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Organic acid metabolites exhibit acidic properties. These metabolites serve as intermediates in major carbon metabolic pathways and are involved in several biochemical pathways, including the tricarboxylic acid (TCA) cycle and glycolysis. They also regulate cellular activity and play crucial roles in epigenetics, tumorigenesis, and cellular signal transduction. Knowledge of the binding proteins of organic acid metabolites is crucial for understanding their biological functions. However, identifying the binding proteins of these metabolites has long been a challenging task owing to the transient and weak nature of their interactions. Moreover, traditional methods are unsuitable for the structural modification of the ligands of organic acid metabolites because these metabolites have simple and similar structures. Even minor structural modifications can significantly affect protein interactions. Thermal proteome profiling (TPP) provides a promising avenue for identifying binding proteins without the need for structural modifications. This approach has been successfully applied to the identification of the binding proteins of several metabolites. In this study, we investigated the binding proteins of two TCA cycle intermediates, i.e., succinate and fumarate, and lactate, an end-product of glycolysis, using the matrix thermal shift assay (mTSA) technique. This technique involves combining single-temperature (52 â) TPP and dose-response curve analysis to identify ligand-binding proteins with high levels of confidence and determine the binding affinity between ligands and proteins. To this end, HeLa cells were lysed, followed by protein desalting to remove endogenous metabolites from the cell lysates. The desalted cell lysates were treated with fumarate or succinate at final concentrations of 0.004, 0.04, 0.4, and 2 mmol/L in the experimental groups or 2 mmol/L sodium chloride in the control group. Considering that the cellular concentration of lactate can be as high as 2-30 mmol/L, we then applied lactate at final concentrations of 0.2, 1, 5, 10, and 25 mmol/L in the experimental groups or 25 mmol/L sodium chloride in the control group. Using high-sensitivity mass spectrometry coupled with data-independent acquisition (DIA) quantification, we quantified 5870, 5744, and 5816 proteins in succinate, fumarate, and lactate mTSA experiments, respectively. By setting stringent cut-off values (i.e., significance of changes in protein thermal stability (p-value)<0.001 and quality of the dose-response curve fitting (square of Pearson's correlation coefficient, R2)>0.95), multiple binding proteins for these organic acid metabolites from background proteins were confidently determined. Several known binding proteins were identified, notably fumarate hydratase (FH) as a binding protein for fumarate, and α-ketoglutarate-dependent dioxygenase (FTO) as a binding protein for both fumarate and succinate. Additionally, the affinity data for the interactions between these metabolites and their binding proteins were obtained, which closely matched those reported in the literature. Interestingly, ornithine aminotransferase (OAT), which is involved in amino acid biosynthesis, and 3-mercaptopyruvate sulfurtransferase (MPST), which acts as an antioxidant in cells, were identified as lactate-binding proteins. Subsequently, an orthogonal assay technique developed in our laboratory, the solvent-induced precipitation (SIP) technique, was used to validate the mTSA results. SIP identified OAT as the top target candidate, validating the mTSA-based finding that OAT is a novel lactate-binding protein. Although MPST was not identified as a lactate-binding protein by SIP, statistical analysis of MPST in the mTSA experiments with 10 or 25 mmol/L lactate revealed that MPST is a lactate-binding protein with a high level of confidence. Peptide-level empirical Bayes t-tests combined with Fisher's exact test also supported the conclusion that MPST is a lactate-binding protein. Lactate is structurally similar to pyruvate, the known binding protein of MPST. Therefore, assuming that lactate could potentially occupy the binding site of pyruvate on MPST. Overall, the novel binding proteins identified for lactate suggest their potential involvement in amino acid synthesis and redox balance regulation.
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Ciclo del Ácido Cítrico , Humanos , Células HeLa , Ácido Succínico/metabolismo , Ácido Succínico/química , Fumaratos/metabolismo , Fumaratos/químicaRESUMEN
BACKGROUND: Statins are widely used for treating patients with ischemic stroke at risk of secondary cerebrovascular events. It is unknown whether Asian populations benefit from more intensive statin-based therapy for stroke recurrence. Therefore, in the present study we evaluated the effectiveness and safety of high-dose and moderate-dose statins for patients who had experienced mild ischemic stroke during the acute period. METHODS AND RESULTS: This multicenter prospective study included patients with mild ischemic stroke who presented within 72 hours of symptom onset. The outcomes of patients in the high-intensity and moderate-intensity statin treatment groups were compared, with the main efficacy outcome being stroke recurrence and the primary safety end point being intracranial hemorrhage. The propensity score matching method was employed to control for imbalances in baseline variables. Subgroup analyses were conducted to evaluate group differences. In total, the data of 2950 patients were analyzed at 3 months, and the data of 2764 patients were analyzed at 12 months due to loss to follow-up. According to the multivariable Cox analyses adjusted for potential confounders, stroke recurrence occurred similarly in the high-intensity statin and moderate-intensity statin groups (3 months: adjusted hazard ratio [HR], 1.12 [95% CI, 0.85-1.49]; P=0.424; 12 months: adjusted HR, 1.08 [95% CI, 0.86-1.34]; P=0.519). High-intensity statin therapy was associated with an increased risk of intracranial hemorrhage (3 months: adjusted HR, 1.81 [95% CI, 1.00-3.25]; P=0.048; 12 months: adjusted HR, 1.86 [95% CI, 1.10-3.16]; P=0.021). The results from the propensity score-matched analyses were consistent with those from the Cox proportional hazards analysis. CONCLUSIONS: Compared with moderate-intensity statin therapy, high-dose statin therapy may not decrease the risk of mild, noncardiogenic ischemic stroke recurrence but may increase the risk of intracranial hemorrhage. REGISTRATION: URL: www.chictr.org.cn/. Unique Identifier: ChiCTR1900025214.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Accidente Cerebrovascular Isquémico , Recurrencia , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Femenino , Masculino , Estudios Prospectivos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/diagnóstico , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Factores de Tiempo , Factores de Riesgo , Puntaje de Propensión , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/epidemiología , Índice de Severidad de la Enfermedad , Prevención Secundaria/métodosRESUMEN
OBJECTIVES: Recent studies have suggested that neuroinflammation may play a role in the progression of spinal muscular atrophy (SMA), and this may influence the efficacy of antisense oligonucleotide treatment. This study explored the biomarkers associated with SMA and the efficacy of nusinersen therapy. METHODS: Fifteen patients with SMA were enrolled and their motor function (World Health Organization motor milestone, Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb Module [RULM] scores, and 6-minute walking test) was evaluated before, during (63 days), and after (6 months) nusinersen treatment. The concentrations of monocyte chemoactive protein 1 (MCP1), tumour necrosis factor-alpha (TNF-α), and interleukin (IL)-10 in the cerebrospinal fluid were measured at the indicated time points, and their correlations with motor function were analysed. RESULTS: A significant increase in MCP1 was observed after 6 month's treatment compared with that before treatment, while TNF-α gradually decreased over the course of treatment. IL-10 levels were negatively correlated with HFMSE scores before treatment, and reductions in IL-10 levels were correlated with improvements in RULM scores. CONCLUSIONS: This study suggests that neuroinflammation may be associated with the severity of SMA and with the therapeutic effects of nusinersen, which could have clinical implications in the treatment of SMA.
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Citocinas , Oligonucleótidos , Humanos , Masculino , Femenino , Oligonucleótidos/uso terapéutico , Citocinas/líquido cefalorraquídeo , Preescolar , Pronóstico , Biomarcadores/líquido cefalorraquídeo , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/líquido cefalorraquídeo , Lactante , Resultado del Tratamiento , Niño , Interleucina-10/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Quimiocina CCL2/líquido cefalorraquídeoRESUMEN
A novel mangrove soil-derived actinomycete, strain S2-29T, was found to be most closely related to Saccharopolyspora karakumensis 5K548T based on 16 S rRNA sequence (99.24% similarity) and genomic phylogenetic analyses. However, significant divergence in digital DNA-DNA hybridization, average nucleotide identity, and unique biosynthetic gene cluster possession distinguished S2-29T as a distinct Saccharopolyspora species. Pan genome evaluation revealed exceptional genomic flexibility in genus Saccharopolyspora, with > 95% accessory genome content. Strain S2-29T harbored 718 unique genes, largely implicated in energetic metabolisms, indicating different metabolic capacities from its close relatives. Several uncharacterized biosynthetic gene clusters in strain S2-29T highlighted the strain's untapped capacity to produce novel functional compounds with potential biotechnological applications. Designation as novel species Saccharopolyspora mangrovi sp. nov. (type strain S2-29T = JCM 34,548T = CGMCC 4.7716T) was warranted, expanding the known Saccharopolyspora diversity and ecology. The discovery of this mangrove-adapted strain advances understanding of the genus while highlighting an untapped source of chemical diversity.
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ADN Bacteriano , Genoma Bacteriano , Filogenia , ARN Ribosómico 16S , Saccharopolyspora , Microbiología del Suelo , Saccharopolyspora/genética , Saccharopolyspora/metabolismo , Saccharopolyspora/clasificación , ARN Ribosómico 16S/genética , ADN Bacteriano/genética , Familia de Multigenes , Genómica , Análisis de Secuencia de ADN , Humedales , Hibridación de Ácido Nucleico , Técnicas de Tipificación BacterianaRESUMEN
Snake venoms, comprising a complex array of protein-rich components, an important part of which are snake venom metalloproteinases (SVMPs). These SVMPs, which are predominantly isolated from viperid venoms, are integral to the pathology of snakebites. However, SVMPs derived from elapid venoms have not been extensively explored, and only a handful of SVMPs have been characterized to date. Atrase A, a nonhemorrhagic P-III class metalloproteinase from Naja atra venom, exhibits weak proteolytic activity against fibrinogen in vitro but has pronounced anticoagulant effects in vivo. This contrast spurred investigations into its anticoagulant mechanisms. Research findings indicate that atrase A notably extends the activated partial thromboplastin time, diminishes fibrinogen levels, and impedes platelet aggregation. The anticoagulant action of atrase A primarily involves inhibiting coagulation factor VIII and activating the endogenous fibrinolytic system, which in turn lowers fibrinogen levels. Additionally, its effect on platelet aggregation further contributes to its anticoagulant profile. This study unveils a novel anticoagulant mechanism of atrase A, significantly enriching the understanding of the roles of cobra venom metalloproteinases in snake venom. Furthermore, these findings underscore the potential of atrase A as a novel anticoagulant drug, offering insights into the functional evolutions of cobra venom metalloproteinases.
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The placenta plays a crucial role in maintaining normal pregnancy. The failure of spiral artery remodeling (SAR) is a key factor leading to placental ischemia and poor perfusion which is strongly associated with obstetric diseases, including preeclampsia (PE) and fetal growth restriction (FGR). Existing interventions for PE and FGR are limited and termination of pregnancy is inevitable when the maternal or fetus condition deteriorates. Considering the safety of the mother and fetus, treatments that may penetrate the placental barrier and harm the fetus are not accepted. Developing targeted treatment strategies for these conditions is urgent and necessary. With the proven efficacy of targeted therapy in treating conditions such as endometrial cancer and trophoblastic tumors, research on placental dysfunction continues to deepen. This article reviews the studies on placenta-targeted treatment and drug delivery strategies, summarizes the characteristics proposes corresponding improvement measures in targeted treatment, provides solutions for existing problems, and makes suggestions for future studies.
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Retardo del Crecimiento Fetal , Placenta , Preeclampsia , Humanos , Embarazo , Retardo del Crecimiento Fetal/tratamiento farmacológico , Preeclampsia/tratamiento farmacológico , Femenino , Placenta/metabolismo , Sistemas de Liberación de Medicamentos/métodosRESUMEN
The Osiris gene family is believed to play important roles in insect biology. Previous studies mainly focused on the roles of Osiris in Drorophila, how Osiris operates during the development of other species remains largely unknown. Here, we investigated the role of LmOsi17 in development of the hemimetabolous insect Locusta migratoria. LmOsi17 was highly expressed in the intestinal tract of nymphs. Knockdown of LmOsi17 by RNA interference (RNAi) in nymphs resulted in growth defects. The dsLmOsi17-injected nymphs did not increase in body weight or size and eventually died. Immunohistochemical analysis showed that LmOsi17 was localized to the epithelial cells of the foregut and the gastric caecum. Histological observation and hematoxylin-eosin staining indicate that the foregut and gastric caecum are deformed in dsLmOsi17 treated nymphs, suggesting that LmOsi17 is involved in morphogenesis of foregut and gastric caecum. In addition, we observed a significant reduction in the thickness of the new cuticle in dsLmOsi17-injected nymphs compared to control nymphs. Taken together, these results suggest that LmOsi17 contributes to morphogenesis of intestinal tract that affects growth and development of nymphs in locusts.
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Proteínas de Insectos , Locusta migratoria , Morfogénesis , Ninfa , Animales , Locusta migratoria/crecimiento & desarrollo , Locusta migratoria/genética , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Ninfa/crecimiento & desarrollo , Interferencia de ARN , IntestinosRESUMEN
Background: In thyroid cancers, a reduction in the expression of the sodium/iodide symporter (NIS) is observed concomitant with a diminution in cancer cell differentiation. The ß-catenin/LEF-1 pathway emerges as a crucial regulatory pathway influencing the functional expression of NIS in human thyroid cancer cells. Further research is required to comprehensively elucidate the role of NIS overexpression in impeding the progression of thyroid cancer cells. Methods: Human papillary thyroid carcinoma (PTC) cell lines, specifically PTC-1 and KTC-1, were subjected to Scratch and Transwell assays, colony formation, and tumor sphere formation tests to investigate invasion and migration, focusing on the impact of NIS overexpression. The assessment involved the use of western blot to analyze the expression levels of ß-catenin, NIS, CD133, SRY-related HMG box2 (Sox2), lymphoid enhancer-binding factor 1 (LEF-1), NANOG, octamer-binding transcription factor 4 (Oct4), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), and epithelial cellular adhesion molecule (EpCAM). Statistical analysis was conducted using SPSS version 20.0, and the graphs were developed using GraphPad Prism 7 (GraphPad Software, Inc.). Results: Our observations revealed that Nthy-ori-3-1 cell lines exhibited notably higher average expression levels of NIS, yet significantly lower levels of LEF-1 and ß-catenin compared to PTC-1 and KTC-1 cell lines. Furthermore, the overexpression of ß-catenin resulted in reduced binding of LEF-1 to NIF promotion but concurrently increased the expression of NIS. The downregulation of NIS markedly enhanced the expression of ALDH1A1, CD133, OCT4, Nanog, SOX2, and EpCam-all of which are targets within the Wnt/ß-catenin signaling pathway. Conversely, the upregulation of NIS suppressed the expression of these proteins. Moreover, cells treated with ß-catenin activators demonstrated an increased capability to form more spheroids and displayed heightened aggressiveness. Conversely, the NIS overexpression (OE) group exhibited suppressed abilities in invasion and colony formation. Conclusion: Thyroid cancer cells exhibit diminished expression of NIS, and the invasion and maintenance of stem cells in thyroid cancer cells were hindered by NIS OE through the inhibition of the ß-catenin/LEF-1 pathway. Further research is warranted to comprehensively assess this outcome, which holds promise as a potential targeted treatment for thyroid cancer.
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Environmental issues caused by waste polyethylene are becoming increasingly severe. Among potential treatment processes, microwave-assisted catalytic pyrolysis is promising for converting waste plastics into valuable products owing to its energy efficiency and environmental sustainability. Herein, a modified citric acid combustion method was used to prepare a series of metal oxide catalysts with loose porous structures. The prepared Fe-based catalysts doped with Co, Ni, or Cu were employed in the microwave-assisted catalytic pyrolysis of polyethylene. The bimetallic Co1Fe1Ox catalyst exhibited the best performance, yielding hydrogen at a rate of 60.7â mmol/gplastic. Further variation in the Co : Fe ratio revealed that the Co1Fe9Ox catalyst achieved the highest hydrogen production efficiency (63.64â mmol/gplastic). Similar oil-phase products were obtained over the various catalysts, as revealed by infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Furthermore, scanning electron microscopy (SEM) identified carbon nanotubes as the major solid product of pyrolysis, which were attached to the catalyst surface. Finally, a combination of thermogravimetric analysis, SEM, and energy-dispersive X-ray spectroscopy indicated that the reduction in catalytic activity following recycling was caused by the accumulation of carbonaceous products on the catalyst surface. Overall, Co1Fe9Ox catalysts were favorable for obtaining H2 and carbon nanotubes by the microwave-assisted pyrolysis of polyethylene.
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Objective: To explore the effect of chitosan (CS) hydrogel loaded with tendon-derived stem cells (TDSCs; hereinafter referred to as TDSCs/CS hydrogel) on tendon-to-bone healing after rotator cuff repair in rabbits. Methods: TDSCs were isolated from the rotator cuff tissue of 3 adult New Zealand white rabbits by Henderson step-by-step enzymatic digestion method and identified by multidirectional differentiation and flow cytometry. The 3rd generation TDSCs were encapsulated in CS to construct TDSCs/CS hydrogel. The cell counting kit 8 (CCK-8) assay was used to detect the proliferation of TDSCs in the hydrogel after 1-5 days of culture in vitro, and cell compatibility of TDSCs/CS hydrogel was evaluated by using TDSCs alone as control. Another 36 adult New Zealand white rabbits were randomly divided into 3 groups ( n=12): rotator cuff repair group (control group), rotator cuff repair+CS hydrogel injection group (CS group), and rotator cuff repair+TDSCs/CS hydrogel injection group (TDSCs/CS group). After establishing the rotator cuff repair models, the corresponding hydrogel was injected into the tendon-to-bone interface in the CS group and TDSCs/CS group, and no other treatment was performed in the control group. The general condition of the animals was observed after operation. At 4 and 8 weeks, real-time quantitative PCR (qPCR) was used to detect the relative expressions of tendon forming related genes (tenomodulin, scleraxis), chondrogenesis related genes (aggrecan, sex determining region Y-related high mobility group-box gene 9), and osteogenesis related genes (alkaline phosphatase, Runt-related transcription factor 2) at the tendon-to-bone interface. At 8 weeks, HE and Masson staining were used to observe the histological changes, and the biomechanical test was used to evaluate the ultimate load and the failure site of the repaired rotator cuff to evaluate the tendon-to-bone healing and biomechanical properties. Results: CCK-8 assay showed that the CS hydrogel could promote the proliferation of TDSCs ( P<0.05). qPCR results showed that the expressions of tendon-to-bone interface related genes were significantly higher in the TDSCs/CS group than in the CS group and control group at 4 and 8 weeks after operation ( P<0.05). Moreover, the expressions of tendon-to-bone interface related genes at 8 weeks after operation were significantly higher than those at 4 weeks after operation in the TDSCs/CS group ( P<0.05). Histological staining showed the clear cartilage tissue and dense and orderly collagen formation at the tendon-to-bone interface in the TDSCs/CS group. The results of semi-quantitative analysis showed that compared with the control group, the number of cells, the proportion of collagen fiber orientation, and the histological score in the TDSCs/CS group increased, the vascularity decreased, showing significant differences ( P<0.05); compared with the CS group, the proportion of collagen fiber orientation and the histological score in the TDSCs/CS group significantly increased ( P<0.05), while there was no significant difference in the number of cells and vascularity ( P>0.05). All samples in biomechanical testing failed at the repair site during the testing process. The ultimate load of the TDSCs/CS group was significantly higher than that of the control group ( P<0.05), but there was no significant difference compared to the CS group ( P>0.05). Conclusion: TDSCs/CS hydrogel can induce cartilage regeneration to promote rotator cuff tendon-to-bone healing.
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Quitosano , Lesiones del Manguito de los Rotadores , Conejos , Animales , Manguito de los Rotadores/cirugía , Hidrogeles , Lesiones del Manguito de los Rotadores/cirugía , Cicatrización de Heridas , Tendones/cirugía , Colágeno , Células Madre , Fenómenos BiomecánicosRESUMEN
Rocaglaol, embedding a cyclopenta[b]benzofuran scaffold, was isolated mainly from the plants of Aglaia and exhibited nanomolar level antitumor activity. However, the drug-like properties of these compounds are poor. To improve the physicochemical properties of rocaglaol, 36 nitrogen-containing phenyl-substituted rocaglaol derivatives were designed and synthesized. These derivatives were tested for the inhibitory effects on three tumor cell lines, HEL, MDA-231, and SW480, using the MTT assay. Among them, 22 derivatives exhibited good cytotoxic activities with IC50 values between 0.11 ± 0.07 and 0.88 ± 0.02 µM. Fourteen derivatives exhibited stronger cytotoxicity than the positive control, adriamycin. In particular, a water-soluble derivative revealed selective cytotoxic effects on HEL cells (IC50 = 0.19 ± 0.01 µM). This compound could induce G1 cell cycle arrest and apoptosis in HEL cells. Western blot assays suggested that the water-soluble derivative could downregulate the expression of the marker proteins of apoptosis, PARP, caspase-3, and caspase-9, thus inducing apoptosis. Further CETSA and Western blot studies implied that this water-soluble derivative might be an inhibitor of friend leukemia integration 1 (Fli-1). This water-soluble derivative may serve as a potential antileukemia agent by suppressing the expression of Fli-1.
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Antineoplásicos , Benzofuranos , Antineoplásicos/farmacología , Apoptosis , Doxorrubicina , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
OBJECTIVES: To observe the effect of electroacupuncture (EA) on nuclear transcription factor E2 related factor 2 (Nrf2)/NOD-like receptor family pyrin domain-containing protein 3 (NLRP3)/cysteine aspartic acid specific protease-1 (Caspase-1) pathway in the substantia nigra (SN) of mice with Parkinson's disease (PD), so as to explore the neuroprotective mechanism of EA. METHODS: Forty C57BL/6 male mice were randomly divided into 4 groups, namely, control, PD model, EA and sham-EA groups, with 10 mice in each group. The PD mouse model was established by gavage of rotenone for 4 weeks. Mice in the EA group were given EA stimulation (1 mA, 2 Hz) at "Fengfu" (GV36), bilateral "Taichong" (LR3) and "Zusanli" (ST36) for 30 min, once daily for 2 consecutive weeks. And mice in the sham-EA group were given acupuncture at the subcutaneous areas of the same acupoints without EA stimulation. The open-field test was used for assessment of mouse behavior. The levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in the serum were detected by enzyme-linked immunosorbent assay . The positive expression of tyrosine hydroxylase (TH) in SN was determined by immunohistochemistry. The mRNA expression levels of Nrf2, NLRP3, Caspase-1, gasdermin D(GSDMD), IL-1ß, IL-18 and the protein expression levels of Nrf2, NLRP3, Caspase-1 and GSDMD in the SN were detected by quantitative real-time PCR and Western blot, separately. RESULTS: After modeling, compared with the control group, the behavioral score was increased (P<0.01), the total exercise time, the total distance and the average speed were decreased (P<0.01), and the positive expression of TH and the mRNA and protein expression levels of Nrf2 in the SN were decreased (P<0.01), while the contents of IL-1ß and IL-18 in serum, the mRNA and protein expression levels of NLRP3, Caspase-1 and GSDMD and the mRNA expression levels of IL-1ß and IL-18 in the SN were up-regulated (P<0.01) in the PD model group. Following EA intervention, the behavioral score was decreased(P<0.01), the total exercise time, total distance and average speed were increased (P<0.01), the positive expression of TH and the mRNA and protein expressions of Nrf2 in SN were up-regulated (P<0.01, P<0.05), while the contents of IL-1ß and IL-18 in serum, the mRNA and protein expression levels of NLRP3, Caspase-1 and GSDMD as well as the mRNA expression levels of IL-1ß and IL-18 in the SN were down-regulated (P<0.01, P<0.05) in the EA group relative to the PD model and sham-EA groups. There were no significant differences in the above indicators between the PD model and sham-EA groups. CONCLUSIONS: EA stimulation of GV36, LR3 and ST36 can improve motor deficits, reduce the loss of dopamine neurons in the SN, and inhibit neuroinflammatory responses in mice with PD, which may be related to its effects in regulating the Nrf2/NLRP3/Caspase-1 pathway mediated pyroptosis.
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Electroacupuntura , Enfermedad de Parkinson , Ratones , Masculino , Animales , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Interleucina-18 , Factor 2 Relacionado con NF-E2/genética , Caspasa 1/genética , Piroptosis , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Ratones Endogámicos C57BL , Interleucina-1beta/genética , ARN MensajeroRESUMEN
Newcastle disease (ND) and infectious bursal disease (IBD) are two viral infectious diseases that are extremely damaging to the poultry industry and are widespread throughout the world. It is necessary to develop a safe and effective vaccine against IBD and ND because vaccination is an effective preventive measure. It has been discovered that recombinant proteins expressed by an expression system in which a fragment of mammalian Immunoglobulin G (IgG) Fragment crystallizable (Fc) is linked to a segment of a gene have antibody-like properties that increase the exogenous protein's serum half-life. Heavy chain constant region 3 and heavy chain constant region 4 (CH3-CH4) of Avian Immunoglobulin Y (IgY) is structurally very similar to mammalian Ig G Fc. In this study, a bivalent vaccine rClone30-VP2L-CH3-CH4-GMCSF was developed by using NDV rClone30-chGM-CSF vector to produce VP2L-CH3-CH4 fusion protein. The vaccine has been given to 14-day-old specific pathogen free (SPF) free chickens to test whether it has the potential to prevent IBD and ND. Anti-IBDV and anti-NDV antibody levels in serum were evaluated using ELISA and HI, respectively, and the contents of CD4+ T, CD8+ T, and B cells in leukocytes were determined via flow cytometry. The contents and mRNA transcription levels of four inflammatory factors, IL-1ß, IL-4, IFN-γ and chGM-CSF, were detected by ELISA and real-time PCR respectively. The results showed that after vaccination with the rClone30-VP2L-CH3-CH4-GMCSF vaccine, the levels of anti NDV and anti IBDV antibodies in chickens were significantly higher than those of the rClone30 vaccine and commercial vaccines. Meanwhile, the contents and transcription levels of inflammatory factors in chickens inoculated with rClone30-VP2L-CH3-CH4-GMCSF were significantly increased, and the proliferation response of B cells, CD4+ and CD8+ T cells was also stronger. However, the rClone30-VP2L-CH3-CH4-GMCSF vaccine had no significant advantage over the rClone30-VP2L-GMCSF vaccine in any of the above-mentioned features. In summary, rClone30-VP2L-CH3-CH4-GMCSF can stimulate the body to produce a stronger immune response, showing its potential to be considered as vaccine against IBD and ND, but the addition of CH3-CH4 did not improve the vaccine's immune effect as expected. The research lays the foundation for developing vaccines for other infectious viral diseases and avoids a unrealistic vaccine optimization method.
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Infecciones por Birnaviridae , Virus de la Enfermedad Infecciosa de la Bolsa , Enfermedad de Newcastle , Enfermedades de las Aves de Corral , Vacunas Virales , Animales , Pollos , Virus de la Enfermedad de Newcastle/genética , Vacunas Combinadas , Organismos Libres de Patógenos Específicos , Linfocitos T CD8-positivos , Anticuerpos Antivirales , Enfermedad de Newcastle/prevención & control , Infecciones por Birnaviridae/prevención & control , Infecciones por Birnaviridae/veterinaria , MamíferosRESUMEN
Physalis angulata Linn. is an exotic Amazonian fruit that is commonly recognized as wild tomato, winter cherry, and gooseberry. While its fruit is known to contain many nutrients, such as minerals, fibers, and vitamins, few papers have investigated withanolide derivatives from its fruits. UPLC-Q-Orbitrap-MS/MS, which produces fragmentation spectra, was applied for the first time to guide the isolation of bioactive withanolide derivatives from P. angulata fruits. As a result, twenty-six withanolide derivatives, including two novel 1,10-secowithanolides (1 and 2) and a new derivative (3), were obtained. Compounds 1 and 2 are rare rearranged 1,10-secowithanolides with a tetracyclic 7/6/6/5 ring system. All structures were assigned through various spectroscopic data and quantum chemical calculations. Nine withanolide derivatives exhibited significant inhibitory effects on three tumor cell lines with IC50 values of 0.51-13.79 µM. Moreover, three new compounds (1-3) exhibited potential nitric oxide inhibitory effects in lipopolysaccharide-stimulated RAW264.7 cells (IC50: 7.51-61.8 µM). This investigation indicated that fruits of P. angulata could be applied to treat and prevent cancer and inflammatory-related diseases due to their potent active withanolide derivatives.
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Physalis , Witanólidos , Physalis/química , Relación Estructura-Actividad , Witanólidos/farmacología , Witanólidos/química , Frutas , Espectrometría de Masas en Tándem , Extractos Vegetales/farmacología , Extractos Vegetales/químicaRESUMEN
OBJECTIVES: To observe the effects of electroacupuncture (EA) at "Fengfu" (GV16), "Taichong" (LR3) and "Zusanli" (ST36) on α-synuclein (α-syn), Occludin, Claudin-1, thioredoxin interaction protein (TXNIP) and Nod-like receptor 3 (NLRP3) in Parkinson's disease (PD) mice, so as to investigate the mechanisms of EA on intestinal barrier function and inflammation in PD mice. METHODS: Thirty six C57BL/6 mice were randomly divided into control, model and EA groups, with 12 mice in each group. PD mice model was induced by rotenone intragastric administration for 28 days. Mice in the EA group were treated with EA (2 Hz, 1 mA) at GV16, LR3 and ST36 for 30 min, once a day for 14 days. The behavioral scores were observed. The total distance of autonomic movement was measured by open field test. The expression level of α-syn in substantia nigra and colon tissue was determined by immunohistochemistry. The colonic morphology and goblet cell distribution were observed by Alcian blue staining. The expression levels of Occludin, Claudin-1, TXNIP and NLRP3 mRNA in colon tissue were detected by real-time fluorescence quantitative PCR. RESULTS: Compared with the control group, the behavioral scores of rats were increased (P<0.01)ï¼the total distance of autonomous movement was decreased (P<0.01)ï¼the positive expression level of α-syn in the substantia nigra and colon was increased (P<0.01)ï¼the goblet cells and crypts in colon tissue were reduced, and the muscular layer was thinnerï¼the expression levels of Occludin and Claudin-1 mRNAs in colon tissue were decreased (P<0.01) while TXNIP and NLRP3 mRNAs were increased (P<0.01) in the model group. Compared with the model group, the surface villi of colon tissue was more complete, the goblet cells and crypts were increased, and the muscular layer was thickenedï¼the other indexes were reversed (P<0.01, P<0.05) in the EA group. CONCLUSIONS: EA at GV16, LR3 and ST36 can reduce the abnormal accumulation of α-syn in the substania nigra and colon tissue of PD mice, alleviate the damage of intestinal barrier, regulate TXNIP/NLRP3 signaling pathway, so as to delay the occurrence and development of PD.
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Electroacupuntura , Enfermedad de Parkinson , Animales , Ratones , Ratas , Proteínas de Ciclo Celular/metabolismo , Claudina-1 , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Ocludina , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Ratas Sprague-Dawley , ARN Mensajero , Transducción de Señal , TiorredoxinasRESUMEN
BACKGROUND: Iterative decomposition of water and fat with echo asymmetry and least squares estimation quantification sequence (IDEAL-IQ) is based on chemical shift-based water and fat separation technique to get proton density fat fraction. Multiple studies have shown that using IDEAL-IQ to test the stability and repeatability of liver fat is acceptable and has high accuracy. AIM: To explore whether Gadoxetate Disodium (Gd-EOB-DTPA) interferes with the measurement of the hepatic fat content quantified with the IDEAL-IQ and to evaluate the robustness of this technique. METHODS: IDEAL-IQ was used to quantify the liver fat content at 3.0T in 65 patients injected with Gd-EOB-DTPA contrast. After injection, IDEAL-IQ was estimated four times, and the fat fraction (FF) and R2* were measured at the following time points: Pre-contrast, between the portal phase (70 s) and the late phase (180 s), the delayed phase (5 min) and the hepatobiliary phase (20 min). One-way repeated-measures analysis was conducted to evaluate the difference in the FFs between the four time points. Bland-Altman plots were adopted to assess the FF changes before and after injection of the contrast agent. P < 0.05 was considered statistically significant. RESULTS: The assessment of the FF at the four time points in the liver, spleen and spine showed no significant differences, and the measurements of hepatic FF yielded good consistency between T1 and T2 [95% confidence interval: -0.6768%, 0.6658%], T1 and T3 (-0.3900%, 0.3178%), and T1 and T4 (-0.3750%, 0.2825%). R2* of the liver, spleen and spine increased significantly after injection (P < 0.0001). CONCLUSION: Using the IDEAL-IQ sequence to measure the FF, we can obtain results that will not be affected by Gd-EOB-DTPA. The high reproducibility of the IDEAL-IQ sequence makes it available in the scanning interval to save time during multiphase examinations.
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All fluorescence white organic light-emitting diodes (WOLEDs) based on thermally activated delayed fluorescence (TADF) emitters are an attractive route to realize highly efficient and high color quality white light sources. However, harvesting triplet excitons in these devices remains a formidable challenge, particularly for WOLEDs involving conventional fluorescent emitters. Herein, we report a universal design strategy based on a co-host system and a cascaded exciton transfer configuration. The co-host system furnishes a broad and charge-balanced exciton generation zone, which simultaneously endows the devices with low efficiency roll-off and good color stability. A yellow TADF layer is put forward as an intermediate sensitizer layer between the blue TADF light-emitting layer (EML) and the red fluorescence EML, which not only constructs an efficient cascaded Förster energy transfer route but also blocks the triplet exciton loss channel through Dexter energy transfer. With the proposed design strategy, three-color all fluorescence WOLEDs reach a maximum external quantum efficiency (EQE) of 22.4% with a remarkable color rendering index (CRI) of 92 and CIE coordinates of (0.37, 0.40). Detailed optical simulation confirms the high exciton utilization efficiency. Finally, by introducing an efficient blue emitter 5Cz-TRZ, a maximum EQE of 30.1% is achieved with CIE coordinates of (0.42, 0.42) and a CRI of 84 at 1000 cd m-2. These outstanding results demonstrate the great potential of all fluorescence WOLEDs in solid-state lighting and display panels.
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Polymer composites with good thermal conductivity are gaining more and more attention in the current electronics sector, due to their superior heat management capabilities. However, conventional thermally conductive polymer composites are usually subject to interruptions in heat transfer because of physical damage. The present study prepared mechanical property-enhanced thermally-conductive self-healing composites through compositing a self-healing polyurethane matrix with hydroxylated boron nitride (hyBNNSs). The self-healing polyurethane was obtained by incorporating ligands and cerium(III) triflate [Ce(SO3CF3)3] as the metal center into the polyurethane elastomer. An optimal sample (PUp2C) with high tensile strength (6.8 MPa) and stretchability (1053%), ideal toughness (49.2 MJ m-3), and remarkable healing efficiency (97% healing after 48 h at 35 °C) was obtained. An increase in the content of hyBNNSs from 10% to 30% led to a significant increase in the mechanical performance of hyBNNSs20%/PUp2C, which manifested as the increase in the elongation at break (from 1053% to 1302.5%) and stress (from 6.8 MPa to 16.4 MPa). The XRD results revealed that combining PU with hyBNNSs through coordination bonds could significantly promote the crystallization of PUp2C, which was beneficial to enhancing the mechanical properties of the composites. The through-plane (λâ¥) and the in-plane (λâ¥) values of the BNNSs30%/PUp2C composite reached 0.41 and 1.42 W mK-1, respectively, which were 195.2% and 507.1% higher than those of the original PUp2C, respectively.
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Maize (Zea mays L.) is one of the world's staple food crops. In order to feed the growing world population, improving maize yield is a top priority for breeding programs. Ear traits are important determinants of maize yield, and are mostly quantitatively inherited. To date, many studies relating to the genetic and molecular dissection of ear traits have been performed; therefore, we explored the genetic loci of the ear traits that were previously discovered in the genome-wide association study (GWAS) and quantitative trait locus (QTL) mapping studies, and refined 153 QTL and 85 quantitative trait nucleotide (QTN) clusters. Next, we shortlisted 19 common intervals (CIs) that can be detected simultaneously by both QTL mapping and GWAS, and 40 CIs that have pleiotropic effects on ear traits. Further, we predicted the best possible candidate genes from 71 QTL and 25 QTN clusters that could be valuable for maize yield improvement.
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Sitios de Carácter Cuantitativo , Zea mays , Sitios de Carácter Cuantitativo/genética , Zea mays/genética , Estudio de Asociación del Genoma Completo , Fitomejoramiento , Mapeo CromosómicoRESUMEN
Developing economical, efficient, and durable oxygen evolution catalysts is crucial for achieving sustainable energy conversion and storage. Ruddlesden-Popper-type perovskite oxides are at the forefront of oxygen evolution reaction (OER) research. However, their activity and stability are far from satisfactory. Therefore, we emphasize the paradigm shift in designing efficient perovskite-type OER catalysts through anion defect engineering. The Cl anion-doped A2BO4-type perovskite oxides, SrLaCoO4-xClx (SLCOClx), were employed as highly efficient OER catalysts, wherein Cl could tune the electronic structure of SrLaCoO4 (SLCO) to enhance the OER activity effectively. Especially, SLCOCl0.15 demonstrates significantly enhanced OER activity, and the overpotential is only 370 mV at 10 mA·cm-2, which is significantly better than that of SLCO (510 mV). As confirmed by experience results and density functional theory (DFT) calculation, due to the doping of Cl, obviously increasing the ratio of Co2+/Co3+, more abundant oxygen vacancies (O22-/O-) are generated, and the electrical conductivity is increased, which together promote the improvement of OER activity.