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Tuning the active site structure of metal-nitrogen-carbon electrocatalysts has recently attracted increasing interest. Herein, we report a bottom-up synthesis strategy in which atomically regulated N-doped polycyclic aromatic hydrocarbons (N-PAHs) of NxC42-x (x = 1, 2, 3, 4) were used as ligands to allow tuning of the active site's structures of M-Nx and establish correlations between the structures and electrocatalytic properties. Based on the synthesis process, detailed characterization, and DFT calculation results, active structures of Nx-Fe1-Nx in Fe1-Nx/RGO catalysts were constructed. The results demonstrated that the extra uncoordinated N atoms around the Fe1-N4 moieties disrupted the π-conjugated NxC42-x ligands, which led to more localized electronic state in the Fe1-N4 moieties and superior catalytic performance. Especially, the Fe1-N4/RGO exhibited optimized performance for ORR with E1/2 increasing by 80 mV and Jk at 0.85 V improved 18 times (compared with Fe1-N1/RGO). This synthesis strategy utilizing N-PAHs holds significant promise for enhancing the controllability of metal-nitrogen-carbon electrocatalyst preparation.
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The design of active and low-cost electrocatalyst for hydrogen evolution reaction (HER) is the key to achieving a clean hydrogen energy infrastructure. The most successful design principle of hydrogen electrocatalyst is the activity volcano plot, which is based on Sabatier principle and has been used to understand the exceptional activity of noble metal and design of metal alloy catalysts. However, this application of volcano plot in designing single-atom electrocatalysts (SAEs) on nitrogen doped graphene (TM/N4C catalysts) for HER has been less successful due to the nonmetallic nature of the single metal atom site. Herein, by performing ab initio molecular dynamics simulations and free energy calculations on a series of SAEs systems (TM/N4C with TM = 3d, 4d, or 5d metals), we find that the strong charge-dipole interaction between the negatively charged *H intermediate and the interfacial H2O molecules could alter the transition path of the acidic Volmer reaction and dramatically raise its kinetic barrier, despite its favorable adsorption free energy. Such kinetic hindrance is also experimentally confirmed by electrochemical measurements. By combining the hydrogen adsorption free energy and the physics of competing interfacial interactions, we propose a unifying design principle for engineering the SAEs used for hydrogen energy conversion, which incorporates both thermodynamic and kinetic considerations and allows going beyond the activity volcano model.
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Three new leucothane-type (1-3), two new micrathane-type (4, 5), eight new grayanane-type diterpenoids (6-13), and four known compounds were obtained from the ethanol extract of the leaves and twigs of Rhododendron decorum. The structures were determined based on NMR spectra, quantum chemical calculations, and X-ray crystallography. The antinociceptive activities of compounds 1, 3, 4, 6, 8, 10-13, and 15-17 were evaluated via the acetic acid-induced writhing test. Compounds 1, 8, 11-13, and 15 exhibited significant antinociceptive activities. In particular, 12 and 15 were found to be effective at doses of 0.8 and 0.08 mg/kg, respectively.
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Analgésicos/química , Diterpenos/química , Hojas de la Planta/química , Rhododendron/química , Analgésicos/farmacología , Cristalografía por Rayos X/métodos , Diterpenos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Resonancia Magnética Nuclear Biomolecular/métodos , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
To evaluate the efficacy and safety of Choudongning (CDN)capsule in children with Tourette's syndrome of spleen deficiency and phlegm accumulation through a randomized double-blind three-arm controlled phase â ¢ study in 588 patients from 8 hospitals. The included patients were randomly divided into test group, positive control group and placebo group at the ratio of 3â¶1â¶1. Patients in the test group orally took CDN capsules and simulated Tiapridal tablets; the patients in positive control group took Tiapridal tablets and simulated CDN capsules; whereas the patients in placebo group orally took the simulated agents of the above two drugs. The treatment course was 6 weeks for three groups. The global grading rates, YGTSS scores and its factor scores, the degree of social function damage, as well as traditional Chinese medicine syndrome efficacy were evaluated as the outcome measures on efficacy. The AEs/ADRs, vital signs and laboratory testing were observed as outcome measures on safety. The total effective rate of YGTSS was 75.92% in the test group, 72.65% in the positive control group, and 37.29% in the placebo group. Non inferiority test stands between the test group and the positive control group, and they were superior to placebo group in efficacy with statistical difference. Significant difference had also been found among the 3 groups in YGTSS tics score, motor tics score, vocal tics, degree of social function damage and traditional Chinese medicine syndrome efficacy. During the study, there were 5 (1.42%)ADRs in the test group, 10 (8.55%)in the positive control group and 3 (2.54%)in the placebo group. The incidence of ADRs in the test group was lower than that in the positive control group, with statistical difference. It is clear to say that CDN capsule can effectively treat the Tourette's syndrome of spleen deficiency and phlegm accumulation. Its efficacy is not inferior to the commonly used Tiapridal tablets, with even less adverse reactions, so it has clinical application value.
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Medicamentos Herbarios Chinos/uso terapéutico , Síndrome de Tourette/tratamiento farmacológico , Cápsulas , Niño , Método Doble Ciego , Humanos , Medicina Tradicional China , Bazo/fisiopatología , Resultado del TratamientoRESUMEN
Chronic hepatitis C virus (HCV) infection predisposes patients to develop liver failure after acetaminophen (APAP) overdose. Mechanisms involved in this were explored using transgenic mice expressing the HCV structural proteins core, E1 and E2. Treatment of C57BL/6J mice with 200 mg/kg body weight APAP resulted in significant liver injury at 6 h as indicated by elevated ALT levels, focal centrilobular necrosis and nuclear DNA fragmentation. HCV transgenic mice showed a variable response, with approximately half the animals showing exacerbation of all parameters of liver injury, while the other half was protected. HCV transgenic mice with higher liver injury had lower liver glutathione levels, elevated mitochondrial oxidative stress and enhanced release of apoptosis-inducing factor (AIF) from the mitochondria. This was accompanied by induction of a higher ER stress response and induction of autophagy. Transgenic animals showing protection against liver injury had a robust recovery of liver glutathione content at 6 h when compared to wild-type animals, accompanied by reduction in mitochondrial oxidative stress and AIF release. This was accompanied by an elevation in glutathione S-transferase mRNA levels and activity, which suggests that an efficient clearance of the reactive intermediate may contribute to the protection against APAP hepatotoxicity in these mice. These results demonstrate that while HCV infection could exacerbate APAP-induced liver injury due to induction and amplification of mitochondrial oxidant stress, it could also protect against injury by activation of APAP scavenging mechanisms.
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Acetaminofén/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hepatitis C/complicaciones , Proteínas del Envoltorio Viral/efectos adversos , Animales , Autofagia/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias Hepáticas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
The effect of varying proportions (w/w) of natural aromatic extract of black tea (NAEBT) with pre-emulsification on the water-holding capacity (WHC) of pork meat batter was investigated. The addition of NAEBT significantly reduced the cooking loss (CL) of pork meat batter from 23.95 % to 18.30 % (P < 0.05). Furthermore, NAEBT with pre-emulsification significantly improved the color stability and increased the springiness (P < 0.05). The results of TBARS and carbonyls indicated that NAEBT with pre-emulsification significantly alleviated oxidative damage to proteins (P < 0.05), resulting in an increased level of ß-sheet (P < 0.05), as confirmed by FT-IR analysis. As a result, the water mobility of pork meat batter was restricted (P < 0.05), resulting in an increase in the energy storage modulus (P < 0.05) and a decrease in the pore size. In summary, the WHC of pork meat batter was improved by the antioxidant effect of the NAEBT.
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Antioxidantes , Productos de la Carne , Extractos Vegetales , Carne de Cerdo , Té , Agua , Agua/química , Extractos Vegetales/química , Carne de Cerdo/análisis , Animales , Té/química , Productos de la Carne/análisis , Antioxidantes/análisis , Porcinos , Culinaria , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Pulmonary fibrosis is an inflammation-driven lung disease with a poor prognosis and no cure. Here we report that basal toll-like receptor 4 (TLR4) activity is critical for the resolution of acute and chronic inflammation and pulmonary fibrosis in mouse models of lung injury. We found that genetic or pharmacologic inhibition of TLR4 exacerbates bleomycin-induced pulmonary inflammation, fibrosis, dysfunction, and animal death through promoting formation of an immunosuppressive tissue microenvironment and attenuating autophagy-associated degradation of collagen and cell death in the fibrotic lung tissues. In contrast, pharmacologic activation of TLR4 resulted in a quick resolution of acute inflammation, reversed the established pulmonary fibrosis, improved lung function, and rescued mice from death. Similarly, blocking TLR4 impaired the resolution of silica-induced chronic inflammation and fibrosis. Importantly, altering autophagic activity could reverse the TLR4-regulated lung inflammation, fibrosis, dysfunction, and animal death. Rapamycin, an autophagy activator, reversed the effects of TLR4 antagonism. In contrast, inhibition of autophagy by 3-methyladenine reversed the proresolving and antifibrotic roles of TLR4 agonists and increased animal death. These results not only highlight a pivotal role for TLR4-mediated basal immunity, particularly autophagic activity, in the proresolution of inflammation and fibrosis after chemical-induced lung injury but also provide proof for the concept for activating TLR4 signaling, particularly TLR4-mediated autophagy, as a novel therapeutic strategy against chronic fibroproliferative diseases that are unresponsive to current therapy.
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Lesión Pulmonar Aguda/fisiopatología , Fibrosis Pulmonar Idiopática/fisiopatología , Lesión Pulmonar/fisiopatología , Neumonía/fisiopatología , Receptor Toll-Like 4/fisiología , Lesión Pulmonar Aguda/patología , Animales , Apoptosis/fisiología , Autofagia/fisiología , Fibrosis Pulmonar Idiopática/patología , Lesión Pulmonar/patología , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Neumonía/patología , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/deficienciaRESUMEN
AIM: Toll-like receptor 2 (TLR2) signaling plays a critical role in the initiation of atherosclerosis. The aim of this study was to investigate whether blocking TLR2 activity could produce therapeutic effects on advanced atherosclerosis. METHODS: Forty-week old apolipoprotein E-deficient (ApoE(-/-)) mice fed on a normal diet were intravenously injected with a TLR2-neutralizing antibody or with an isotype-matched IgG for 18 weeks. Double-knockout ApoE(-/-)Tlr2(-/-) mice were taken as a positive control. At the end of the treatments, the plasma lipid levels were measured, and the plaque morphology, pro-inflammatory cytokines expression and apoptosis in arteries were analyzed. In the second part of this study, 6-week old ApoE(-/-) and ApoE(-/-)Tlr2(-/-) mice fed on a high-cholesterol diet for 12 to 24 weeks, the expression levels of TLR2 and apoptotic markers in arteries were examined. RESULTS: Blockade of TLR2 activity with TLR2-neutralizing antibody or knockout of Tlr2 gene did not alter the plasma lipid levels in ApoE(-/-) mice. However, the pharmacologic and genetic manipulations significantly reduced the plaque size and vessel stenosis, and increased plaque stability in the brachiocephalic arteries. The protective effects of TLR2 antagonism were associated with the suppressed expression of pro-inflammatory cytokines IL-6 and TNF-α and the inactivation of transcription factors NF-κB and Stat3. In addition, blocking TLR2 activity attenuated ER stress-induced macrophage apoptosis in the brachiocephalic arteries, which could promote the resolution of necrotic cores in advanced atherosclerosis. Moreover, high-cholesterol diet more prominently accelerated atherosclerotic formation and increased the expression of pro-apoptotic protein CHOP and apoptosis in ApoE(-/-) mice than in ApoE(-/-)Tlr2(-/-) mice. CONCLUSION: The pharmacologic or genetic blockade of TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in ApoE(-/-) mice. Thus, targeting TLR2 signaling may be a promising therapeutic strategy against advanced atherosclerosis.
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Apolipoproteínas E/deficiencia , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/metabolismo , Receptor Toll-Like 2/antagonistas & inhibidores , Receptor Toll-Like 2/metabolismo , Animales , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/patología , Distribución AleatoriaRESUMEN
This experiment investigated the underlying mechanism of ultrasonic-assisted stewing to enhance the aroma intensity of chicken broth by measuring fat content, oil droplet sizes, zeta potential, viscosity, surface protein loading, lipid oxidation, and aroma compound concentrations. As the thermo-ultrasound time increased, the fat content increased from 0.3 % to 1.2 %, resulting in a milky white appearance. After 1 h of thermo-ultrasound, the broth had the smallest particle size and the highest surface protein load, viscosity, and emulsion stability, as well as the highest total amount of aroma-active compounds of 314.70 ng/mg. With the further extension of thermo-ultrasound time, lipid oxidation increased, but the stability of chicken broth decreased, lowering the content of aroma-active compounds. These outcomes suggested that thermo-ultrasound could enhance the aroma intensity of chicken broth by increasing the fat content and the emulsion stability of the broth.
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Pollos , Odorantes , Animales , Emulsiones/química , Lípidos , Proteínas de la Membrana , Odorantes/análisis , UltrasonidoRESUMEN
UNLABELLED: Acetaminophen (APAP) overdose is the leading cause of acute liver failure in Western countries. In the last four decades much progress has been made in our understanding of APAP-induced liver injury through rodent studies. However, some differences exist in the time course of injury between rodents and humans. To study the mechanism of APAP hepatotoxicity in humans, a human-relevant in vitro system is needed. Here we present evidence that the cell line HepaRG is a useful human model for the study of APAP-induced liver injury. Exposure of HepaRG cells to APAP at several concentrations resulted in glutathione depletion, APAP-protein adduct formation, mitochondrial oxidant stress and peroxynitrite formation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase (LDH) release. Importantly, the time course of LDH release resembled the increase in plasma aminotransferase activity seen in humans following APAP overdose. Based on propidium iodide uptake and cell morphology, the majority of the injury occurred within clusters of hepatocyte-like cells. The progression of injury in these cells involved mitochondrial reactive oxygen and reactive nitrogen formation. APAP did not increase caspase activity above untreated control values and a pancaspase inhibitor did not protect against APAP-induced cell injury. CONCLUSION: These data suggest that key mechanistic features of APAP-induced cell death are the same in human HepaRG cells, rodent in vivo models, and primary cultured mouse hepatocytes. Thus, HepaRG cells are a useful model to study mechanisms of APAP hepatotoxicity in humans.
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Acetaminofén/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetaminofén/metabolismo , Animales , Línea Celular Tumoral , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cisteína/metabolismo , Femenino , Glutatión/metabolismo , Células Hep G2 , Humanos , Ratones , Modelos Biológicos , Necrosis , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de OxígenoRESUMEN
Fundamental understanding of the dynamic behaviors at the electrochemical interface is crucial for electrocatalyst design and optimization. Here, we revisit the oxygen reduction reaction mechanism on a series of transition metal (M = Fe, Co, Ni, Cu) single atom sites embedded in N-doped nanocarbon by ab initio molecular dynamics simulations with explicit solvation. We have identified the dissociative pathways and the thereby emerged solvated hydroxide species for all the proton-coupled electron transfer (PCET) steps at the electrochemical interface. Such hydroxide species can be dynamically confined in a "pseudo-adsorption" state at a few water layers away from the active site and respond to the redox event at the catalytic center in a coupled manner within timescale less than 1 ps. In the PCET steps, the proton species (in form of hydronium in neutral/acidic media or water in alkaline medium) can protonate the pseudo-adsorbed hydroxide without needing to travel to the direct catalyst surface. This, therefore, expands the reactive region beyond the direct catalyst surface, boosting the reaction kinetics via alleviating mass transfer limits. Our work implies that in catalysis the reaction species may not necessarily bind to the catalyst surface but be confined in an active region.
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Pulmonary fibrosis is a consequence of chronic lung injury and is associated with a high mortality. Despite the pathogenesis of pulmonary fibrosis remaining as an enigma, immune responses play a critical role in the deregulation of wound healing process after lung injury, which leads to fibrosis. Accumulating evidence argues the rationales for current treatments of pulmonary fibrosis using immunosuppressive agents such as corticosteroids. In this study, we report that bleomycin (BLM), a well-known fibrogenic agent functioning as a TLR2 agonist, induced the maturation of dendritic cells and release of cytokines. The BLM activation of TLR2 mediated a time-dependent alteration of immune responses in the lung. These responses resulted in an increase in the tissue-infiltrating proinflammatory cells and cytokines in the early period initially following BLM exposure and an increase in the tissue-infiltrating suppressive immune cells and factors during the later period following BLM exposure. TLR2 deficiency, however, reduced pulmonary inflammation, injury, and subsequently attenuated pulmonary fibrosis. Targeting TLR2 by a TLR2-neutralizing Ab not only markedly decreased animal death but also protected animals from the development of pulmonary fibrosis and reversed the established pulmonary fibrosis through regulating BLM-induced immunosuppressive microenvironments. Our studies suggest that TLR2 is a promising target for the development of therapeutic agents against pulmonary fibrosis and that eliminating immunosuppressive cells and factors via immunostimulants is a novel strategy for fibro-proliferative diseases. Moreover, combining BLM with an anti-TLR2 Ab or TLR2 antagonist for cancer therapy will improve the BLM therapeutic profile by enhancing anti-cancer efficacy and reducing systemic inflammation and pulmonary fibrosis.
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Bleomicina/toxicidad , Inmunosupresores , Mediadores de Inflamación/antagonistas & inhibidores , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/prevención & control , Receptor Toll-Like 2/antagonistas & inhibidores , Receptor Toll-Like 2/deficiencia , Animales , Bleomicina/efectos adversos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Modelos Animales de Enfermedad , Inmunosupresores/efectos adversos , Inmunosupresores/toxicidad , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/fisiología , Intubación Intratraqueal , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/patología , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 2/fisiologíaRESUMEN
AIM: To explore the pathogenic role of Th17 cells and interleukin-17A (IL-17A)-associated signaling pathways in spontaneous pulmonary emphysema induced by a Toll-like receptor 4 mutant (TLR4(mut)). METHODS: Lungs were obtained from wild-type (WT) or TLR4mut mice that were treated with or without recombinant mouse IL-17A (1 µg·kg(-1)·d(-1), ip) from the age of 3 weeks to 3 months. Pulmonary emphysema was determined using histology, immunochemistry, and biochemical analysis. T cell polarization was determined with flow cytometry, the levels of cytokines were measured using ELISA, and the levels of IL-17A-associated signaling molecules were detected using Western blot. RESULTS: Compared to WT mice, 3 month-old TLR4(mut) mice were characterized by significantly reduced infiltration of Th17 cells into lungs (2.49%±1.13 % νs 5.26%±1.39%), and significantly reduced expression levels of IL-17A (3.66±0.99 pg/µg νs 10.67±1.65 pg/µg), IL-23 (12.43±1.28 pg/µg νs 28.71±2.57 pg/µg) and IL-6 (51.82±5.45 pg/µg νs 92.73±10.91 pg/µg) in bronchoalveolar lavage fluid. In addition, p38 MAPK phosphorylation and AP-1 expression were decreased to 27%±9% and 51%±8%, respectively, of that in WT mice. Treatment of TLR4(mut) mice with IL-17A increased the infiltration of Th17 cells into lungs and expression levels of IL-17A, IL-6, and IL-23 in bronchoalveolar lavage fluid, attenuated MDA and apoptosis, and improved emphysema accompanied with increased phosphorylation of p38 MAPK and expression of AP-1. CONCLUSION: Th17 cells, in particular the cytokine IL-17A, play a crucial role in the pathogenesis of TLR4(mut)-induced spontaneous pulmonary emphysema. Both of them are potential targets for therapeutic strategies for pulmonary emphysema.
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Interleucina-17/metabolismo , Enfisema Pulmonar/genética , Enfisema Pulmonar/metabolismo , Células Th17/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Animales , Ratones , Ratones Endogámicos C3H , Mutación/genéticaRESUMEN
Epithelial-mesenchymal transition (EMT) plays an important role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We hypothesized that germline variants in the major EMT regulatory genes (SNAIL1, ZEB1, ZEB2, TWIST1) may influence the development of HBV-related HCC. We included 421 cases of HBsAg-positive patients with HCC, 1371 cases of HBsAg-positive subjects without HCC [patients with chronic hepatitis B (CHB) or liver cirrhosis (LC)] and 618 cases of healthy controls in the case-control study. Genotype, allele, and haplotype associations in the major EMT regulatory genes were tested. Environment-gene and gene-gene interactions were analysed using the non-parametric model-free multifactor dimensionality reduction (MDR) method. The SNAIL1rs4647958T>C was associated with a significantly increased risk of both HCC (CT+CC vs. TT: OR=1.559; 95% confidence interval [CI], 1.073-2.264; P=0.020) and CHB+LC (CT+CC vs. TT: OR=1.509; 95% CI, 1.145-1.988; P=0.003). Carriers of the TWIST1rs2285681G>C (genotypes CT+CC) had an increased risk of HCC (CG+CC vs. GG: OR=1.407; 95% CI, 1.065-1.858; P=0.016). The ZEB2rs3806475T>C was associated with significantly increased risk of both HCC (P recessive =0.001) and CHB+LC (P recessive<0.001). The CG haplotype of the rs4647958/rs1543442 haplotype block was associated with significant differences between healthy subjects and HCC patients (P=0.0347). Meanwhile, the CT haplotype of the rs2285681/rs2285682 haplotype block was associated with significant differences between CHB+LC and HCC patients (P=0.0123). In MDR analysis, the combination of TWIST1rs2285681, ZEB2rs3806475, SNAIL1rs4647958 exhibited the most significant association with CHB+LC and Health control in the three-locus model. Our results suggest significant single-gene associations and environment-gene/gene-gene interactions of EMT-related genes with HBV-related HCC.
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Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the US. Metallothionein (MT) expression attenuates APAP-induced liver injury. However, the mechanism of this protection remains incompletely understood. To address this issue, C57BL/6 mice were treated with 100 micromol/kg ZnCl2 for 3 days to induce MT. Twenty-four hours after the last dose of zinc, the animals received 300 mg/kg APAP. Liver injury (plasma ALT activities, area of necrosis), DNA fragmentation, peroxynitrite formation (nitrotyrosine staining), MT expression, hepatic glutathione (GSH), and glutathione disulfide (GSSG) levels were determined after 6 h. APAP alone caused severe liver injury with oxidant stress (increased GSSG levels), peroxynitrite formation, and DNA fragmentation, all of which were attenuated by zinc-induced MT expression. In contrast, MT knockout mice were not protected by zinc. Hydrogen peroxide-induced cell injury in primary hepatocytes was dependent only on the intracellular GSH levels but not on MT expression. Thus, the protective effect of MT in vivo was not due to the direct scavenging of reactive oxygen species. Zinc treatment had no effect on the early GSH depletion kinetics after APAP administration, which is an indicator of the metabolic activation of APAP to its reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). However, MT was able to effectively trap NAPQI by covalent binding. We conclude that MT scavenges some of the excess NAPQI after GSH depletion and prevents covalent binding to cellular proteins, which is the trigger for the propagation of the cell injury mechanisms through mitochondrial dysfunction and nuclear DNA damage.
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Acetaminofén/toxicidad , Hígado/efectos de los fármacos , Metalotioneína/farmacología , Animales , Western Blotting , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
AIM: to study whether activation of TLR9 by CpG-ODN would protect against and/or reverse renal fibrosis. METHODS: animals were treated with CpG-ODN before or after undergoing a unilateral ureteral obstruction (UUO) procedure. The interstitial fibrotic lesions of obstructed kidneys were evaluated using histology and immunohistostaining. The Th2-type cytokine profile and the expression and activity of sma and mad related protein (Smad)3, signal transducers and activators of transcription (Stat)3, extracellular regulated protein kinases (ERK), and p38 kinase were determined using RT-PCR or Western blot. RESULTS: the obstructed kidneys displayed a significant increase in interstitial fibrosis, an infiltration of macrophages in the interstitium, and an enhanced expression of Th2 cytokines. Prophylactic application of CpG-ODN (40 microg/kg every 3 days from 2 h before UUO until the 14th day after UUO) suppressed the expression of α-smooth muscle actin, collagen deposition, and hydroxyproline in the UUO kidneys of rats. Moreover, CpG-ODN not only decreased the infiltration of macrophages but also inhibited the expression of chemokines CCL2 and CCL5, the Th2 cytokine IL-13, and the profibrogenic cytokines transforming growth factor (TGF)-ß1 and plasminogen activator inhibitor (PAI)-1 in UUO kidneys of rats. Importantly, therapeutic administration of CpG-ODN (10 microg/mouse, ip, every 3 days from the 4th day to 21st day after UUO) reversed the established renal fibrosis, which was accompanied by significant reductions in the activity of ERK, Smad3, and Stat3 and an increase in the activity of p38 kinase. CONCLUSION: the activation of TLR9 by CpG-ODN attenuates UUO-induced renal fibrosis by reversing an immunosuppressive microenvironment in the fibrotic renal tissue, which might be a novel therapeutic strategy against fibrotic renal diseases.
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Riñón/patología , Oligodesoxirribonucleótidos/uso terapéutico , Receptor Toll-Like 9/agonistas , Obstrucción Ureteral/patología , Actinas/metabolismo , Animales , Colágeno/metabolismo , Fibrosis , Interleucina-13/metabolismo , Riñón/metabolismo , Túbulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidor 1 de Activador Plasminogénico/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta1/metabolismo , Obstrucción Ureteral/metabolismoRESUMEN
Previous studies have reported that genome-wide DNA methylation and differentially expressed genes and proteins are closely associated with drug resistance in Mycobacterium tuberculosis (M. tuberculosis). However, no reports have explored such associations in para-aminosalicylic acid (PAS)-resistant M. tuberculosis H37Rv. Here, we investigated genome-wide methylation and transcriptome and proteome changes to explore the associations between specific genes and PAS resistance in M. tuberculosis H37Rv. The results revealed that 1,388 differentially methylated (1,161 hypermethylated and 227 hypomethylated) genes, 214 significantly differentially expressed (103 up- and 111 down-regulated) genes and 137 differentially expressed (48 up- and 89 down-regulated) proteins were regulated by PAS in M. tuberculosis H37Rv. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that metabolic pathways and ABC transporters were closely associated with differentially methylated and expressed genes, respectively. In addition, correlation analysis revealed that differentially methylated genes were negatively correlated with their transcriptional levels in PAS-resistant M. tuberculosis H37Rv. Furthermore, the existence of five hypermethylated candidate genes (esxC, fabG3, fbpB, papA1 and pks2) in PAS-resistant M. tuberculosis H37Rv was verified using protein-protein interaction analysis in the STRING database. The integrated DNA methylation and transcriptome and proteome analysis could provide valuable resources for epigenetics studies in PAS-resistant M. tuberculosis H37Rv.
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Ácido Aminosalicílico/metabolismo , Proteínas Bacterianas/genética , Metilación de ADN , Mycobacterium tuberculosis/genética , Proteínas Bacterianas/metabolismo , Bases de Datos de Proteínas , Farmacorresistencia Bacteriana , Regulación de la Expresión Génica , Genes Bacterianos , Mapeo de Interacción de Proteínas , Proteoma , Transducción de Señal , TranscriptomaRESUMEN
Acne vulgaris is a chronic inflammatory dermatosis affecting approximately 85% of adolescents. There are many factors contributing to the development of this ailment. A recent study indicated that gut microbiota takes part in the pathogenesis of acne. We aimed to investigate the link between acne vulgaris and gut microbiota. A total of 31 moderate to severe acne vulgaris patients and 31 healthy controls were enrolled. We collected their feces, and gut microbiota was evaluated by the hypervariable regions of 16S rRNA genes through high-throughput sequencing. We identified links between acne vulgaris and changes of gut microbiota. At the phylum level, Actinobacteria (0.89% in acne patients and 2.84% in normal controls, P = 0.004) was decreased and Proteobacteria (8.35% in acne patients and 7.01% in normal controls, P = 0.031) was increased. At the genus level, Bifidobacterium, Butyricicoccus, Coprobacillus, Lactobacillus and Allobaculum were all decreased. The observed difference in genera between acne patients and healthy controls provides a new insight into the link between gut microbiota changes and acne vulgaris risk.
Asunto(s)
Acné Vulgar/microbiología , Bacterias/genética , Disbiosis/microbiología , Microbioma Gastrointestinal/genética , Acné Vulgar/diagnóstico , Adolescente , Adulto , Bacterias/aislamiento & purificación , Estudios de Casos y Controles , ADN Bacteriano/aislamiento & purificación , Disbiosis/diagnóstico , Heces/microbiología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , ARN Bacteriano/genética , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
The mechanism of the Ni0 -catalyzed reductive carboxylation reaction of C(sp2 )-O and C(sp3 )-O bonds in aromatic esters with CO2 to access valuable carboxylic acids was comprehensively studied by using DFT calculations. Computational results revealed that this transformation was composed of several key steps: C-O bond cleavage, reductive elimination, and/or CO2 insertion. Of these steps, C-O bond cleavage was found to be rate-determining, and it occurred through either oxidative addition to form a NiII intermediate, or a radical pathway that involved a bimetallic species to generate two NiI species through homolytic dissociation of the C-O bond. DFT calculations revealed that the oxidative addition step was preferred in the reductive carboxylation reactions of C(sp2 )-O and C(sp3 )-O bonds in substrates with extended πâ systems. In contrast, oxidative addition was highly disfavored when traceless directing groups were involved in the reductive coupling of substrates without extended πâ systems. In such cases, the presence of traceless directing groups allowed for docking of a second Ni0 catalyst, and the reactions proceed through a bimetallic radical pathway, rather than through concerted oxidative addition, to afford two NiI species both kinetically and thermodynamically. These theoretical mechanistic insights into the reductive carboxylation reactions of C-O bonds were also employed to investigate several experimentally observed phenomena, including ligand-dependent reactivity and site-selectivity.
RESUMEN
Density functional theory calculations were performed in order to reveal the mysterious catalytic step of the biosynthesis of estrogens. The results indicated two reactive oxidants, ferric-peroxo and ferryl-oxo (compound I) species, to participate in the conversion of androgens to estrogens. The ferric-peroxo species was determined, according to our derived mechanism, to act in the oxidation of 19-OH androgen to yield the 19,19-gem-diol intermediate and generate the ferryl-oxo (compound I) species. This species was then modeled to effect, in the final step, an abstraction of H from an O-H group of 19,19-gem-diol to give the experimentally observed products. We considered our new mechanistic scenario to reasonably explain the latest experimental observations and to provide deep insight complementing the newly accepted compound I (Cpd I) mechanism.