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The rapid advancement of large language models is reshaping research across various fields, offering a novel approach to the complex realm of molecular studies. Our evaluation of GPT-4 and GPT-3.5, focusing on their performance in generating and optimizing molecular structures, highlights GPT-4's strengths in certain aspects of molecular optimization. However, it also revealed challenges in accurately creating complex molecules. Addressing these issues, we propose possible directions for future molecular science research. These suggestions aim to forge new paths for exploring the intricacies of molecular structures, potentially bringing new efficiencies and innovations in the field.
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We investigated how environment symmetry shapes the neural processing of direction by recording directionally tuned retrosplenial neurons in male Lister hooded rats exploring multicompartment environments that had different levels of global rotational symmetry. Our hypothesis built on prior observations of twofold symmetry in the directional tuning curves of rats in a globally twofold-symmetric environment. To test whether environment symmetry was the relevant factor shaping the directional responses, here we deployed the same apparatus (two connected rectangular boxes) plus one with fourfold symmetry (a 2 × 2 array of connected square boxes) and one with onefold symmetry (a circular open-field arena). Consistent with our hypothesis we found many neurons with tuning curve symmetries that mirrored these environment symmetries, having twofold, fourfold, or onefold symmetric tuning, respectively. Some cells expressed this pattern only globally (across the whole environment), maintaining singular tuning curves in each subcompartment. However, others also expressed it locally within each subcompartment. Because multidirectionality has not been reported in naive rats in single environmental compartments, this suggests an experience-dependent effect of global environment symmetry on local firing symmetry. An intermingled population of directional neurons were classic head direction cells with globally referenced directional tuning. These cells were electrophysiologically distinct, with narrower tuning curves and a burstier firing pattern. Thus, retrosplenial directional neurons can simultaneously encode overall head direction and local head direction (relative to compartment layout). Furthermore, they can learn about global environment symmetry and express this locally. This may be important for the encoding of environment structure beyond immediate perceptual reach.SIGNIFICANCE STATEMENT We investigated how environment symmetry shapes the neural code for space by recording directionally tuned neurons from the retrosplenial cortex of rats exploring single- or multicompartment environments having onefold, twofold, or fourfold rotational symmetry. We found that many cells expressed a symmetry in their head direction tuning curves that matched the corresponding global environment symmetry, indicating plasticity of their directional tuning. They were also electrophysiologically distinct from canonical head directional cells. Notably, following exploration of the global space, many multidirectionally tuned neurons encoded global environment symmetry, even in local subcompartments. Our results suggest that multidirectional head direction codes contribute to the cognitive mapping of the complex structure of multicompartmented spaces.
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Giro do Cíngulo , Orientação , Ratos , Masculino , Animais , Orientação/fisiologia , Neurônios/fisiologia , AprendizagemRESUMO
Retrosplenial cortex (RSC) lies at the interface between sensory and cognitive networks in the brain and mediates between these, although it is not yet known how. It has two distinct subregions, granular (gRSC) and dysgranular (dRSC). The present study investigated how these subregions differ with respect to their electrophysiology and thalamic connectivity, as a step towards understanding their functions. The gRSC is more closely connected to the hippocampal formation, in which theta-band local field potential oscillations are prominent. We, therefore, compared theta-rhythmic single-unit activity between the two RSC subregions and found, mostly in gRSC, a subpopulation of non-directional cells with spiking activity strongly entrained by theta oscillations, suggesting a stronger coupling of gRSC to the hippocampal system. We then used retrograde tracers to test for differential inputs to RSC from the anteroventral thalamus (AV). We found that gRSC and dRSC differ in their afferents from two AV subfields: dorsomedial (AVDM) and ventrolateral (AVVL). Specifically: (1) as a whole AV projects more strongly to gRSC; (2) AVVL targets both gRSC and dRSC, while AVDM provides a selective projection to gRSC, (3) the gRSC projection is layer-specific: AVDM targets specifically gRSC superficial layers. These same AV projections are topographically organized with ventral AV neurons innervating rostral RSC and dorsal AV neurons innervating caudal RSC. These combined results suggest the existence of two distinct but interacting RSC subcircuits: one connecting AVDM to gRSC that may comprise part of the cognitive hippocampal system, and the other connecting AVVL to both RSC regions that may link hippocampal and perceptual regions. We suggest that these subcircuits are distinct to allow for differential weighting during integration of converging sensory and cognitive computations: an integration that may take place in thalamus, RSC, or both.
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Córtex Cerebral/fisiologia , Giro do Cíngulo/fisiologia , Vias Neurais/fisiologia , Tálamo/fisiologia , Animais , Eletroencefalografia , Giro do Cíngulo/anatomia & histologia , Masculino , Vias Neurais/anatomia & histologia , Ratos , Ritmo Teta/fisiologiaRESUMO
Chinese herbal medicine ultrafine powder has become a research hotspot for the addition of cosmetic raw materials. Dendrobium candidum is a traditional Chinese herbal medicine. Its extract and stem extract are already cosmetic raw materials and its water extract has the effect of preventing photoaging,but D. candidum ultrafine powder has not been accepted as a raw material for cosmetics,and no relevant research on photoaging prevention has been reported. In this experiment,the ultra-fine powder and fine powder of D. candidum to prevent photoaging were observed and compared,and its mechanism of action was discussed to provide a basis for the prevention of skin photoaging products. Seventy-two female ICR mice were randomly divided into normal group,model group,solvent group,titanium dioxide(Ti O2) group,isooctyl salicylate(2-ES) group,D. candidum ultrafine powder 1(DP1),ultrafine powder 2(DP2) and fine powder(DP3) groups. The photoaging model was established by ultraviolet irradiation for 8 weeks,and the model was intervened while modeling. The skin wrinkle grade,elastic parameters,skin microcirculation blood flow,skin structure and pathological changes(skin thickness,skin collagen fiber,elastic fiber) were observed,the skin transforming growth factor-ß1(TGF-ß1),Smad3 levels were determined,and the type â and type â ¢ collagen,matrix metalloproteinase-1(MMP-1),activated protein-1(AP-1),VEGF expression were detected. The results showed that ultrafine powder(DP1,DP2) significantly reduced the wrinkle level and skin blood flow of the model mice(P<0. 05,P<0. 01); DP1,DP2 and DP3 could significantly reduce the thickness of the epidermis(P<0. 001),improve collagen fiber,elastic fiber hyperplasia,and distortion and decrease VEGF expression,and DP1 is better than DP2 and DP3; each group could up-regulate type â collagen,down-regulate type â ¢ collagen,AP-1,MMP-1 protein expression,and DP1 improvement optimal. However,it has no obvious effect on TGF-ß1 and Smad3. The ultrafine powder and fine powder of D. candidum have certain preventive effect on photoaging,and the effect of ultrafine powder is better than that of fine powder. Ultrafine powder may down-regulate the expression of type â ¢ collagen,AP-1 and MMP-1 by up-regulating type â collagen. Inhibition of collagen degradation plays a role in preventing photoaging.
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Dendrobium , Envelhecimento da Pele , Animais , Feminino , Camundongos , Camundongos Pelados , Camundongos Endogâmicos ICR , Pele , Raios UltravioletaRESUMO
Hypoxia promotes HCC progression and therapy resistance, and there is no systemic treatment for HCC patients after sorafenib resistance. Thus, it is urgent to develop potential therapeutic regimens for HCC patients by targeting hypoxia signaling. In this study, we showed that evodiamine might be a potential therapeutic medicine for HCC by suppressing HIF-1α. In addition, evodiamine could sensitize the anti-HCC effect of vorinostat in HCC cells under hypoxia. Furthermore, evodiamine plus vorinostat accelerated the degradation of HIF-1α in HCC cells under hypoxia. In general, evodiamine might be a potential therapeutic candidate for HCC patients, and evodiamine combining with vorinostat might be an attractive chemotherapy strategy for HCC treatment.
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Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Ácidos Hidroxâmicos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Hipóxia/complicações , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/metabolismo , VorinostatRESUMO
In recent years, the advancement of sensor technology has led to the generation of heterogeneous Internet-of-Things (IoT) data by smart cities. Thus, the development and deployment of various aspects of IoT-based applications are necessary to mine the potential value of data to the benefit of people and their lives. However, the variety, volume, heterogeneity, and real-time nature of data obtained from smart cities pose considerable challenges. In this paper, we propose a semantic framework that integrates the IoT with machine learning for smart cities. The proposed framework retrieves and models urban data for certain kinds of IoT applications based on semantic and machine-learning technologies. Moreover, we propose two case studies: pollution detection from vehicles and traffic pattern detection. The experimental results show that our system is scalable and capable of accommodating a large number of urban regions with different types of IoT applications.
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OBJECTIVE: To investigate the significance of monitoring procalcitonin (PCT) when applying antibiotics to trichlorethylene (TCE)-induced dermatitis. METHODS: One hundred and two patients who were hospitalized and recovered from TCE-induced dermatitis in our hospital from 2006 to 2013 were enrolled as subjects. Based on whether the PCT level was monitored or not, we divided patients into regular group and PCT group. For the regular group, we applied antibiotic treatment and determined the course of treatment based on clinical symptoms, laboratory test results, medical imaging results, and bacterial culture. For the PCT group, in addition to the above treatments, antibiotic treatment was applied when the PCT level was not lower than 0.25 ng/ml and stopped when the PCT level was lower than 0.25 ng/ml. The distribution of bacterial infection sites, type of bacteria, type of antibiotics, average period of hospitalization, and course of antibiotic treatment were compared between the two groups. RESULTS: There were no significant differences in the distribution of bacterial infection sites, type of bacteria, type of antibiotics, and average period of hospitalization between the two groups (P > 0.05). The course of antibiotic treatment for the PCT group was significantly shorter than that for the regular group (25.37 ± 11.66 vs 20.58 ± 7.53 d, P < 0.05). CONCLUSION: Under similar conditions of bacterial infection, antibiotic treatment of TCE-induced dermatitis based on the serum PCT level can significantly shorten the course of treatment and avoid the abuse of antibiotics.
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Antibacterianos/uso terapêutico , Calcitonina/análise , Toxidermias/tratamento farmacológico , Monitorização Fisiológica , Precursores de Proteínas/análise , Tricloroetileno/toxicidade , Bactérias , Infecções Bacterianas , Peptídeo Relacionado com Gene de Calcitonina , Hospitalização , HumanosRESUMO
Studies have shown that the cardio/cerebrovascular toxicity of ambient PM2.5 is related to its bound polycyclic aromatic hydrocarbons (PAHs). Currently, only a few studies have reported the relationship between PM2.5-bound PAHs and promoted blood coagulation and thrombosis, but there isn't a consistent conclusion. Therefore, we conducted a prospective panel study to investigate the association. Thirty-three young healthy adults participated in sixteen repeated visits from 2014 to 2018 in Tianjin, China. During each visit, three pro-thrombotic biomarkers: ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13), D-dimer and Myeloperoxidase (MPO) were measured. Before each visit, ambient PM2.5 samples were daily collected for one week. Sixteen PAHs were determined using Gas Chromatography-Mass Spectrometer, and the positive matrix factorization (PMF) model was applied to identify the sources. Linear mixed-effects models were fitted to investigate the associations between PM2.5-bound PAHs exposure and the biomarkers. Thirteen time-metrics were defined to identify significant time points of PM2.5-bound PAHs' effects. We observed that the increase of PM2.5-bound PAHs exposure was significantly associated with reduced ADAMTS13, elevated D-dimer and MPO. At lag0, each 5.7 ng/m3 increase in Benzo[j]fluoranthene and per 3.4 ng/m3 increase Dibenz[a,h]anthracene could make a maximum change of -19.08 % in ADAMTS13 and 132.60 % in D-dimer. Additionally, per 16.43 ng/m3 increase in Chrysene could lead to a maximum elevation of 32.14 % in MPO at lag4. The PM2.5-bound PAHs often triggered more significant changes at lag 3,4 and 6. The ambient PM2.5-bound PAHs originated from six sources: coal combustion (43.10 %), biomass combustion (20.77 %), diesel emission (14.78 %), gasoline emission (10.95 %), industrial emission (7.58 %), and cooking emission (2.83 %). The greatest contributors to alterations in ADAMTS13, D-dimer and MPO are industrial emission (-48.43 %), biomass combustion (470.32 %) and diesel emission (13.14 %) at lag4. Our findings indicated that short-term exposure to ambient PM2.5-bound PAHs can induce alterations of pro-thrombotic biomarkers among healthy adults.
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Poluentes Atmosféricos , Hidrocarbonetos Policíclicos Aromáticos , Trombose , Adulto , Humanos , Material Particulado/análise , Poluentes Atmosféricos/análise , Monitoramento Ambiental , Hidrocarbonetos Policíclicos Aromáticos/análise , Estudos Prospectivos , China , Estações do AnoRESUMO
Exposure to fine particulate matter (PM2.5) is a significant concern for respiratory health. However, the sources, trigger points, and effect size of specific associations between PM2.5 components, particularly polycyclic aromatic hydrocarbons (PAHs) and the airway inflammatory marker fractional exhaled nitric oxide (FeNO) have not been fully explored. In this study, 69 healthy college students were enrolled and followed up 16 times from 2014 to 2018. Individual FeNO was measured and ambient air PM2.5 samples were collected for 7 consecutive days before each follow-up. PAHs were quantified using Gas Chromatography-Mass Spectrometry. Linear mixed-effect regression models were employed to evaluate the associations between PM2.5-bound PAHs and FeNO. Additionally, PMF (Positive Matrix Factorization) was utilized to identify sources of PM2.5-bound PAHs and assess their impact on FeNO. Throughout the study, the average (SD) of ΣPAHs concentrations was 78.50 (128.9) ng/m3. PM2.5 and PM2.5-bound PAHs were significantly associated with FeNO at various lag days. Single-day lag analyses revealed maximum effects of PM2.5 on FeNO, with an increase of 7.71% (95% CI: 4.67%, 10.83%) per interquartile range (IQR) (48.10 µg/m3) increase of PM2.5 at lag2, and ΣPAHs showed a maximum elevation in FeNO of 6.40% (95% CI: 2.33%, 10.63%) at lag4 per IQR (57.39 ng/m3) increase. Individual PAHs exhibited diversity peak effects on FeNO at lag3 (6 of 17), lag4 (9 of 17) in the single-day model, and lag0-5 (8 of 17) (from lag0-1 to lag0-6) in the cumulative model. Source apportionment indicated coal combustion as the primary contributor (accounting for 30.7%). However, a maximum effect on FeNO (an increase of 21.57% (95% CI: 13.58%, 30.13%) per IQR increase) was observed with traffic emissions at lag4. The findings imply that strategic regulation of particular sources of PAHs, like traffic emissions, during specific periods could significantly contribute to safeguarding public health.
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Poluentes Atmosféricos , Óxido Nítrico , Material Particulado , Hidrocarbonetos Policíclicos Aromáticos , Hidrocarbonetos Policíclicos Aromáticos/análise , Humanos , Material Particulado/análise , Poluentes Atmosféricos/análise , Óxido Nítrico/metabolismo , Óxido Nítrico/análise , Masculino , Feminino , Adulto Jovem , Adulto , Seguimentos , Monitoramento Ambiental , Expiração , Exposição Ambiental/estatística & dados numéricos , Exposição Ambiental/análiseRESUMO
Perception is internally constructed by integrating brain states with external sensory inputs, a process depending on the topdown modulation of sensory representations. A wealth of earlier studies described task-dependent modulations of sensory cortex corroborating perceptual and behavioral phenomena. But only with recent technological advancements, the underlying circuit-level mechanisms began to be unveiled. We review recent progress along this line of research. It begins to be appreciated that topdown signals can encode various types of task-related information, ranging from task engagement, and category knowledge to decision execution; these signals are transferred via feedback pathways originating from distinct association cortices and interact with sensory cortical circuits. These plausible mechanisms support a broad range of computations from predictive coding to inference making, ultimately form dynamic percepts and endow behavioral flexibility.
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Mapeamento Encefálico , Encéfalo , Córtex CerebralRESUMO
BACKGROUND: Under the paradigm of precision medicine (PM), patients with the same disease can receive different personalized therapies according to their clinical and genetic features. These therapies are determined by the totality of all available clinical evidence, including results from case reports, clinical trials, and systematic reviews. However, it is increasingly difficult for physicians to find such evidence from scientific publications, whose size is growing at an unprecedented pace. OBJECTIVE: In this work, we propose the PM-Search system to facilitate the retrieval of clinical literature that contains critical evidence for or against giving specific therapies to certain cancer patients. METHODS: The PM-Search system combines a baseline retriever that selects document candidates at a large scale and an evidence reranker that finely reorders the candidates based on their evidence quality. The baseline retriever uses query expansion and keyword matching with the ElasticSearch retrieval engine, and the evidence reranker fits pretrained language models to expert annotations that are derived from an active learning strategy. RESULTS: The PM-Search system achieved the best performance in the retrieval of high-quality clinical evidence at the Text Retrieval Conference PM Track 2020, outperforming the second-ranking systems by large margins (0.4780 vs 0.4238 for standard normalized discounted cumulative gain at rank 30 and 0.4519 vs 0.4193 for exponential normalized discounted cumulative gain at rank 30). CONCLUSIONS: We present PM-Search, a state-of-the-art search engine to assist the practicing of evidence-based PM. PM-Search uses a novel Bidirectional Encoder Representations from Transformers for Biomedical Text Mining-based active learning strategy that models evidence quality and improves the model performance. Our analyses show that evidence quality is a distinct aspect from general relevance, and specific modeling of evidence quality beyond general relevance is required for a PM search engine.
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Uncovering the tissue molecular architecture at single-cell resolution could help better understand organisms' biological and pathological processes. However, bulk RNA-seq can only measure gene expression in cell mixtures, without revealing the transcriptional heterogeneity and spatial patterns of single cells. Herein, we introduce Bulk2Space ( https://github.com/ZJUFanLab/bulk2space ), a deep learning framework-based spatial deconvolution algorithm that can simultaneously disclose the spatial and cellular heterogeneity of bulk RNA-seq data using existing single-cell and spatial transcriptomics references. The use of bulk transcriptomics to validate Bulk2Space unveils, in particular, the spatial variance of immune cells in different tumor regions, the molecular and spatial heterogeneity of tissues during inflammation-induced tumorigenesis, and spatial patterns of novel genes in different cell types. Moreover, Bulk2Space is utilized to perform spatial deconvolution analysis on bulk transcriptome data from two different mouse brain regions derived from our in-house developed sequencing approach termed Spatial-seq. We have not only reconstructed the hierarchical structure of the mouse isocortex but also further annotated cell types that were not identified by original methods in the mouse hypothalamus.
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Neoplasias , Transcriptoma , Camundongos , Animais , RNA-Seq , Transcriptoma/genética , Algoritmos , Sequenciamento do Exoma , Análise de Célula Única/métodos , Análise de Sequência de RNA , Perfilação da Expressão Gênica/métodosRESUMO
Given the increasing global trend toward unhealthy lifestyles and dietary decisions, such as "over-consumption of alcohol, and high sugar and fat diets" (ACHSFDs), it is not surprising that metabolic hypertension (MH) is now the most common type of hypertension. There is an urgent, global need for effective measures for the prevention and treatment of MH. Improper diet leads to decreased short-chain fatty acid (SCFA) production in the gut, leading to decreased gastrointestinal function, metabolism, and blood pressure as a result of signaling through G-protein-coupled receptors (GPCRs), ultimately causing MH. Previous studies have suggested that Dendrobium officinale (DO) may improve gastrointestinal function, lower blood pressure, and regulate metabolic abnormalities, but it is not clear whether it acts on MH by increasing SCFA and, if so, how. In this research, it was observed that Dendrobium officinale ultrafine powder (DOFP) could lower blood pressure and improve lipid abnormalities in ACHSFD-induced MH model rats. Moreover, DOFP was found to improve the intestinal flora and increased the SCFA level in feces and serum, as well as increased the expressions of GPCR43/41 and eNOS and the nitric oxide (NO) level. An experiment on isolated aorta rings revealed that DOFP improved the vascular endothelial relaxation function in MH rats, and this effect could be blocked by the eNOS inhibitor l-NAME. These experimental results suggest that DOFP improved the intestinal flora and increased the production, transportation, and utilization of SCFA, activated the intestinal-vascular axis SCFA-GPCR43/41 pathway, improved vascular endothelial function, and finally lowered blood pressure in MH model rats. This research provides a new focus for the mechanism of the effect of DOFP against MH by triggering the enteric-origin SCFA-GPCR43/41 pathway.
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Dendrobium/química , Suplementos Nutricionais , Ácidos Graxos Voláteis/metabolismo , Hipertensão/dietoterapia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Pressão Sanguínea , Colesterol/sangue , Dieta , Modelos Animais de Doenças , Fezes , Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Fígado/patologia , Masculino , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Transdução de SinaisRESUMO
Dendrobium officinale (DOF) is a traditional Chinese edible and officinal plant. Ultrafine DOF powder (DOFP) can regulate lipids and histopathology in the liver, but the underlying mechanisms of hepatic fatty acid (FA) metabolism, which is generally correlated with the development of nonalcoholic fatty liver disease (NAFLD), remain unclear. The purpose of the present study was to investigate whether DOFP treatment alters hepatic FA metabolism in NAFLD mice by using multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) and analyse the underlying mechanisms. A 3-week DOFP treatment prevented lipid deposition and improved hepatic histopathology in NAFLD mice after withdrawal from the high-sucrose, high-fat (HSHF) diet, and it decreased triglyceride and FA content in the liver. Furthermore, the C16 : 0/C14 : 0 and C18 : 1/18 : 0 ratios in FAs were significantly decreased in the DOFP treatment group, and the C20 : 4/C20 : 3 and C22 : 4/C22 : 3 ratios were increased, and saturated FA was inhibited. Additionally, DOFP treatment significantly increased the content of two FA ß-oxidation-related proteins (carnitine palmitoyltransferase 1-α and acyl-coenzyme A oxidase 1). It also decreased the content of a FA synthesis-related protein (fatty acid synthase), a FA desaturation-related protein (stearoyl-coenzyme A desaturase-1), and a FA uptake-related protein (fatty acid transport protein 2). Moreover, DOFP treatment improved dysregulated levels of major phospholipids in the livers of model mice. The results of this study confirm that DOFP treatment in NAFLD mice has liver recovery effects by regulating FA metabolism.
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The synergistic photocatalytic Fenton reaction is a powerful advanced oxidation technique for the degradation of persistent organic pollutants. However, microwave-induced thermal effects on the formation of novel structures facilitating the photocatalytic degradation have been rarely reported. Herein, a two-step microwave thermal strategy was developed to synthesize a new hybrid catalyst comprising defective WO3-x nanowires coupled with reduced graphene oxides (rGOs). Conventionally, microwave methods could induce superhot spots on the GO surface, resulting in the site-specific crystallization and oriented growth of WO3. However, in the solid phase, localized microwave thermal effects could reduce the interfacial area between WO3 and rGO and enhance the bonding between them. As for the unique structure and surface properties, the synthesized catalyst enhanced the light absorption, promoted the interfacial charge separation, and increased the carrier density in the photocatalytic processes. In addition, surface formation of W4+ provided a new pathway for Fe3+/Fe2+ cycling which linked the photocatalytic reaction and the Fenton process. The optimized catalyst exhibited a remarkable performance in the degradation of bisphenol A with a â¼83% removal yield via a photo-Fenton route. These microwave-induced functionalities of materials for synergistic reactions could also give a new avenue to other photoelectrocatalytic fields and solar cells.
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Objectives. Hyperuricemia (HUA) is a disease caused by increased production of uric acid (UA) or reduced excretion of UA in the body. Results of an epidemiological survey show that 60% of patients with HUA have hyperlipidemia (HPA). Dendrobium officinalis (DOF) six nostrum (DOS) is based on the theory of traditional Chinese medicine for the transformation of the traditional Chinese nostrum Si Miao Wan. In this article, we aim to discuss the efficacy and mechanism of DOS in reducing UA and regulating lipid metabolism. The rat model of HUA with HPA was induced by potassium oxonate (PO) combined with high-fat sorghum feed. We monitored the serum UA and blood lipids. Liver xanthine oxidase (XOD), adenosine deaminase (ADA), lipoprotein lipase (LPL), and fatty acid-binding protein (FABP1) activities were measured by enzyme-linked immunosorbent assay (ELISA) after the last administration of DOS. We performed a histopathological examination of rat kidney and intestine. Immunohistochemistry (IHC) was used to detect the expression of renal inflammatory proteins NLRP3 / Caspase-1 and intestinal inflammatory proteins TLR4 / NLRP3. We used western blot for measurement of liver hypoxanthine-guanine phosphoribosyl transferase (HPRT1) protein expression and renal PDZ domain protein kidney 1 (PDZK1) protein expression. DOS administration significantly reduced serum UA, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-c) level, and improved liver steatosis in the model rat. At the same time, DOS treatment effectively inhibited liver XOD and ADA, increased the level of liver HPRT1, and reduced the production of UA. Additional studies had shown that DOS can restore normal UA excretion function in the intestine and kidney and regulated liver lipids metabolism. IHC and histopathological sections showed that DOS reduced the level of kidney, intestinal inflammatory body (NLRP3, Caspase-1, and TLR4), improved inflammation of the kidney and intestinal tract in rats. DOS is a promising drug that can effectively reduce serum UA and lipid level in the model rat. The mechanism of action may be related to inhibition of UA production, promotion of UA excretion, regulation of lipids metabolism, and anti-inflammatory response.
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Antibody dependent (AD) functions such as AD cellular cytotoxicity (ADCC) were associated with lower viral load (VL) in untreated HIV progressors and protection from HIV infection in the modestly protective RV144 HIV vaccine trial. Target cells used to measure ADCC, AD complement deposition (ADCD), and AD cellular trogocytosis (ADCT) have been either HIV envelope (Env) gp120-coated CEM.NKr.CCR5 cells or HIV infected cell cultures. In HIV infected cell cultures, uninfected bystander cells take up gp120 shed from infected cells. Both gp120-coated and gp120+ bystander cells expose CD4 induced (CD4i) epitopes, which are normally hidden in native trimeric Env expressed by genuinely HIV infected cells since Nef and Vpu downmodulate cell surface CD4. Antibody dependent assays using either of these target cells probe for CD4i Abs that are abundant in HIV+ plasma but that do not recognize HIV-infected cells. Here, we examined ADCC, ADCD, and ADCT functions using a target cell line, sorted HIV-infected cell line cells, whose HIV infection frequency nears 100% and that expresses HIV Env in a native trimeric closed conformation. Using sorted HIV-infected cells (siCEM) as targets, we probed the binding and AD functions of anti-gp120/Env Abs in plasma from HIV-infected untreated progressor (UTP, n = 18) and treated (TP, n = 24) subjects, compared to that in Elite controllers (EC, n = 37) and Viral Controllers (VC, n = 16), which are rare subsets of HIV-infected individuals who maintain undetectable or low VL, respectively, without treatment. Gp120-coated beads were used to measure AD cellular phagocytosis. Equivalent concentrations of input IgG in plasma from UTPs, ECs, and VCs supported higher levels of all AD functions tested than plasma from TPs. When AD activities were normalized to the concentration of anti-gp120/Env-specific Abs, between-group differences largely disappeared. This finding suggests that the anti-gp120/Env Abs concentrations and not their potency determined AD functional levels in these assays. Elite controllers did differ from the other groups by having AD functions that were highly polyfunctional and highly correlated with each other. PCR measurement of HIV reservoir size showed that ADCC activity was higher in ECs and VCs with a reservoir size below the limit of detection compared to those having a measurable HIV reservoir size.
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Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Epitopos/imunologia , Humanos , Imunoglobulina G/imunologia , Plasma/imunologia , Carga Viral/imunologiaRESUMO
The polysaccharide was first successfully isolated from the leaf of Dendrobium officinale by hot water extraction and alcohol precipitation and further purified using DEAE-52 and Sephadex G-100 chromatography. The structure of LDOP-1 was characterized by HPLC, GPC, and FT-IR and NMR spectroscopy, and its protective effect on LPS-induced GES-1 cell injury was analyzed. Results showed that LDOP was a homogeneous polysaccharide with average molecular weight of 91.8 kDa and consisted of Man, Gla, Glc, Glc acid, and Ara at a molar ratio of 2.0:1.3:1.6:1.7:0.7. LDOP had two types of residues, including 1,6-linked α-d-Glup and 1,4-linked α-d-Manp. Activity studies indicated that LDOP-1 can significantly suppress the release of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 from LPS-induced GES-1 cell injury, decreased the protein expressions of TLR4, phospho-NF-κB, ASC, NLRP3, cleaved-IL-1ß, IL-6, and Bax, increased the protein expression of Bcl-2, and downregulated the ratios of cleaved caspase-1 to pro-caspase-1, phospho-IκBα to IκBα, and phospho-NF-кB to NF-κB. These findings strongly suggested that LDOP can prevent LPS-induced GES-1 cell injury by inhibiting the release of inflammatory cytokines regulated via the TLR4/NF-κB signal pathways.
Assuntos
Dendrobium/química , Inflamação/tratamento farmacológico , Lipopolissacarídeos/química , Polissacarídeos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Polissacarídeos/classificação , Transdução de Sinais/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
Hepatocellular carcinoma (HCC) is associated with some of the highest cancer-associated mortality rates. Histone deacetylase (HDAC) inhibitors anti-HCC activities have been shown to promote Snail-induced metastasis. In the present study, it was shown that BAY 87-2243, a hypoxia-inducible transcription factor-1α inhibitor, could enhance the anti-HCC effects of HDAC inhibitors, including trichostatin A and vorinostat. In addition, BAY 87-2243 plus HDAC inhibitors exhibited synergistic cytotoxicity and induced significant cell death in Hep3B cells. Additionally, BAY 87-2243 combined with HDAC inhibitors-treated Hep3B cells formed fewer and smaller colonies as compared with either the control or single agent-treated cells. Furthermore, glycogen synthase kinase-3ß might be involved in the enhanced cell death induced by BAY 87-2243 plus HDAC inhibitors. The present data also indicated that BAY 87-2243 combined with HDAC inhibitors could suppress the migration of Hep3B cells, and BAY 87-2243 could reverse the HDAC inhibitor-induced Snail activation in Hep3B cells. In conclusion, BAY 87-2243 combined with HDAC inhibitors might be an attractive chemotherapy strategy for HCC therapy.
RESUMO
Quantifying HIV Envelope (Env)-specific antibodies in HIV+ plasma is useful for interpreting antibody dependent cellular cytotoxicity assay results. HIV Env, the only viral protein expressed on the surface of infected cells, has a native trimeric closed conformation on cells infected with wild-type HIV. However, CD4+ uninfected bystander cells in HIV+ cell cultures bind gp120 shed from HIV+ cells exposing CD4-induced epitopes normally hidden in native Env. We used flow-cytometry based assays to quantify antibodies in HIV+ plasma specific for native trimeric Env or gp120/CD4 conjugates using CEM.NKr.CCR5 (CEM) cells infected with HIV (iCEM) or coated with recombinant gp120 (cCEM), as a surrogate for gp120+ HIV- bystander cells. Results from both assays were compared to those of a plate-based ELISA to monomeric gp120. The levels of Env-specific antibodies to cCEM and iCEM, measured by flow cytometry, and to gp120 by ELISA were positively correlated. More antibodies in HIV+ plasma recognized the gp120 conformation exposed on cCEM than on iCEM. Comparisons of plasma from untreated progressors, treated progressors, and elite controllers revealed that antibodies to Env epitopes were the lowest in treated progressors. Plasma from elite controllers and untreated progressors had similarly high levels of Env-specific antibodies, despite elite controllers having undetectable HIV viral loads, while untreated progressors maintained high viral loads.