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The strategy of in vivo self-assembly has been developed for improved enrichment and long-term retention of anticancer drug in tumor tissues. However, most self-assemblies with non-covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling-induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation-responsive peptide-porphyrin conjugate P1 is synthesized, which self-assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2-fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria-targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies.
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Cancer is a severe threat to humans, as it is the second leading cause of death after cardiovascular diseases and still poses the biggest challenge in the world of medicine. Due to its higher mortality rates and resistance, it requires a more focused and productive approach to provide the solution for it. Many therapies promising to deliver favorable results, such as chemotherapy and radiotherapy, have come up with more negatives than positives. Therefore, a new class of medicinal solutions and a more targeted approach is of the essence. This review highlights the alluring properties, configurations, and self-assembly of peptide molecules which benefit the traditional approach toward cancer therapy while sparing the healthy cells in the process. As targeted drug delivery systems, self-assembled peptides offer a wide spectrum of conjugation, biocompatibility, degradability-controlled responsiveness, and biomedical applications, including cancer treatment and cancer imaging.
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Neoplasias , Peptídeos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Peptídeos/uso terapêutico , Peptídeos/química , Sistemas de Liberação de Medicamentos/métodos , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologiaRESUMO
With the rapid growth of global energy consumption, the environment will further deteriorate, and the competition among countries to reduce emissions will become more intense. Photovoltaic power generation using solar energy as a clean energy source is of strategic importance for achieving a carbon-neutral planet. Therein, centralized photovoltaic power stations in terrestrial ecosystems cover the earth's surface, which leads to changes in land use and has a significant effect on the surface energy balance and precipitation regimes, altering soil nutrient cycling and plant productivity, and ultimately significantly affects ecosystem functions and services. By synthesizing relevant studies on this topic over the past 20 years, we summarized the effects of photovoltaic power station construction on microclimate, soil, flora and fauna, and potential changes in terrestrial ecosystem functions. Overall, the photovoltaic power stations improved the quality of the soil condition, especially in harsh environments, and increased the vegetation coverage. In addition, photovoltaic power stations could affect ecosystem functions including plant productivity, soil erosion resistance, and soil carbon sequestration by regulating microclimatic factors such as solar radiation intensity, air temperature and humidity, wind speed, and wind direction. Although numerous studies have anticipated the potential effect of photovoltaic power stations on ecosystem structure and functions, empirical evidence remains scarce. Therefore, more studies focusing on the regional variability of the ecological impacts of photovoltaic power stations and the potential pathways of photovoltaic power stations affecting ecosystem functions are needed in the future. Improving the understanding of the ecological effects of photovoltaic power stations may help to provide a basis for ecological protection and restoration.
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Immunoglobulin E (IgE) is a key driver of type 1 hypersensitivity reactions and allergic disorders, which are globally increasing in number and severity. Although eliminating pathogenic IgE may be a powerful way to treat allergy, no therapeutic strategy reported to date can fully ablate IgE production. Interleukin-4 receptor α (IL-4Rα) signaling is required for IgE class switching, and IL-4Rα blockade gradually reduces, but does not eliminate, IgE. The persistence of IgE after IL-4Rα blockade may be due to long-lived IgE+ plasma cells that maintain serological memory to allergens and thus may be susceptible to plasma cell-targeted therapeutics. We demonstrate that transient administration of a B cell maturation antigen x CD3 (BCMAxCD3) bispecific antibody markedly depletes IgE, as well as other immunoglobulins, by ablating long-lived plasma cells, although IgE and other immunoglobulins rapidly rebound after treatment. Concomitant IL-4Rα blockade specifically and durably prevents the reemergence of IgE by blocking IgE class switching while allowing the restoration of other immunoglobulins. Moreover, this combination treatment prevented anaphylaxis in mice. Together with additional cynomolgus monkey and human data, our studies demonstrate that allergic memory is primarily maintained by both non-IgE+ memory B cells that require class switching and long-lived IgE+ plasma cells. Our combination approach to durably eliminate pathogenic IgE has potential to benefit allergy in humans while preserving antibody-mediated immunity.
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Anafilaxia , Imunoglobulina E , Camundongos , Humanos , Animais , Macaca fascicularis , Plasmócitos , AlérgenosRESUMO
The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies recognizing IL-2RG has made it difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. Here, we generated a γc cytokine receptor antibody, REGN7257, to determine whether γc cytokines might be targeted for T cell-mediated disease prevention and treatment. Biochemical, structural, and in vitro analysis showed that REGN7257 binds with high affinity to IL-2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that γc cytokines drive T cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis by affecting multiple aspects of the pathogenic response. We found that our xenogeneic GVHD mouse model recapitulates hallmarks of acute and chronic GVHD, with T cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. Our findings indicate that γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases.
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Anemia Aplástica , Doença Enxerto-Hospedeiro , Subunidade gama Comum de Receptores de Interleucina , Linfócitos T , Animais , Camundongos , Anemia Aplástica/metabolismo , Anticorpos Monoclonais/metabolismo , Citocinas/metabolismo , Doença Enxerto-Hospedeiro/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Subunidade gama Comum de Receptores de Interleucina/antagonistas & inibidores , Subunidade gama Comum de Receptores de Interleucina/metabolismo , PrimatasRESUMO
Vitiligo is a skin depigmentation disorder. GATA3 expression is downregulated in vitiligo patients, and its role and regulatory mechanism in vitiligo are unclear. GATA3 and HMGB1 levels were detected by qRT-PCR in peripheral blood cells of vitiligo patients and healthy controls, as well as H2 O2 -treated PIG1 cells. Their expression correlation was assessed by Pearson analysis. qRT-PCR, MTT assay, Ki67 immunostaining, flow cytometry, ELISA and Western blot were applied to determine GATA3 expression, cell survival, cell proliferation, cell apoptosis, melanin contents, and melanin-related protein expressions. The cellular distributions of HMGB1 and its deacetylation levels were detected by Western blot. The binding of GATA3 to SIRT3 promoter and effects on SIRT3 expression and HMGB1 deacetylation was determined by dual-luciferase assay, ChIP assay, and Western blot. GATA3 was decreased, and HMGB1 was increased in vitiligo. Pearson correlation assay showed that they were negatively correlated. H2 O2 significantly inhibited cell survival, proliferation, melanin secretion, and melanin-related protein expressions but remarkably increased cell apoptosis. GATA3 overexpression could distinctly reverse the effects of H2 O2 through decreasing HMGB1 expression and retained HMGB1 in nuclear due to the decreased HMGB1 acetylation. GATA3 bound to the SIRT3 and subsequently decreased H2 O2 -induced HMGB1 acetylation. Overexpressing HMGB1 or knockdown of SIRT3 could reverse the effects of GATA3 overexpression. GATA3 inhibited H2 O2 -induced injury in PIG1 cells and enhanced melanin secretion by SIRT3-regulated HMGB1 deacetylation, which might provide new evidence to treat vitiligo.
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Proteína HMGB1 , Hipopigmentação , Sirtuína 3 , Vitiligo , Humanos , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sirtuína 3/farmacologia , Melaninas/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Melanócitos , Apoptose , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismoRESUMO
RATIONALE: Type 2 (T2) asthma is characterized by airflow limitations and elevated levels of blood and sputum eosinophils, fractional exhaled nitric oxide, IgE, and periostin. While eosinophils are associated with exacerbations, the contribution of eosinophils to lung inflammation, remodeling and function remains largely hypothetical. OBJECTIVES: To determine the effect of T2 cytokines IL-4, IL-13 and IL-5 on eosinophil biology and compare the impact of depleting just eosinophils versus inhibiting all aspects of T2 inflammation on airway inflammation. METHODS: Human eosinophils or endothelial cells stimulated with IL-4, IL-13 or IL-5 were assessed for gene changes or chemokine release.Mice exposed to house dust mite extract received anti-IL-4Rα (dupilumab), anti-IL-5 or control antibodies and were assessed for changes in lung histological and inflammatory endpoints. MEASUREMENTS AND MAIN RESULTS: IL-4 or IL-13 stimulation of human eosinophils and endothelial cells induced gene expression changes related to granulocyte migration; whereas, IL-5 induced changes reflecting granulocyte differentiation.In a mouse model, blocking IL-4Rα improved lung function by impacting multiple effectors of inflammation and remodeling, except peripheral eosinophil counts, thereby disconnecting blood eosinophils from airway inflammation, remodeling and function. Blocking IL-5 globally reduced eosinophil counts but did not impact inflammatory or functional measures of lung pathology. Whole lung transcriptome analysis revealed that IL-5 or IL-4Rα blockade impacted eosinophil associated genes, whereas IL-4Rα blockade also impacted genes associated with multiple cells, cytokines and chemokines, mucus production, cell:cell adhesion and vascular permeability. CONCLUSIONS: Eosinophils are not the sole contributor to asthma pathophysiology or lung function decline and emphasizes the need to block additional mediators to modify lung inflammation and impact lung function.
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Asma , Pneumonia , Animais , Humanos , Camundongos , Asma/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Células Endoteliais/metabolismo , Inflamação/metabolismo , Interleucina-13/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Interleucina-4/farmacologiaRESUMO
OBJECTIVE@#Arsenic (As) and fluoride (F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level (microbiome and metabolome).@*METHODS@#We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period.@*RESULTS@#Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome,featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic (GABAergic) synapse, and arachidonic acid (AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated.@*CONCLUSION@#Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.
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Ratos , Animais , Arsênio/toxicidade , Fluoretos , RNA Ribossômico 16S/genética , Ratos Sprague-Dawley , Metaboloma , MicrobiotaRESUMO
BACKGROUND: Blocking the major cat allergen, Fel d 1, with mAbs was effective in preventing an acute cat allergic response. OBJECTIVES: This study sought to extend the allergen-specific antibody approach and demonstrate that a combination of mAbs targeting Bet v 1, the immunodominant and most abundant allergenic protein in birch pollen, can prevent the birch allergic response. METHODS: Bet v 1-specific mAbs, REGN5713, REGN5714, and REGN5715, were isolated using the VelocImmune platform. Surface plasmon resonance, x-ray crystallography, and cryo-electron microscopy determined binding kinetics and structural data. Inhibition of IgE-binding, basophil activation, and mast cell degranulation were assessed via blocking ELISA, flow cytometry, and the passive cutaneous anaphylaxis mouse model. RESULTS: REGN5713, REGN5714, and REGN5715 bind with high affinity and noncompetitively to Bet v 1. A cocktail of all 3 antibodies, REGN5713/14/15, blocks IgE binding to Bet v 1 and inhibits Bet v 1- and birch pollen extract-induced basophil activation ex vivo and mast cell degranulation in vivo. Crystal structures of the complex of Bet v 1 with immunoglobulin antigen-binding fragments of REGN5713 or REGN5715 show distinct interaction sites on Bet v 1. Cryo-electron microscopy reveals a planar and roughly symmetrical complex formed by REGN5713/14/15 bound to Bet v 1. CONCLUSIONS: These data confirm the immunodominance of Bet v 1 in birch allergy and demonstrate blockade of the birch allergic response with REGN5713/14/15. Structural analyses show simultaneous binding of REGN5713, REGN5714, and REGN5715 with substantial areas of Bet v 1 exposed, suggesting that targeting specific epitopes is sufficient to block the allergic response.
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Alérgenos/imunologia , Anticorpos Monoclonais/farmacologia , Antígenos de Plantas/imunologia , Epitopos Imunodominantes/imunologia , Imunoglobulina G/farmacologia , Anafilaxia Cutânea Passiva/imunologia , Animais , Basófilos/efeitos dos fármacos , Basófilos/imunologia , Humanos , Imunoglobulina E/imunologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos Endogâmicos BALB C , Rinite Alérgica Sazonal/sangue , Rinite Alérgica Sazonal/imunologiaRESUMO
Background Atmospheric fine particulate matter (PM2.5) can induce abnormal early embryo development, resulting in adverse pregnancy outcomes such as embryo damage and spontaneous abortion. The vascular remodeling of maternal-fetal interface regulated by hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) axis is a key link in early embryo development. Objective To investigate the effects of pre-pregnancy PM2.5 exposure on the uterine state of mice before conception and the vascular remodeling of maternal-fetal interface after conception, and to further explore the regulatory role of the HIF-1α/VEGF axis. Methods Forty eight-week-old C57BL/6J sexually mature female mice and several males (for mating, without any treatment) were adaptive fed for 1 week. The female mice were divided into a PM2.5 exposure group and a control group, 20 mice per group. The PM2.5 exposure group was given 3 mg·kg−1 PM2.5 suspension by nasal instillation, once every other day for four weeks; the control group were treated with the same dose of blank sampling membrane suspension. Body weight of the mice was recorded every week during the experimental period. At the end of the exposure, six mice from each group were sacrificed. Then the uterus was weighted and its organ coefficients were calculated, a histopathological morphology evaluation was conducted by HE staining, and the mRNA expressions of HIF-1α, VEGF and its receptors Flt-1 and Flk-1 in the uterus samples were further examined. The remaining 14 female mice in each group were caged with male mice overnight with a sex ratio of 2:1, then we calculated the pregnancy rate. On gestation day 10 (GD10), the female mice were decapitated and the uterus was dissected, the histopathological morphology of embryo and placenta were observed by HE staining, and the mRNA expressions of HIF-1α, VEGF and its receptors Flt-1 and Flk-1 were detected as well in the uterus samples. Results Compared with the control group, the pre-pregnancy PM2.5 exposure had no significant effect on body weight gain of the female mice, but decreased uterine organ coefficient, accompanied by pathological damage such as endometrium thinning as well as decreased mRNA expressions of HIF-1α, VEGF and its receptors Flt-1 and Flk-1 (all Ps<0.05). After mating, the pre-pregnancy PM2.5 exposure induced a decrease of the pregnancy rate (control group: 9/14; exposure group: 5/14) and abnormal embryo arrangement, small placenta, narrowing of spiral arteries (control group: 1.00±0.06; exposure group: 0.86±0.08; P=0.01), as well as significant decreases in HIF-1α, VEGF and its receptor Flk-1 mRNA expressions. (all Ps <0.05). Conclusion Pre-pregnancy PM2.5 exposure has adverse effects on the pathological structure and angiogenesis in female mice uterus, leading to abnormal vascular network remodeling at the mother-fetal interface after conception, and the HIF-1α/VEGF axis may play a regulatory role.
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Breast cancer is one of the most common malignancies. Pathological image processing of breast has become an important means for early diagnosis of breast cancer. Using medical image processing to assist doctors to detect potential breast cancer as early as possible has always been a hot topic in the field of medical image diagnosis. In this paper, a breast cancer recognition method based on image processing is systematically expounded from four aspects: breast cancer detection, image segmentation, image registration, and image fusion. The achievements and application scope of supervised learning, unsupervised learning, deep learning, CNN, and so on in breast cancer examination are expounded. The prospect of unsupervised learning and transfer learning for breast cancer diagnosis is prospected. Finally, the privacy protection of breast cancer patients is put forward.
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Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Processamento de Imagem Assistida por Computador , Neoplasias da Mama/diagnóstico , Feminino , HumanosRESUMO
Therapeutic peptides have been widely concerned, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK]2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP), KYp can be dephosphorylated and self-assembles in situ, which induces the aggregation of ALP and the protein-lipid phase separation on cell membrane. Consequently, KYp internalization is 2-fold enhanced compared to non-responsive peptide, and IC50 value of KYp is approximately 5 times lower than that of free peptide. Therefore, the in vivo self-assembly induced phase separation on cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.
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Membrana Celular/química , Peptídeos/isolamento & purificação , Fosfatase Alcalina/metabolismo , Membrana Celular/metabolismo , Humanos , Peptídeos/química , Peptídeos/metabolismo , Conformação ProteicaRESUMO
Aspartic proteinases are one of the four families of proteinase enzymes that are widely present in living organisms. They are involved in various physiological events, such as protein degradation, development, and host defense. However, the characterization and functional roles of aspartic proteinases remain to be elucidated in crustaceans. Here, we characterized a fragment of cathepsin D-like cDNA from red swamp crayfish, Procambarus clarkii (Pc-cathepsin D-like). The open reading frame of the Pc-cathepsin D-like gene contained 1152 bp, encoding a protein of 383 amino acid residues. We also evaluated the immunological role of the Pc-cathepsin D-like gene in vivo. Spatial distribution analysis revealed that the Pc-cathepsin D-like mRNA was high in the hepatopancreas, followed by the gut, gills, and hemocytes of P. clarkii. The expression levels of the Pc-cathepsin D-like gene increased following challenge with viral (polyinosinic: polycytidylic acid) and bacterial (lipopolysaccharides, peptidoglycan) PAMPs compared with PBS injection. The suppression of the Pc-cathepsin D-like gene by RNA interference significantly increased the expression of immune-associated genes. These results showed that the Pc-cathepsin D-like gene has an essential biological role in innate immune responses because it regulates the expression of immune-associated genes.
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Proteínas de Artrópodes , Astacoidea , Catepsina D , Animais , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/metabolismo , Astacoidea/genética , Astacoidea/metabolismo , Catepsina D/genética , Catepsina D/metabolismo , Regulação da Expressão Gênica , Imunidade Inata/genética , Lisossomos/metabolismo , FilogeniaRESUMO
OBJECTIVE Epimedium is rich in a variety of beneficial active ingredients, and has been widely used in the ethnopharmacological practices, however, its biotransformation in gastrointestinal digestions remain unclear. This study aimed to investigate the dynamic changes of components and biological activity of Epimedium in the in vitro simu? lated digestion and subsequent human faecal fermentation. METHODS The models of in vitro simulated saliva, gastric and intestinal digestion, as well as colonic fermentation were constructed to simulate the digestion process of Epimedium. The dynamic changes of components of Epimedium during the simulated digestions in vitro and subsequent human faecal fermentation were investigated by UPLC-MS, HPLC-DAD combined with principal component analysis (PCA) and multi-ingredient quantitative analysis. RESULTS A variety of metabolites with high contents were produced after 0.5 h of intestinal digestion and colonic fermentation 0.5 h. Application of PCA to HPLC data showed the obvious separation of colonic fermentation 0.5 h stage samples from other colonic fermentation stages samples (24, 48 and 72 h). Addition? ally, non-digestion and saliva digestion stage samples clustered together, and there was obvious separation between intestinal digestion samples and gastric digestion samples. The contents of epimedium C, icariin and baohuside I all increased significantly after intestinal digestion [58.70 ± 7.08, 47.15 ± 5.68 and (12.78 ± 0.55) mg · g-1] compared with gastric digestion [29.00 ± 5.65, 17.40 ± 4.55 and (2.77 ± 0.19) mg·g-1]. There were significant differences between sample after 0.5 h of colonic fermentation [64.22 ± 9.32, 51.26 ± 6.33 and (16.68 ± 3.19) mg·g-1] and other time points (24, 48 and 72 h) in components and the contents of active ingredient, and the content of these components all decreased with the fermentation time. The ability of scavenging ABTS free radicals [IC50=(0.29 ± 0.02) g · L-1] increased significantly compared with gastric digestion [(1.57 ± 0.02) g·L-1], and after 0.5 h of colonic fermentation, the ability also increased significantly. CONCLUSION Gastrointestinal digestion had a significant impact on the contents of active components in Epimedium, and the metabolism of these components mainly occurred in the colon. The intestinal digestion and colonic fermentation significantly improved the anti-ABTS activity of epimedium.
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The Qinba areas, located in the Central China, represent 317000 km2, cover 6 provinces. The major mountain of Qinba areas, the Qinling, separates China North and South. This region is one of the areas with the most bio?diversity and ecological importance in China and globally, and considered as natural gene bank and bio-resource bank. Qinba mountain areas, together with the Alps in Europe and the Rocky Mountains in North America, are known as the"Three sisters of the earth"by the geological and biological circles. Most of the lands in this region are protected as national park, natural reserve, water resource protection area, etc. These areas have well preserved ecosystem and breeding and habitat area for many endangered species of plants and animals, inculding Panda. In this region, there are more than 4000 species of higher plants, about 2000 species of medicinal plants and animals, 200 species of wild ornamental plants and 180 species of economic fungi with edible and medicinal value in those areas. Medicinal plant cultivation, eco-agricul?ture and ecotourism are the major industries in this region. The State Key Laboratory of Biological Resources and Ecological Environment of Qinba Areas, located in Hanzhong, the central city of Qinba, is focusing on pan-regional biological resources research and rational utilization, ecological protection, and comprehensive and coordinated regional development.
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OBJECTIVES: Osteoarthritis (OA) is a common degenerative joint disease with the pathological features of the reduced cartilage cellularity. Celastrol, a compound from Tripterygium wilfordii, exerted therapeutic effects on arthritis, but the potential mechanism remains unclear. METHODS: Tunicamycin was used to establish a model of OA in vitro, and ACLT surgery model in rats was applied to verify the mechanism. Chondrocytes were isolated from the knee articular cartilage of rabbit. MTT and flow cytometry assay were used to detect cell viability and apoptosis rate. Haematoxylin-eosin staining was used to assess for the histopathological changes. The activity and expression of apoptosis-related factors and ERs (endoplasmic reticulum stress)-related factors were detected by ELISA, WB, PCR and IHC, respectively. KEY FINDINGS: Celastrol exhibited significant enhancement on cell viability and reduced the rate of apoptosis in Tm-exposed chondrocytes. Celastrol reduced enzyme activity and protein expression of caspase-3, caspase-6 and caspase-9, decreased Bip, Atf6, Chop and Xbp-1 expression both at protein and mRNA levels. Celastrol showed a more significant effect on cell apoptosis rate and mRNA expression in the combination with 4-PBA. CONCLUSIONS: This study reveals that celastrol may prevent OA by inhibiting the ERs-mediated apoptosis. All these might supply beneficial hints for celastrol on OA treatment.
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Fator 6 Ativador da Transcrição/metabolismo , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Fator de Transcrição CHOP/metabolismo , Triterpenos/farmacologia , Animais , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Feminino , Osteoartrite/induzido quimicamente , Triterpenos Pentacíclicos , Ratos , Ratos Wistar , Triterpenos/química , Tunicamicina/farmacologiaRESUMO
Cathepsins are a group of lysosomal hydrolytic enzymes, broadly distributed in animals, and regulate various physiological processes. However, the immune functions of cathepsins are poorly understood in invertebrates. Therefore, to further provide information about the importance of cathepsins in the innate immune system of crustaceans, cathepsin A from Procambarus clarkii (Pc-cathepsin A) was characterized and its distribution in different tissues was determined. The immunological functions of the Pc-cathepsin A were also evaluated. The Pc-cathepsin A showed high sequence homology to cathepsins of other species, as it contained serine and histidine active sites. Quantitative RT-PCR analysis revealed that the expression of Pc-cathepsin A was highest in the gill, gut, and the hepatopancreas, with variable amounts in the muscle, stomach, heart, and hemocytes. The mRNA expression of Pc-cathepsin A was significantly increased in hepatopancreas challenged with lipopolysaccharide (LPS), peptidoglycan (PGN), and polycytidylic acid (poly I:C). The results of an in vivo analysis revealed that Pc-cathepsin A knockdown by double-stranded RNA in P. clarkii modulated the expression of immune-pathway associated genes in hepatopancreas. Collectively, these results suggest that Pc-cathepsin A modulates innate immune responses by affecting the expression of immune-pathway associated genes, thus revealing a regulatory link between Pc-cathepsin A and immune pathways in P. clarkii, and that Pc-cathepsin A plays an essential biological role in the immune defence against microbial pathogens.
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Astacoidea , Catepsina A/farmacologia , Fatores Imunológicos/farmacologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Catepsina A/química , Catepsina A/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Fatores Imunológicos/química , Fatores Imunológicos/genéticaRESUMO
BackgroundSevere ill patients with 2019 novel coronavirus (2019-nCoV) infection progressed rapidly to acute respiratory failure. We aimed to select the most useful prognostic factor for severe illness incidence. MethodsThe study prospectively included 61 patients with 2019-nCoV infection treated at Beijing Ditan Hospital from January 13, 2020 to January 31, 2020. Prognostic factor of severe illness was selected by the LASSO COX regression analyses, to predict the severe illness probability of 2019-CoV pneumonia. The predictive accuracy was evaluated by concordance index, calibration curve, decision curve and clinical impact curve. ResultsThe neutrophil-to-lymphocyte ratio (NLR) was identified as the independent risk factor for severe illness in patients with 2019-nCoV infection. The NLR had a c-index of 0.807 (95% confidence interval, 0.676-0.38), the calibration curves fitted well, and the decision curve and clinical impact curve showed that the NLR had superior standardized net benefit. In addition, the incidence of severe illness was 9.1% in age [≥] 50 and NLR < 3.13 patients, and half of patients with age [≥] 50 and NLR [≥] 3.13 would develop severe illness. Based on the risk stratification of NLR with age, the study developed a 2019-nCoV pneumonia management process. ConclusionsThe NLR was the early identification of risk factors for 2019-nCoV severe illness. Patients with age [≥] 50 and NLR [≥] 3.13 facilitated severe illness, and they should rapidly access to intensive care unit if necessary.
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BACKGROUND: The infraorbital groove can be corrected by lower blepharoplasty, microfat grafting, and soft tissue filler injection. Recently, multiple twisted polydioxanone threads were developed for facial rejuvenation. OBJECTIVE: This study aimed to examine the efficacy and associated risks of the use of new synthetic threads for infraorbital groove correction. METHODS: From March 2018 to June 2019, 40 patients (mean age: 43.4 years; range: 25-56 years) underwent transcutaneous multiple twisted thread insertion to correct the infraorbital groove. Three threads were inserted along the infraorbital groove on each side. The outcomes were assessed based on a comparison between preprocedure and postprocedure findings. Barton's grading and Global Aesthetic Improvement Scale scores were assessed by two physicians. Patient satisfaction with the aesthetic outcome of the procedure was evaluated at the end of the procedure and after 3 months. Ultrasonographic evaluation was performed to confirm that the threads had been properly placed. The anatomical layer in which the threads were placed was evaluated in a cadaveric study. RESULTS: The mean Barton grade improved significantly (P < .001) without decline throughout the 12-week period. Improvement was found in all patients who were designated with a score >2 ("improved"). More than 77.5% of the patients were satisfied with the outcomes, and the rest of the patients reported some extent of correction with little satisfaction. CONCLUSIONS: The findings indicate the benefits of the multiple twisted polydioxanone thread insertion in the treatment of patients with infraorbital groove without septal protrusion. This evaluation raised no major safety concerns.
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Blefaroplastia , Ritidoplastia , Adulto , Face , Humanos , Polidioxanona , RejuvenescimentoRESUMO
Immunoglobulin E (IgE) plays an important role in allergic diseases. Nevertheless, the source of IgE serological memory remains controversial. We reexamined the mechanism of serological memory in allergy using a dual reporter system to track IgE+ plasma cells in mice. Short-term allergen exposure resulted in the generation of IgE+ plasma cells that resided mainly in secondary lymphoid organs and produced IgE that was unable to degranulate mast cells. In contrast, chronic allergen exposure led to the generation of long-lived IgE+ plasma cells that were primarily derived from sequential class switching of IgG1, accumulated in the bone marrow, and produced IgE capable of inducing anaphylaxis. IgE+ plasma cells were found in the bone marrow of human allergic, but not nonallergic donors, and allergen-specific IgE produced by these cells was able to induce mast cell degranulation when transferred to mice. These data demonstrate that long-lived IgE+ bone marrow plasma cells arise during chronic allergen exposure and establish serological memory in both mice and humans.