in patients with WMH is closely related to changes in the expression of serum inflammatory markers. This article reviews the correlation between WMH and cognitive function, as well as the correlation between cognitive impairment and serum inflammatory markers in patients with WMH. Methods: We searched the China National Knowledge Infrastructure (CNKI), PubMed, Medline and EMBASE databases to identify studies on the correlation between cognitive impairment and serum inflammatory markers in patients with WMH published between the databases' dates of inception and December 2021. Key Content and Findings: Serum inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor α (TNF-α), plasma lipoprotein phospholipase A2 (Lp-PLA2) and interleukins (ILs) are closely related to cognitive impairment in patients with WMH. Conclusions: CRP, TNF-α, ILs and others systemic inflammatory markers can be used to help diagnose and predict cognitive impairment in WMH patients. But more in-depth and comprehensive research is needed to determine the role of systemic inflammatory markers in diagnosing WMH cognitive impairment.
RESUMEN
More than 300 missense mutations in PSEN1 gene have been correlated to the early-onset Alzheimer's disease (EOAD), but given the high diversity of PS1 (the PSEN1 gene product) substrates and the involvement of PS1 in multiple biological functions, different mutants may represent different EOAD etiologies, and how each mutant contributes to the EOAD remains to be further investigated. Here we report the identification of a novel PSEN1 p.Tyr159Ser in a family with multiple EOAD cases. The mutant PS1 protein (PS1Y159S) was analyzed for its activity in producing amyloid-ß (Aß) and for the efficiency in maturation in vitro. We also screened other mutations and SNPs that may modify the effect of PSEN1 p.Tyr159Ser on AD pathogenesis. The blood samples of the family were collected for whole-exome gene sequencing and analysis. The identified mutant PS1 and several other PS1 mutants were co-expressed with the APP Swedish mutant to compare the effects on APP processing and PS1 maturation.1. The proband and her siblings over 50 years old showed typical AD or MCI symptoms. Exon sequencing identified the p.Tyr159Ser mutation in the PSEN1 gene. As not until the age of 78 did the proband's mother who carried this mutation displayed the symptoms of uncharacterized neuropsychiatry instead of AD, but all the mutation bearing lower generation developed AD or MCI after the age of 50, we also analyzed mutations/SNPs that are different between the mother and the lower generation. By in vitro assays, we found that the Y159S substitution strongly increased Aß42/Aß40 ratio and significantly affected PS1 maturation. The newly discovered PSEN1 p.Tyr159Ser is an AD-causing mutation, yet, the carriers are not obligated AD patients. Mutations/SNPs in other gene may modify the effects of this mutation, and the identification of these mutations/SNPs may facilitate the discovery of AD-preventing mechanisms and methods.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Femenino , Humanos , Persona de Mediana Edad , Mutación , Presenilina-1/genéticaRESUMEN
Gut fungi is known to play many important roles in human health regulations. Herein, we investigate the anti-obesity efficacy of the antifungal antibiotics (amphotericin B, fluconazole and 5-fluorocytosine) in the high fat diet-fed (HFD) mice. Supplementation of amphotericin B or fluconazole in water can effectively inhibit obesity and its related disorders, whereas 5-fluorocytosine exhibit little effects. The gut fungus Candida parapsilosis is identified as a key commensal fungus related to the diet-induced obesity by the culture-dependent method and the inoculation assay with C. parapsilosis in the fungi-free mice. In addition, the increase of free fatty acids in the gut due to the production of fungal lipases from C. parapsilosis is confirmed as one mechanism by which C. parapsilosis promotes obesity. The current study demonstrates the gut C. parapsilosis as a causal fungus for the development of diet-induced obesity in mice and highlights the therapeutic strategy targeting the gut fungi.
Asunto(s)
Antifúngicos/farmacología , Candida parapsilosis/fisiología , Dieta Alta en Grasa/efectos adversos , Obesidad/microbiología , Simbiosis , Anfotericina B/farmacología , Animales , Fluconazol/farmacología , Flucitosina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Acute ischemic stroke has become the major cause of mortality and disability worldwide. Following ischemic stroke, the reperfusion injury is mainly mediated by the burst of reactive oxygen and nitrogen species (RONS). Therefore, blocking the excessive production or removing RONS holds great promise as a potential therapeutic strategy. Herein, we developed a Co-doped Fe3O4 nanozyme that is capable of scavenging H2O2, O2â¢-, â¢NO, and ONOO- in vitro and in vivo and provides neuroprotection against ischemic stroke. In vitro experiments showed that pre-incubation with the Co-Fe3O4 nanozyme could prevent neurotoxicity and neuroinflammation induced by H2O2 or lipopolysaccharide, respectively, in HT22 cells. After intravenous administration, the Co-Fe3O4 nanozyme showed no signs of toxicity in peripheral organs of C57BL/6J mice, even after prolonged delivery for 4 weeks. In permanent photothrombotic stroke model and transient middle cerebral artery occlusion stroke model, the Co-Fe3O4 nanozyme specifically accumulated in the infarct rim at 72 h post-stroke and was endocytosed by neurons, astrocytes, microglia, and endothelial cells. Importantly, the Co-Fe3O4 nanozyme delivery reduced the infarct volume in both stroke models. The observation that the Co-Fe3O4 nanozyme was efficacious in two well-characterized ischemic stroke models provides strong evidence that it represents a powerful tool for targeting oxidative and nitrosative stress in the ischemic brain.
Asunto(s)
Depuradores de Radicales Libres/uso terapéutico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Nanopartículas de Magnetita/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Catálisis , Línea Celular , Cobalto/química , Cobalto/toxicidad , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/toxicidad , Lipopolisacáridos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/toxicidad , Masculino , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/toxicidad , Oxidación-Reducción , Especies de Nitrógeno Reactivo/química , Especies Reactivas de Oxígeno/químicaRESUMEN
We used a simple MOFs-assisted synthesis strategy based on the encapsulation and in-situ carburizing reaction of Cu-based metallic organic frameworks (NENU-5) to synthesize porous nano-octahedral materials, MoWN/MoWC@NCTs (T = 700, 800, and 900). Together with the vapor deposition strategy, the volatile nitrogen species from the pyrolysis of dicyandiamide were captured by the nano-octahedral materials, and formed tungsten-molybdenum-based carbonitride nanocrystals encapsulated in nitrogen-doped carbon. The porous nano-octahedron has a unique heterostructure composed of Mo2N/MoC/W2N/WC. The representative MoWN/MoWC@NC800 showed trifunctional electrocatalytic activity in oxygen reduction reaction/oxygen evolution reaction/hydrogen evolution reaction (ORR/OER/HER) in an alkaline medium (0.1 M KOH). The total oxygen electrode activity index ΔE = 0.795 V (vs. RHE) was found in OER/ORR, and the material also exhibits excellent HER performance. The minimum potential of -0.17 V (vs. RHE) was provided at a current density of -10 mA cm-2. MoWN/MoWC@NC800 showed excellent cycle stability and durability in ORR/OER/HER with the same electrolyte (0.1 M KOH). More importantly, MoWN/MoWC@NC800 could be used to construct high-performance zinc-air batteries and sued for driving electrocatalytic water splitting in a self-powered manner. The successful preparation of the materials indicate that the synthetic strategy provides new reference ideas for developing functional materials with high catalytic properties for various applications.
RESUMEN
Rationale: Prior chronic treatment with statins has been shown to be associated with more favorable outcomes in patients with acute coronary syndrome (ACS). Specific changes in the gut microbiota and microbial metabolites have been shown to influence the progression of coronary artery disease. However, the critical microbial and metabolomic changes associated with the cardiovascular protective effects of statins in ACS remain elusive. Methods: In the present study, we performed 16S rRNA sequencing and serum metabolomic analysis in 36 ACS patients who had received chronic statin treatment, 67 ACS patients who had not, and 30 healthy volunteers. A follow-up study was conducted. Metagenomic functional prediction of important bacterial taxa was achieved using PICRUSt2. Results: Statins modulated the gut microbiome of ACS patients towards a healthier status, i.e., reducing potentially pathogenic bacteria such as Parabacteroides merdae but increasing beneficial bacteria such as Bifidobacterium longum subsp. longum, Anaerostipes hadrus and Ruminococcus obeum. Moreover, prior chronic statin therapy was associated with improved outcome in ACS patients. Multi-omics analysis revealed that specific changes in bacterial taxa were associated with disease severity or outcomes either directly or by mediating metabolites such as fatty acids and prenol lipids. Finally, we discovered that important taxa associated with statins were correlated with fatty acid- and isoprenoid-related pathways that were predicted by PICRUSt2. Conclusions: Our study suggests that statin treatment might benefit ACS patients by modulating the composition and function of the gut microbiome, which might result in improved circulating metabolites and reduced metabolic risk. Our findings provide new insights for understanding the heterogenic roles of statins in ACS patients through host gut microbiota metabolic interactions.
Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Homeostasis/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Síndrome Coronario Agudo/metabolismo , Síndrome Coronario Agudo/microbiología , Bacterias/efectos de los fármacos , Femenino , Estudios de Seguimiento , Voluntarios Sanos , Humanos , Masculino , Metabolómica/métodos , Persona de Mediana Edad , ARN Ribosómico 16S/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Eighteen Incompatible Medicaments (EIM) belongs to the category of incompatibility of Traditional Chinese medicine (TCM). This theory forbids concomitant using any one of the eighteen herbal pairs such as Radix Glycyrrhizae (RG)-Radix Euphorbiae Pekinensis (REP), Radix Aconiti-Bulbus Fritiliariae Cirrhosae, and Radix et Rhizoma Veratri Nigri-Radix Ginseng. Concomitant using RG and REP could result in more serious adverse effects on major organs such as kidney, heart, and liver. AIM OF THE STUDY: To investigate the effects of RG-REP decoctions on gut microbiota and short-chain fatty acids (SCFAs) for the purpose of elucidating the mechanism of RG-REP incompatibility. MATERIALS AND METHODS: Six groups of male SD rats were intragastrically administrated with distilled water, RG decoction, REP decoction, 1:1 RG-REP decoction, 2:1 RG-REP decoction and 3:1 RG-REP decoction, respectively, twice daily for 30 consecutive days, and the feces of each rat was separately sampled for gut microbiota analysis and SCFAs assay. 16S rDNA sequencing was employed to comparatively investigate the structure and abundance of intestinal bacteria in rat feces. Gas chromatography (GC) was used to quantitatively determine the contents of SCFAs in rat feces and in vitro samples. The correlation between bacteria and the production of SCFAs was analyzed by Spearman correlation analysis. An in vitro model of human intestinal bacteria was also constructed to simulate and validate the in vivo experiment. RESULTS: The contents of butyric acid in both rat feces and in vitro samples decreased in RG-REP groups. The general structure of gut microbiota in RG-REP groups was not significantly different from that in control group. However, RG alone increased the abundance of Lactobacillus while this effect was counteracted by concomitant using with REP. REP alone decreased the abundance of two interrelated species, Akkermansia and Butyricimonas, and this effect was strengthened by concomitant using REP with RG in the ratio of 1:1. In comparison with REP alone, RG-REP combination also significantly increased the abundance of Streptococcus and Prevotella. CONCLUSION: The incompatibility of RG-REP combination is associated with its negative effect against probiotic bacteria and positive effect on conditional pathogenic bacteria as well as its inhibition on butyric acid production.
Asunto(s)
Medicamentos Herbarios Chinos/efectos adversos , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Glycyrrhiza/química , Adulto , Animales , Bacterias/efectos de los fármacos , Incompatibilidad de Medicamentos , Medicamentos Herbarios Chinos/uso terapéutico , Euphorbiaceae/química , Ácidos Grasos Volátiles/análisis , Ácidos Grasos Volátiles/química , Heces/química , Heces/microbiología , Femenino , Humanos , Masculino , Raíces de Plantas/química , Análisis de Componente Principal , Ratas Sprague-Dawley , Adulto JovenRESUMEN
Intracerebral hemorrhage is the most dangerous complication in tPA thrombolytic therapy for ischemic stroke, which occurs as a consequence of endothelial cell death at the blood-brain barrier (BBB) during thrombolytic reperfusion. We have previously shown that cerebral ischemia-induced rapid occludin degradation and BBB disruption. Here we demonstrated an important role of occludin degradation in facilitating the evolution of ischemic endothelial cells toward death. Cultured brain microvascular endothelial cells (bEnd.3 cells) were exposed to oxygen-glucose deprivation (OGD) or incubated with occludin siRNA or occludin AAV to achieve an occludin deficiency or over-expression status before exposing to reoxygenation (R) or TNF-α treatment. Cell death was assessed by measuring lactate dehydrogenase release, TUNEL staining, and flow cytometry analysis. Inhibition of OGD-induced occludin degradation with SB-3CT or over-expression of occludin with occludin AAV both significantly attenuated OGD/R-induced apoptosis and pyroptosis in bEnd.3 cells. Consistently, knockdown of occludin with siRNA potentiated TNF-α-induced apoptosis, supporting an important role of occludin integrity in endothelial cell survival. Similar results were observed for pyroptosis, in which occludin knockdown with siRNA led to a significant augmentation of cytokines secretion, inflammasome activation, and pyroptosis occurrence in TNF-α-treated bEnd.3 cells. Lastly, up-regulation of c-Yes, PI3K/AKT, and ERK concurrently occurred with occludin degradation after OGD/R or TNF-α treatment, and the level of these proteins were further increased when inhibition of occludin degradation or over-expression of occludin. These data indicate that occludin degradation inflicted during ischemia makes BBB endothelial cells more vulnerable to reperfusion-associated stress stimuli.
Asunto(s)
Barrera Hematoencefálica/patología , Células Endoteliales/patología , Ocludina/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Animales , Apoptosis/fisiología , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patología , Células Endoteliales/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , RatonesRESUMEN
AIMS: Neuronal apoptosis acts as the pivotal pathogenesis of cerebral ischemia/reperfusion (I/R) injury after ischemic stroke. PAQR3 (progestin and adipoQ receptor family member 3) is a crucial player who participates in the regulation of cell death. We aim to explore the specific function and the underlying mechanism of PAQR3 in cerebral I/R induced neuronal injury. MAIN METHODS: We established a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model and rat adrenal pheochromocytoma (PC12) cell oxygen-glucose deprivation/reperfusion (OGD/R) model to detect the expression and of PAQR3 after I/R treatment in vivo and in vitro. We used lentivirus to knockdown PAQR3 and investigated the function of PAQR3 in I/R induced neuronal apoptosis. KEY FINDINGS: PAQR3 expression is markedly increased in the ischemic hemisphere of C57BL/6 mice and PC12 cells after I/R stimulation. Knockdown PAQR3 can attenuate neuronal apoptosis induced by I/R in PC12 cells and exerts neuroprotective effects. PAQR3 deficiency can significantly raise cell viability and suppress LDH leakage under I/R treatment. Silencing PAQR3 attenuates neuronal apoptosis remarkably with fewer TUNEL-positive cells and lower apoptosis rate under I/R treatment. Mechanistically, knockdown of PAQR3 can inhibit the apoptosis pathway through inducing anti-apoptotic proteins and inhibiting pro-apoptotic proteins. Besides, PI3K/AKT signaling suppression with LY294002 abolished the neuroprotective functions induced by silencing PAQR3. SIGNIFICANCE: Our results elucidate that silencing PAQR3 can protect PC12 from OGD/R injury via activating PI3K/AKT pathway. And therefore, provide a novel therapeutic target for the prevention of cerebral I/R injury.
Asunto(s)
Isquemia Encefálica/metabolismo , Glucosa/deficiencia , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Proteínas de la Membrana/biosíntesis , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Daño por Reperfusión/metabolismo , Animales , Apoptosis/fisiología , Isquemia Encefálica/genética , Isquemia Encefálica/prevención & control , Hipoxia de la Célula/fisiología , Silenciador del Gen/fisiología , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Células PC12 , Ratas , Daño por Reperfusión/genética , Daño por Reperfusión/prevención & controlRESUMEN
Alcohol abuse and alcoholic liver diseases (ALD) have been worldwide spread. Chronic alcoholism-induced overgrowth of intestinal bacteria and fungi together with the enteric dysbiosis are important pathogenic mechanisms in ALD. We demonstrated that the water-insoluble polysaccharides (WIP) from Wolfporia cocos effectively ameliorated the hepatic inflammatory injury and fat accumulation through modulating gut microbiota in mice with alcoholic hepatic steatosis (AHS). Oral administration of WIP significantly enhanced the ratio of Firmictues to Proteobacteria, increased the abundance of Lachnospiraceae including Ruminoclostridum and unidentified_clostridials, and inhibited the ethanol-induced fungal overgrowth. Treatment with WIP activated the PPAR-γ signaling and reduced the inflammation in the colonic epithelia cell, facilitating a hypoxic state that suppresses the overgrowth of fungi and Proteobacteria in the gut. In addition, we found an overwhelming increase of the commensal fungus Meyerozyma guilliermondii in the feces of mice with AHS by culturing and ITS sequencing. Inoculation of M. guilliermondii into fungi-free mice aggravated the features of AHS. M. guilliermondii was found to generate PGE2 by biotransformation of arachidonic acid. Furthermore, the gut fungi (M. guilliermondii)-induced PGE2 production in the liver was confirmed as one of the mechanisms in the chronic AHS. The current study supports the manipulation of the gut microbiota (bacteria and fungi) as an effective and alternative strategy for alleviating ALD.
Asunto(s)
Dinoprostona/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Hepatopatías Alcohólicas/tratamiento farmacológico , Polisacáridos/administración & dosificación , Wolfiporia/química , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/crecimiento & desarrollo , Bacterias/metabolismo , Hongos/clasificación , Hongos/genética , Hongos/crecimiento & desarrollo , Hongos/aislamiento & purificación , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/microbiología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
An iron-catalyzed radical cascade cyclization of dienes initiated by an alkoxycarbonyl radical has been developed in the presence of (NH4)2S2O8, leading to a series of fused nitrogen heterocyclic compounds under relatively mild reaction conditions. The reaction is triggered by the addition of an alkyoxycarbonyl radical derived from the cleavage of alkoxyformyl hydrazide. Afterward, the formed nucleophilic radical preferred addition to the electron-neutral vinyl rather than the electron-deficient vinyl, followed by cascade 6-endo cyclization and further radical cyclization.