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BACKGROUND: Surgical site infection (SSI) is a common complication of colorectal surgery. Minimally invasive surgery notably reduces the incidence of SSI. This study aimed to compare the incidences of SSI after robot-assisted colorectal surgery (RACS) vs that after laparoscopic assisted colorectal surgery (LACS) and to analyze associated risk factors for SSI in minimally invasive colorectal surgery. AIM: To compare the incidences of SSI after RACS and LACS, and to analyze the risk factors associated with SSI after minimally invasive colorectal surgery. METHODS: Clinical data derived from patients who underwent minimally invasive colorectal surgery between October 2020 and October 2022 at the First Affiliated Hospital of Soochow University were collated. Differences in clinical characteristics and surgeryrelated information associated with RACS and LACS were compared, and possible risk factors for SSI were identified. RESULTS: A total of 246 patients (112 LACS and 134 RACS) were included in the study. Fortythree (17.5%) developed SSI. The proportions of patients who developed SSI were similar in the two groups (17.9% vs 17.2%, P = 0.887). Diabetes mellitus, intraoperative blood loss ≥ 100 mL, and incision length were independent risk factors for SSI. Possible additional risk factors included neoadjuvant therapy, lesion site, and operation time. CONCLUSION: There was no difference in SSI incidence in the RACS and LACS groups. Diabetes mellitus, intraoperative blood loss ≥ 100 mL, and incision length were independent risk factors for postoperative SSI.
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A methanol-based economy offers an efficient solution to current energy transition challenges, where the zeolite-catalyzed methanol-to-hydrocarbons (MTH) process would be a key enabler in yielding synthetic fuels/chemicals from renewable sources. Despite its original discovery over half a century ago over the zeolite ZSM-5, the practical application of this process in a CO2 -neutral scenario has faced several obstacles. One prominent challenge has been the intricate mechanistic complexities inherent in the MTH process over the zeolite ZSM-5, impeding its widespread adoption. This work takes a significant step forward by providing critical insights that bridge the gap in our understanding of the MTH process. It accomplishes this by connecting the (Koch-carbonylation-led) direct and dual cycle mechanisms, which operate during the early and steady-state phases of MTH catalysis, respectively. To unravel these mechanistic intricacies, we have performed catalytic and operando (i.e., UV/Vis coupled with an online mass spectrometer) and solid-state NMR spectroscopic-based investigations on the MTH process, involving co-feeding methanol and acetone (cf. a key Koch-carbonylated species), including selective isotope-labeling studies. Our iterative research approach revealed that (Koch-)carbonyl group selectively promotes the side-chain mechanism within the arene cycle of the dual cycle mechanism, impacting the preferential formation of BTX fraction (i.e., benzene-toluene-xylene) primarily.
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Introducing sustainability into advanced catalytic material design is essential to address growing environmental concerns. Among them, synthesizing inorganic zeolite materials from non-traditional sources (like natural clay) offers several advantages, contributing to sustainability and environmental stewardship. With this objective, we used kaolin to synthesize zeolites with different topologies: SSZ-13 (8-MR with CHA topology), ZSM-5 (10-MR with MFI topology), and Beta (12-MR with BEA topology) (MR: member ring), where a simple and flexible synthetic protocol was adopted without any significant changes. All these zeolites were subjected to catalytic performance evaluation concerning the industrially relevant methanol-to-hydrocarbon (MTH) process. Herein, the kaolin-derived zeolites, especially ZSM-5, led to superior performance and demonstrated enhanced catalyst deactivation-resistant behavior compared to their zeolite counterparts prepared from traditional synthetic routes. Various characterization tools (including under operando conditions) were employed to understand their reactions and deactivation mechanisms. Overall, making zeolites from non-traditional sources presents a pathway for sustainable and environmentally friendly material production, offering benefits such as reduced resource dependence, lower energy consumption, and tailored physicochemical properties beneficial to catalysis. In a broader context, such a research approach contributes to the transition toward a more sustainable and circular economy.
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Misregulation of spermatogenesis transcription factors (TF) in hybrids can lead to misexpression, which is a mechanism for hybrid male sterility (HMS). We used dzo (male offspring of Bos taurus â × Bos grunniens â) in bovines to investigate the relationship of the key TF with HMS via RNA sequencing and assay for transposase-accessible chromatin with high-throughput sequencing analyses. RNA sequencing showed that the widespread misexpression in dzo was associated with spermatogenesis-related genes and somatic or progenitor genes. The transition from leptotene or zygotene spermatocytes to pachytene spermatocytes may be the key stage for meiosis arrest in dzo. The analysis of TF-binding motif enrichment revealed that the male meiosis-specific master TF MYB proto-oncogene like 1 (MYBL1, known as A-MYB) motif was enriched on the promoters of downregulated pachytene spermatocyte genes in dzo. Assay for transposase-accessible chromatin with high-throughput sequencing revealed that TF-binding sites for MYBL1, nuclear transcription factor Y, and regulatory factor X were enriched in the low-chromatin accessibility region of dzo. The target genes of the MYBL1-binding motif were associated with meiosis-specific genes and significantly downregulated in dzo testis. The transcription factor MYBL1 may be the candidate master regulator for pachytene spermatocyte genes dysregulated in interspecific HMS dzo. This study reported that a few upstream TF regulation changes might exert a cascading effect downstream in a regulatory network as a mechanism for HMS.
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Espermatócitos , Fatores de Transcrição , Bovinos , Masculino , Animais , Espermatócitos/fisiologia , Fatores de Transcrição/genética , Espermatogênese , Testículo , CromatinaRESUMO
Decarbonizing the transportation sector is among the biggest challenges in the fight against climate change. CO2 -neutral fuels, such as those obtained from renewable methanol, have the potential to account for a large share of the solution, since these could be directly compatible with existing power trains. Although discovered in 1977, the zeolite-catalyzed methanol-to-gasoline (MTG) process has hardly reached industrial maturity, among other reasons, because maximizing the production of gasoline range hydrocarbons from methanol has proved complicated. In this work, we apply multimodal operando UV/Vis diffuse reflectance spectroscopy coupled with an online mass spectrometer and "mobility-dependent" solid-state NMR spectroscopy to better understand the reaction mechanism over zeolites H-Beta and Zn-Beta. Significantly, the influential co-catalytic role of oxymethylene species is linked to gasoline formation, which impacts the MTG process more than carbonylated species.
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Background: The ciliary muscle plays a role in changing the shape of the crystalline lens to maintain the clear retinal image during near work. Studying the dynamic changes of the ciliary muscle during accommodation is necessary for understanding the mechanism of presbyopia. Optical coherence tomography (OCT) has been frequently used to image the ciliary muscle and its changes during accommodation in vivo. However, the segmentation process is cumbersome and time-consuming due to the large image data sets and the impact of low imaging quality. Objectives: This study aimed to establish a fully automatic method for segmenting and quantifying the ciliary muscle on the basis of optical coherence tomography (OCT) images. Design: A perspective cross-sectional study. Methods: In this study, 3500 signed images were used to develop a deep learning system. A novel deep learning algorithm was created from the widely used U-net and a full-resolution residual network to realize automatic segmentation and quantification of the ciliary muscle. Finally, the algorithm-predicted results and manual annotation were compared. Results: For segmentation performed by the system, the total mean pixel value difference (PVD) was 1.12, and the Dice coefficient, intersection over union (IoU), and sensitivity values were 93.8%, 88.7%, and 93.9%, respectively. The performance of the system was comparable with that of experienced specialists. The system could also successfully segment ciliary muscle images and quantify ciliary muscle thickness changes during accommodation. Conclusion: We developed an automatic segmentation framework for the ciliary muscle that can be used to analyze the morphological parameters of the ciliary muscle and its dynamic changes during accommodation.
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The primary symptom of diabetic encephalopathy (DE), a kind of central diabetic neuropathy caused by diabetes mellitus (DM), is cognitive impairment. In addition, the tetracyclic oxindole alkaloid isorhynchophylline (IRN) helps lessen cognitive impairment. However, it is still unclear how IRN affects DM and DE and what mechanisms are involved. The effectiveness of IRN on brain insulin resistance was carefully examined in this work, both in vitro and in vivo. We found that IRN accelerates spliced form of X-box binding protein 1 (sXBP1) translocation into the nucleus under high glucose conditions in vitro. IRN also facilitates the nuclear association of pCREB with sXBP1 and the binding of regulatory subunits of phosphatidylinositol 3-kinase (PI3K) p85α or p85ß with XBP1 to restore high glucose impairment. Also, IRN treatment improves high glucose-mediated impairment of insulin signaling, endoplasmic reticulum stress, and pyroptosis/apoptosis by depending on sXBP1 in vitro. In vivo studies suggested that IRN attenuates cognitive impairment, ameliorating peripheral insulin resistance, activating insulin signaling, inactivating activating transcription factor 6 (ATF6) and C/EBP homology protein (CHOP), and mitigating pyroptosis/apoptosis by stimulation of sXBP1 nuclear translocation in the brain. In summary, these data indicate that IRN contributes to maintaining insulin homeostasis by activating sXBP1 in the brain. Thus, IRN is a potent antidiabetic agent as well as an sXBP1 activator that has promising potential for the prevention or treatment of DE.
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Diabetes Mellitus , Resistência à Insulina , Humanos , Oxindóis/farmacologia , Proteína 1 de Ligação a X-Box , Fosfatidilinositol 3-Quinases , Estresse do Retículo Endoplasmático , Insulina , Glucose , Diabetes Mellitus/tratamento farmacológicoRESUMO
Acute respiratory distress syndrome (ARDS), a common respiratory critical illness with multiple causes, is associated with high mortality. The high degree of heterogeneity may be the reason why it is lack of highly specific and sensitive biological biomarkers. Therefore, it is an urgent need to explore biomarkers, perform phenotypic analysis and establish risk stratification model for diagnosis, prognosis, and treatment of ARDS. Endothelial cells specificity molecular-1 (ESM-1, endocan), is a soluble dermatan sulfate proteoglycan, and be involved in regulating biological behaviors such as cell proliferation, differentiation and migration. Numerous studies have confirmed that ESM-1 is closely related to inflammation, endothelial activation and dysfunction. However, the role of ESM-1 in the initiating and developing process of ARDS is still unclear. To provide a scientific basis for its clinical applications in ARDS, such as early prognosis assessment and timely prevent strategies, this paper focuses on the biological properties and the clinical value of ESM-1 as a potential biomarker for ARDS.
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Células Endoteliais , Síndrome do Desconforto Respiratório , Biomarcadores , Estado Terminal , Humanos , PrognósticoRESUMO
Zeolite chemistry and catalysis are expected to play a decisive role in the next decade(s) to build a more decentralized renewable feedstock-dependent sustainable society owing to the increased scrutiny over carbon emissions. Therefore, the lack of fundamental and mechanistic understanding of these processes is a critical "technical bottleneck" that must be eliminated to maximize economic value and minimize waste. We have identified, considering this objective, that the chemistry related to the first-generation reaction intermediates (i.e., carbocations, radicals, carbenes, ketenes, and carbanions) in zeolite chemistry and catalysis is highly underdeveloped or undervalued compared to other catalysis streams (e.g., homogeneous catalysis). This limitation can often be attributed to the technological restrictions to detect such "short-lived and highly reactive" intermediates at the interface (gas-solid/solid-liquid); however, the recent rise of sophisticated spectroscopic/analytical techniques (including under in situ/operando conditions) and modern data analysis methods collectively compete to unravel the impact of these organic intermediates. This comprehensive review summarizes the state-of-the-art first-generation organic reaction intermediates in zeolite chemistry and catalysis and evaluates their existing challenges and future prospects, to contribute significantly to the "circular carbon economy" initiatives.
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Zeolitas , Carbono , CatáliseRESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by motor dysfunction. Growing evidence has demonstrated that gut dysbiosis is involved in the occurrence, development and progression of PD. Numerous clinical trials have identified the characteristics of the changed gut microbiota profiles, and preclinical studies in PD animal models have indicated that gut dysbiosis can influence the progression and onset of PD via increasing intestinal permeability, aggravating neuroinflammation, aggregating abnormal levels of α-synuclein fibrils, increasing oxidative stress, and decreasing neurotransmitter production. The gut microbiota can be considered promising diagnostic and therapeutic targets for PD, which can be regulated by probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, diet modifications, and Chinese medicine. This review summarizes the recent studies in PD-associated gut microbiota profiles and functions, the potential roles, and mechanisms of gut microbiota in PD, and gut microbiota-targeted interventions for PD. Deciphering the underlying roles and mechanisms of the PD-associated gut microbiota will help interpret the pathogenesis of PD from new perspectives and elucidate novel therapeutic strategies for PD.
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Microbioma Gastrointestinal , Doenças Neurodegenerativas , Doença de Parkinson , Animais , Disbiose/terapia , Transplante de Microbiota Fecal , Doença de Parkinson/patologiaRESUMO
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a challenging clinical problem. Discovering the potential metabolic alterations underlying the ARDS is important to identify novel therapeutic target and improve the prognosis. Serum and urine metabolites can reflect systemic and local changes and could help understanding metabolic characterization of community-acquired pneumonia (CAP) with ARDS. METHODS: Clinical data of patients with suspected CAP at the First Affiliated Hospital of Wenzhou Medical University were collected from May 2020 to February 2021. Consecutive patients with CAP were enrolled and divided into two groups: CAP with and without ARDS groups. 1H nuclear magnetic resonance-based metabolomics analyses of serum and urine samples were performed before and after treatment in CAP with ARDS (n = 43) and CAP without ARDS (n = 45) groups. Differences metabolites were identifed in CAP with ARDS. Furthermore, the receiver operating characteristic (ROC) curve was utilized to identify panels of significant metabolites for evaluating therapeutic effects on CAP with ARDS. The correlation heatmap was analyzed to further display the relationship between metabolites and clinical characteristics. RESULTS: A total of 20 and 42 metabolites were identified in the serum and urine samples, respectively. Serum metabolic changes were mainly involved in energy, lipid, and amino acid metabolisms, while urine metabolic changes were mainly involved in energy metabolism. Elevated levels of serum 3-hydroxybutyrate, lactate, acetone, acetoacetate, and decreased levels of serum leucine, choline, and urine creatine and creatinine were detected in CAP with ARDS relative to CAP without ARDS. Serum metabolites 3-hydroxybutyrate, acetone, acetoacetate, citrate, choline and urine metabolite 1-methylnicotinamide were identified as a potential biomarkers for assessing therapeutic effects on CAP with ARDS, and with AUCs of 0.866 and 0.795, respectively. Moreover, the ROC curve analysis revealed that combined characteristic serum and urine metabolites exhibited a better classification system for assessing therapeutic effects on CAP with ARDS, with a AUC value of 0.952. In addition, differential metabolites strongly correlated with clinical parameters in patients with CAP with ARDS. CONCLUSIONS: Serum- and urine-based metabolomics analyses identified characteristic metabolic alterations in CAP with ARDS and might provide promising circulatory markers for evaluating therapeutic effects on CAP with ARDS.
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Infecções Comunitárias Adquiridas , Pneumonia , Síndrome do Desconforto Respiratório , Ácido 3-Hidroxibutírico , Acetoacetatos , Acetona , Biomarcadores , Infecções Comunitárias Adquiridas/diagnóstico , Humanos , Espectroscopia de Ressonância Magnética/métodos , Metabolômica/métodos , Pneumonia/diagnóstico por imagem , Curva ROC , Síndrome do Desconforto Respiratório/diagnóstico por imagemRESUMO
There are still many challenges in understanding the absorption and transport mechanism of liposomes in the gastrointestinal tract of infants, especially for liposome-coentrapped two or more substances. In this study, novel docosahexaenoic acid (DHA)-anthocyanidin-codelivery liposomes (DA-LPs) were fabricated and characterized, and their digestive and absorptive behaviors were evaluated using the in vitro infant digestive method combined with the Caco-2 cell model. The liposomal bilayer structure remained intact with the particles aggregated in simulated infant gastric fluid, while their phospholipid membrane underwent enzymatic lipolysis under simulated intestinal conditions. Compared to single substance-loaded liposomes (DHA- or anthocyanidin-loaded liposomes), the digested DA-LPs showed better cell viability, higher cellular uptake and membrane fluidity, and lower reactive oxygen species (ROS). It can be concluded that DA-LPs are promising carriers for simultaneously transporting hydrophobic and hydrophilic molecules and may be beneficial for improving nutrient absorption and alleviating intestinal stress oxidation.
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Antocianinas , Ácidos Docosa-Hexaenoicos , Células CACO-2 , Digestão , Humanos , Lactente , LipossomosRESUMO
It has been demonstrated that the action of dopamine (DA) could enhance the production of tumour necrosis factor-α (TNF-α) by astrocytes and potentiate neuronal apoptosis in minimal hepatic encephalopathy (MHE). Recently, sodium hydrosulfide (NaHS) has been found to have neuroprotective properties. Our study addressed whether NaHS could rescue DA-challenged inflammation and apoptosis in neurons to ameliorate memory impairment in MHE rats and in the neuron and astrocyte coculture system. We found that NaHS suppressed DA-induced p65 acetylation, resulting in reduced TNF-α production in astrocytes both in vitro and in vivo. Furthermore, decreased apoptosis was observed in neurons exposed to conditioned medium from DA + NaHS-challenged astrocytes, which was similar to the results obtained in the neurons exposed to TNF-α + NaHS, suggesting a therapeutic effect of NaHS on the suppression of neuronal apoptosis via the reduction of TNF-α level. DA triggered the inactivation of p70 S6 ribosomal kinase (S6K1) and dephosphorylation of Bad, resulting in the disaggregation of Bclxl and Bak and the release of cytochrome c (Cyt. c), and this process could be reversed by NaHS administration. Our work demonstrated that NaHS attenuated DA-induced astrocytic TNF-α release and ameliorated inflammation-induced neuronal apoptosis in MHE. Further research into this approach may uncover future potential therapeutic strategies for MHE.
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Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Dopamina/efeitos adversos , Encefalopatia Hepática/complicações , Encefalopatia Hepática/metabolismo , Sulfeto de Hidrogênio/farmacologia , Doenças Neurodegenerativas/etiologia , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Biomarcadores , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Suscetibilidade a Doenças , Dopamina/metabolismo , Encefalopatia Hepática/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismo , Proteína bcl-X/metabolismoRESUMO
BACKGROUND: Increased fucosylation is associated with the chemoresistance phenotype. Meanwhile, fucosyltransferase IV (FUT4) amounts are frequently elevated in lung cancer and may be related to increased chemoresistance. METHODS: In the present work, FUT4's role in cisplatin-induced apoptosis was assessed in A549 and H1975 cells, respectively. To clarify whether the FUT4 gene attenuates chemosensitivity in tumor cells, we constructed FUT4siRNA and evaluated its effects on cisplatin-induced apoptosis and cell growth inhibition. Cell viability, apoptosis, migration and invasion assay were conducted to investigate cisplatin sensitivity. The activation of EGFR/AKT/FOXO1 signaling were measured by western blot. The translocation of FOXO1 was assessed by IFC using Laser Scanning Confocal Microscope. RESULTS: We found that FUT4 knockdown dose-dependently increased cisplatin-associated cytotoxicity. Furthermore, FUT4 silencing induced apoptosis and inhibited proliferation in A549 and H1975 cells by suppressing Akt and FOXO1 phosphorylation induced by cisplatin administration, which resulted in nuclear translocation of FOXO1. CONCLUSION: These results suggested FUT4 might control chemoresistance to cisplatin in lung cancer by suppressing FOXO1-induced apoptosis.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/uso terapêutico , Proteína Forkhead Box O1/metabolismo , Fucosiltransferases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Apoptose , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/farmacologia , Humanos , Neoplasias Pulmonares/patologia , TransfecçãoRESUMO
Dopamine (DA)-induced learning and memory impairment is well documented in minimal hepatic encephalopathy (MHE), but the contribution of DA to neurodegeneration and the involved underlying mechanisms are not fully understood. In this study, the effect of DA on neuronal apoptosis was initially detected. The results showed that MHE/DA (10 µg)-treated rats displayed neuronal apoptosis. However, we found that DA (10 µM) treatment did not induce evident apoptosis in primary cultured neurons (PCNs) but did produce TNF-α in primary cultured astrocytes (PCAs). Furthermore, co-cultures between PCAs and PCNs exposed to DA exhibited increased astrocytic TNF-α levels and neuronal apoptosis compared with co-cultures exposed to the vehicle, indicating the attribution of the neuronal apoptosis to astrocytic TNF-α. We also demonstrated that DA enhanced TNF-α production from astrocytes by activation of the TLR4/MyD88/NF-κB pathway, and secreted astrocytic TNF-α-potentiated neuronal apoptosis through inactivation of the PI3K/Akt/mTOR pathway. Overall, the findings from this study suggest that DA stimulates substantial production and secretion of astrocytic TNF-α, consequently and indirectly triggering progressive neurodegeneration, resulting in cognitive decline and memory loss in MHE.
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Astrócitos/metabolismo , Dopamina/metabolismo , Encefalopatia Hepática/metabolismo , Encefalopatia Hepática/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose , Astrócitos/patologia , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND: We previously reported that elevation of intracranial dopamine (DA) levels from cirrhotic livers is implicated in the pathogenesis of minimal hepatic encephalopathy (MHE). Intracellular events in neurons, which lead to memory loss in MHE by elevated DA, however, remain elusive. METHODS: In our present study, an MHE rat model, a DA - intracerebroventricularly (i.c.v.) injected rat model and DA-treated primary cortical neurons (PCNs) were used to study this issue using behavioral tests, double-labeled fluorescent staining, immunoblotting, and semi-quantitative RT-PCR. RESULTS: Cognitive impairment was observed in MHE rats and DA (10 µg, i.c.v.)-treated rats. The levels of DA in the cerebral cortex of both MHE and DA (10 µg)-treated rats were increased. DA conversely modulated the p-JAK2/p-STAT3 levels in PCNs. In accordance, DA downregulated an anacetylcholine-producing enzyme, choline acetyltransferase (ChAT), and desensitized the M1-type muscarinic acetylcholine receptor (M1 mAChR). Furthermore, naringin completely restored cognitive function in MHE/DA (10 µg)-treated models by activating the JAK2/STAT3 axis, paralleling the upregulation of ChAT and sensitization of M1 mAChR. CONCLUSIONS: We propose a hypothesis accounting for memory impairment related to MHE: DA-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in MHE but also a novel target in MHE therapy.
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Flavanonas/administração & dosagem , Encefalopatia Hepática/tratamento farmacológico , Janus Quinase 2/genética , Fator de Transcrição STAT3/genética , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Encefalopatia Hepática/metabolismo , Encefalopatia Hepática/patologia , Humanos , Janus Quinase 2/biossíntese , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , Transtornos da Memória/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Fator de Transcrição STAT3/biossínteseRESUMO
BACKGROUND: We previously demonstrated that dopamine (DA) overload may be a key mechanism behind development of minimal hepatic encephalopathy (MHE) in rats. It has been shown that low-grade cerebral oedema and oxidative stress play important roles in the pathogenesis of MHE. In the current study, DA-triggered oxidative injury in cerebral cortex was studied. METHODS: An MHE rat model was used. DA was injected intracerebroventricularly (i.c.v.) into rats and added to primary cortical astrocytes (PCAs). Immunoblotting, immunoprecipitation and immunostaining were conducted after DA injection. RESULTS: Cognitive impairment and cerebral edema were observed in MHE rats and rats injected with 10 µg DA. Astrocyte swelling was increased by DA. Astrocytic protein tyrosine nitration (PTN) was induced by DA. DA-induced PTN was insensitive to l-NMMA but was blunted by apocynin, superoxide dismutase, catalase and uric acid. Exposure to DA substantially increased levels of astrocytic NADPH oxidase subunits and induced p47(phox) phosphorylation and reactive oxygen species production but decreased the expression and activity of neuronal-type nitric oxide synthase (nNOS). CONCLUSIONS: PTN induced by DA, which was attributed to NADPH oxidase and not to nNOS, may alter astrocyte function and thereby contribute to the precipitation of MHE episodes.
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Astrócitos/efeitos dos fármacos , Dopamina/farmacologia , Encefalopatia Hepática/metabolismo , NADPH Oxidases/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Edema Encefálico/diagnóstico , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Células Cultivadas , Cognição/efeitos dos fármacos , Dopamina/administração & dosagem , Inibidores Enzimáticos/farmacologia , Encefalopatia Hepática/fisiopatologia , Immunoblotting , Imuno-Histoquímica , Injeções Intraventriculares , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Tirosina/metabolismo , ômega-N-Metilarginina/farmacologiaRESUMO
In a previous study by our group memory impairment in rats with minimal hepatic encephalopathy (MHE) was associated with the inhibition of the glutamatenitric oxidecyclic guanosine monophosphate (GluNOcGMP) pathway due to elevated dopamine (DA). However, the effects of DA on the GluNOcGMP pathway localized in primary cortical astrocytes (PCAs) had not been elucidated in rats with MHE. In the present study, it was identified that when the levels of DA in the cerebral cortex of rats with MHE and highdose DA (3 mg/kg)treated rats were increased, the colocalization of Nmethyldaspartate receptors subunit 1 (NMDAR1), calmodulin (CaM), nitric oxide synthase (nNOS), soluble guanylyl cyclase (sGC) and cyclic guanine monophosphate (cGMP) with the glial fibrillary acidic protein (GFAP), a marker protein of astrocytes, all significantly decreased, in both the MHE and highdose DAtreated rats (P<0.01). Furthermore, NMDAinduced augmentation of the expression of NMDAR1, CaM, nNOS, sGC and cGMP localized in PCAs was decreased in MHE and DAtreated rats, as compared with the controls. Chronic exposure of cultured cerebral cortex PCAs to DA treatment induced a dosedependent decrease in the concentration of intracellular calcium, nitrites and nitrates, the formation of cGMP and the expression of NMDAR1, CaM, nNOS and sGC/cGMP. High doses of DA (50 µM) significantly reduced NMDAinduced augmentation of the formation of cGMP and the contents of NMDAR1, CaM, nNOS, sGC and cGMP (P<0.01). These results suggest that the suppression of DA on the GluNOcGMP pathway localized in PCAs contributes to memory impairment in rats with MHE.