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Recent insights into Parkinson's disease (PD), a progressive neurodegenerative disorder, suggest a significant influence of the gut microbiome on its pathogenesis and progression through the gut-brain axis. This study integrates 16S rRNA sequencing, high-throughput transcriptomic sequencing, and animal model experiments to explore the molecular mechanisms underpinning the role of gut-brain axis in PD, with a focus on short-chain fatty acids (SCFAs) mediated by the SCFA receptors FFAR2 and FFAR3. Our findings highlighted prominent differences in the gut microbiota composition between PD patients and healthy individuals, particularly in taxa such as Escherichia_Shigella and Bacteroidetes, which potentially impact SCFA levels through secondary metabolite biosynthesis. Notably, fecal microbiota transplantation (FMT) from healthy to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models significantly improved motor function, enhanced dopamine and serotonin levels in the striatum, and increased the number of dopaminergic neurons in the substantia nigra while reducing glial cell activation. This therapeutic effect was associated with increased levels of SCFAs such as acetate, propionate, and butyrate in the gut of MPTP-lesioned mice. Moreover, transcriptomic analyses revealed upregulated expression of FFAR2 and FFAR3 in MPTP-lesioned mice, indicating their crucial role in mediating the benefits of FMT on the central nervous system. These results provide compelling evidence that gut microbiota and SCFAs play a critical role in modulating the gut-brain axis, offering new insights into PD's etiology and potential targets for therapeutic intervention.
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Palatine tonsils are the only air-contacted lymphoid organs that constantly engage in crosstalk with commensal microorganisms and serve as the first handling sites against microbial antigens. While tonsil inflammations have been implicated in various autoimmune diseases, including rheumatoid arthritis (RA), the precise role of tonsillar microbiota in autoimmune pathogenesis remains inadequately characterized. In this study, we conducted a profiling of the tonsillar microbiota and identified a notable dysbiosis in RA patients, particularly within the Streptococcus genus. Specifically, RA patients exhibited an enrichment of pathogenic Streptococcus species, including S. pyogenes, S. dysgalactiae, and S. agalactiae. Colonization with these bacteria significantly exacerbated arthritis severity and increased autoimmune responses in collagen-induced arthritis (CIA). Furthermore, immunization with peptides derived from these pathogenic Streptococcus species directly induced experimental arthritis. Conversely, RA patients demonstrated a marked deficiency in commensal Streptococcus members, notably S. salivarius. Treatment of CIA mice with S. salivarius attenuated the progression of arthritis and downregulated autoimmune responses. These findings highlight a functional link between tonsillar microbiota and RA, shedding light on their contribution to autoimmunity.
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BACKGROUND: Knee osteoarthritis (KOA) is a very common musculoskeletal disorder, and patients with KOA often exhibit significant quadriceps femoris muscle atrophy. It is well established that curcumin (CUR) exerts protective effects on skeletal muscle. However, the efficacy of CUR in treating KOA-induced quadriceps femoris muscle atrophy and its underlying mechanisms remain uncertain. In this study, we employed network pharmacology to investigate the mechanism by which CUR promotes regenerative repair of the quadriceps femoris muscle in rats with KOA. METHODS: The potential targets of CUR were obtained from Swiss Target Prediction. The targets of skeletal muscle regeneration were identified from GeneCard and OMIM. A Venn diagram was generated to visualize the intersection of CUR targets and skeletal muscle regeneration targets, and the core targets were identified using STRING. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted using DAVID. Finally, the network pharmacology results were further validated by establishing a KOA rat model using the Hulth method. RESULTS: Network pharmacology analysis and molecular docking results revealed that CUR affects skeletal muscle regeneration through multiple targets and pathways. In vivo experimental results were validated by demonstrating that KOA causes atrophy and induces apoptosis in the quadriceps femoris muscle. Furthermore, CUR was shown to inhibit apoptosis in the quadriceps femoris muscle by regulating STAT3 and FOS, as well as the PI3K/AKT signaling pathway. CONCLUSIONS: Our study revealed the apoptosis-inhibiting effects of CUR and its underlying mechanisms. Consequently, CUR has the potential to improve quadriceps femoris muscle atrophy caused by KOA.
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BACKGROUND: Oral cancer is one of the most common cancers in China and seriously threaten life and health of Chinese people. We analysed the trends and disparities of oral cancer mortality rates and the disease burden of oral cancer in China from 2006 to 2021 to provide a reference for its prevention and control. METHODS: Annual death data for oral cancer was gleaned from the China Death Surveillance Database. The age-standardized mortality rate (ASMR), annual percentage change (APC), and average APC (AAPC) were used to analyze the trend of mortality. Loss of life expectancy (LLE) and years of life lost (YLL) were adopted to assess disease burden. RESULTS: From 2006 to 2021, the overall ASMR of oral cancer lightly declined (AAPC: - 0.97%; 95% CI: - 1.89%, - 0.04%), and the similar trend was observed among females (AAPC: - 1.22%; 95% CI: - 1.89%, - 0.55%). The ASMR of males was 2.31-3.16 times higher than that of females per year. The median of LLE for overall, males and females caused by oral cancer from 2006 to 2021 were 0.05, 0.06 and 0.03 years, respectively. There was a decrease of standardized YLL rate from 2006 to 2021 for overall (AAPC: - 1.31%, 95% CI: - 2.24% ~ - 0.37%) and for female (AAPC: - 1.63%, 95% CI: - 2.30% ~ - 0.95%). ASMR in urban areas was 1.02-1.28 times higher than that in rural areas from 2006 to2011, but 0.85-0.97 times lower in urban areas than that in rural areas from 2018 to 2021. The disease burden was higher in urban areas than in rural areas in 2006, whereas the reverse was observed in 2021. CONCLUSIONS: There are severe health gaps and disparities in trends between sexes and different areas in China. Males and rural populations need to be focused on targeted interventions for the main influencing factors.
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Efeitos Psicossociais da Doença , Expectativa de Vida , Neoplasias Bucais , Humanos , China/epidemiologia , Masculino , Neoplasias Bucais/mortalidade , Neoplasias Bucais/epidemiologia , Feminino , Pessoa de Meia-Idade , Expectativa de Vida/tendências , Idoso , Adulto , Bases de Dados Factuais , Mortalidade/tendências , População Rural/estatística & dados numéricos , Vigilância da População , Idoso de 80 Anos ou maisRESUMO
Precise diagnostic biomarkers of anticitrullination protein antibody (ACPA)-negative and early-stage RA are still to be improved. We aimed to screen autoantibodies in ACPA-negative patients and evaluated their diagnostic performance. The human genome-wide protein arrays (HuProt arrays) were used to define specific autoantibodies from the sera of 182 RA patients and 261 disease and healthy controls. Statistical analysis was performed with SPSS 17.0. In Phase I study, 51 out of 19,275 recombinant proteins covering the whole human genome were selected. In Phase II validation study, anti-ANAPC15 (anaphase promoting complex subunit 15) exhibited 41.8% sensitivity and 91.5% specificity among total RA patients. There were five autoantibodies increased in ACPA-negative RA, including anti-ANAPC15, anti-LSP1, anti-APBB1, anti-parathymosin, and anti-UBL7. Anti-parathymosin showed the highest prevalence of 46.2% (p = 0.016) in ACPA-negative early stage (<2 years) RA. To further improve the diagnostic efficacy, a prediction model was constructed with 44 autoantibodies. With increased threshold for RA calling, the specificity of the model is 90.8%, while the sensitivity is 66.1% (87.8% in ACPA-positive RA and 23.8% in ACPA-negative RA) in independent testing patients. Therefore, HuProt arrays identified RA-associated autoantibodies that might become possible diagnostic markers, especially in early stage ACPA-negative RA.
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Spinibarbus sinensis, also known as Qingbo, is an important economic fish in China. However, the detailed mechanisms underlying its growth are still unknown. To excavate the genes and signaling pathways related to its growth, we compared the transcriptome profiles of the hepatopancreas tissues of S. sinensis, with two groups of growth rate for evaluation. An average of 66,304,909 and 68,739,585 clean reads were obtained in the fast growth (FG) and slow growth (SG) group, respectively. The differential gene expression analysis results showed that 272 differentially expressed genes (DEGs) were screened between the FG and SG groups, including 101 up-regulated genes and 171 down-regulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results showed that GO terms related to metabolic process, organic substance metabolic process, and catalytic activity were enriched, pathway signals related to steroid biosynthesis and protein digestion and absorption were also detected. Meanwhile, the potential key regulatory genes sst2, fndc4, and cckra related to the growth of S. sinensis were screened. Reverse transcript fluorescence quantitative PCR (RT-qPCR) validation of 18 DEGs associated with growth differences showed that the RT-qPCR results were consistent with RNA-seq analysis, and nine genes, stk31, gpr149, angptl1, fstl1, sik1, ror2, nlrc3, pdlim2, and nav2 were significantly expressed in the FG group. bmp1, stc1, gpatch8, sstrt2, s100a1, ktf6, cckar6, sync1, bhlha15, a total of nine genes were significantly expressed in the SG group. This study provides basic information for improving the growth characteristics of S. sinensis and the functional research of candidate genes.
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Perfilação da Expressão Gênica , Hepatopâncreas , Transcriptoma , Animais , Hepatopâncreas/metabolismo , Hepatopâncreas/crescimento & desenvolvimento , Transcriptoma/genética , Perfilação da Expressão Gênica/métodos , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Ontologia GenéticaRESUMO
BACKGROUND: Severe COVID-19 infection has been associated with the development of pulmonary fibrosis, a condition that significantly affects patient prognosis. Understanding the underlying cellular communication mechanisms contributing to this fibrotic process is crucial. OBJECTIVE: In this study, we aimed to investigate the role of the TNFSF12-TNFRSF12A pathway in mediating communication between alveolar macrophages and fibroblasts, and its implications for the development of pulmonary fibrosis in severe COVID-19 patients. METHODS: We conducted single-cell RNA sequencing (scRNA-seq) analysis using lung tissue samples from severe COVID-19 patients and healthy controls. The data was processed, analyzed, and cell types were annotated. We focused on the communication between alveolar macrophages and fibroblasts and identified key signaling pathways. In vitro experiments were performed to validate our findings, including the impact of TNFRSF12A silencing on fibrosis reversal. RESULTS: Our analysis revealed that in severe COVID-19 patients, alveolar macrophages communicate with fibroblasts primarily through the TNFSF12-TNFRSF12A pathway. This communication pathway promotes fibroblast proliferation and expression of fibrotic factors. Importantly, silencing TNFRSF12A effectively reversed the pro-proliferative and pro-fibrotic effects of alveolar macrophages. CONCLUSION: The TNFSF12-TNFRSF12A pathway plays a central role in alveolar macrophage-fibroblast communication and contributes to pulmonary fibrosis in severe COVID-19 patients. Silencing TNFRSF12A represents a potential therapeutic strategy for mitigating fibrosis in severe COVID-19 lung disease.
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COVID-19 , Fibroblastos , Macrófagos Alveolares , Fibrose Pulmonar , Transdução de Sinais , Receptor de TWEAK , Humanos , COVID-19/complicações , COVID-19/patologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/complicações , Receptor de TWEAK/metabolismo , Receptor de TWEAK/genética , Citocina TWEAK/metabolismo , Comunicação Celular , Masculino , SARS-CoV-2 , Feminino , Pessoa de Meia-Idade , Proliferação de Células , Pulmão/patologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly cancer with no clinically ideal biomarkers for early diagnosis. The objective of this study was to develop and validate a user-friendly diagnostic tool for early ESCC detection. METHODS: The study encompassed three phases: discovery, verification, and validation, comprising a total of 1309 individuals. Serum autoantibodies were profiled using the HuProtTM human proteome microarray, and autoantibody levels were measured using the enzyme-linked immunosorbent assay (ELISA). Twelve machine learning algorithms were employed to construct diagnostic models, and evaluated using the area under the receiver operating characteristic curve (AUC). The model application was facilitated through R Shiny, providing a graphical interface. RESULTS: Thirteen autoantibodies targeting TAAs (CAST, FAM131A, GABPA, HDAC1, HDGFL1, HSF1, ISM2, PTMS, RNF219, SMARCE1, SNAP25, SRPK2, and ZPR1) were identified in the discovery phase. Subsequent verification and validation phases identified five TAAbs (anti-CAST, anti-HDAC1, anti-HSF1, anti-PTMS, and anti-ZPR1) that exhibited significant differences between ESCC and control subjects (P < 0.05). The support vector machine (SVM) model demonstrated robust performance, with AUCs of 0.86 (95% CI: 0.82-0.89) in the training set and 0.83 (95% CI: 0.78-0.88) in the test set. For early-stage ESCC, the SVM model achieved AUCs of 0.83 (95% CI: 0.79-0.88) in the training set and 0.83 (95% CI: 0.77-0.90) in the test set. Notably, promising results were observed for high-grade intraepithelial neoplasia, with an AUC of 0.87 (95% CI: 0.77-0.98). The web-based implementation of the early ESCC diagnostic tool is publicly accessible at https://litdong.shinyapps.io/ESCCPred/ . CONCLUSION: This study provides a promising and easy-to-use diagnostic prediction model for early ESCC detection. It holds promise for improving early detection strategies and has potential implications for public health.
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BACKGROUND: Primary pulmonary myxoid sarcoma (PPMS) is a rare, low-grade malignant tumor, constituting approximately 0.2% of all lung tumors. Despite its rarity, PPMS possesses distinctive histological features and molecular alterations, notably the presence of EWSR1-CREB1 gene fusion. However, its precise tissue origin remains elusive, posing challenges in clinical diagnosis. CASE DEMONSTRATION: A 20-year-old male patient underwent a routine physical examination 6 months prior, revealing a pulmonary mass. Following surgical excision, microscopic evaluation unveiled predominantly short spindle-shaped tumor cells organized in a fascicular, beam-like, or reticular pattern. The stromal matrix exhibited abundant mucin, accompanied by lymphocytic and plasma cell infiltration, with Russell bodies evident in focal areas. Immunophenotypic profiling revealed positive expression of vimentin and epithelial membrane antigen in tumor cells, whereas smooth muscle actin and S-100, among others, were negative. Ki-67 proliferation index was approximately 5%. Subsequent second-generation sequencing identified the characteristic EWSR1-CREB1 gene fusion. The definitive pathological diagnosis established PPMS. The patient underwent no adjuvant chemotherapy or radiotherapy and remained recurrence-free during a 30-month follow-up period. CONCLUSIONS: We report a rare case of PPMS located within the left lung lobe interlobar fissure, featuring Russell body formation within the tumor stroma, a novel finding in PPMS. Furthermore, the histomorphological characteristics of this case highlight the diagnostic challenge it poses, as it may mimic inflammatory myofibroblastic tumor, extraskeletal myxoid chondrosarcoma, or hemangiopericytoma-like fibrous histiocytoma. Therefore, accurate diagnosis necessitates an integrated approach involving morphological, immunohistochemical, and molecular analyses.
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Neoplasias Pulmonares , Humanos , Masculino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Adulto Jovem , Proteínas de Fusão Oncogênica/genética , Tomografia Computadorizada por Raios X , Mixossarcoma/patologia , Mixossarcoma/genética , Mixossarcoma/cirurgia , Mixossarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patologia , Sarcoma/diagnóstico , Sarcoma/cirurgia , Pulmão/patologia , Pulmão/diagnóstico por imagemRESUMO
Biomarkers screening is a benefit approach for early diagnosis of major diseases. In this study, magnetic nanoparticles (MNPs) have been utilized as labels to establish a multi-line immunochromatography (MNP-MLIC) for simultaneous detection of carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA 19-9), and alpha-fetoprotein (AFP) in a single serum sample. Under the optimal parameters, the three biomarkers can be rapidly and simultaneously qualitative screening within 15 min by naked eye. As for quantitative detection, the MNP-MLIC test strips were precisely positioned and captured by a smartphone, and signals on the test and control lines were extracted by ImageJ software. The signal ratio of test and control lines has been calculated and used to plot quantitative standard curves with the logarithmic concentration, of which the correlation coefficients are more than 0.99, and the limit of detection for CEA, CA 19-9, and AFP were 0.60 ng/mL, 1.21 U/mL, and 0.93 ng/mL, respectively. The recoveries of blank serum were 75.0 ~ 112.5% with the relative standard deviation ranging from 2.5 to 15.3%, and the specificity investigation demonstrated that the MNP-MLIC is highly specific to the three biomarkers. In conclusion, the developed MNP-MLIC offers a rapid, simple, accurate, and highly specific method for simultaneously detecting multiple biomarkers in serum samples, which provides an efficient and accurate approach for the early diagnosis of diseases.
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Antígeno Carcinoembrionário , Cromatografia de Afinidade , Limite de Detecção , Nanopartículas de Magnetita , alfa-Fetoproteínas , Humanos , Antígeno Carcinoembrionário/sangue , alfa-Fetoproteínas/análise , Nanopartículas de Magnetita/química , Cromatografia de Afinidade/métodos , Biomarcadores Tumorais/sangue , Antígeno CA-19-9/sangue , Biomarcadores/sangueRESUMO
Doxorubicin (DOX) is an anti-tumor agent for chemotherapy, but its use is often hindered by the severe and life-threatening side effect of cardiovascular toxicity. In recent years, studies have focused on dysregulated iron metabolism and ferroptosis, a unique type of cell death induced by iron overload, as key players driving the development of DOX-induced cardiotoxicity (DIC). Recent advances have demonstrated that DOX disturbs normal cellular iron metabolism, resulting in excessive iron accumulation and ferroptosis in cardiomyocytes. This review will explore how dysregulated iron homeostasis and ferroptosis drive the progression of DIC. We will also discuss the current approaches to target iron metabolism and ferroptosis to mitigate DIC. Besides, we will discuss the limitations and challenges for clinical translation for these therapeutic regimens.
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Cardiotoxicidade , Doxorrubicina , Ferroptose , Ferro , Humanos , Doxorrubicina/efeitos adversos , Ferro/metabolismo , Cardiotoxicidade/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Ferroptose/efeitos dos fármacos , Animais , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologiaRESUMO
Scarce and expensive iridium oxide is still the cornerstone catalyst of polymer-electrolyte membrane electrolyzers for green hydrogen production because of its exceptional stability under industrially relevant oxygen evolution reaction (OER) conditions. Earth-abundant transition metal oxides used for this task, however, show poor long-term stability. We demonstrate here the use of nitrogen-doped cobalt oxide as an effective iridium substitute. The catalyst exhibits a low overpotential of 240 mV at 10 mA cm-2 and negligible activity decay after 1000 h of operation in an alkaline electrolyte. Incorporation of nitrogen dopants not only triggers the OER mechanism switched from the traditional adsorbate evolution route to the lattice oxygen oxidation route but also achieves oxygen nonbonding (ONB) states as electron donors, thereby preventing structural destabilization. In a practical anion-exchange membrane water electrolyzer, this catalyst at anode delivers a current density of 1000 mA cm-2 at 1.78 V and an electrical efficiency of 47.8 kW-hours per kilogram hydrogen.
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Osteoclast-mediated bone erosion and deformation represent significant pathological features in rheumatoid arthritis (RA). Myeloid-derived suppressor cells (MDSCs) and B cells have emerged as key contributors to the progression of RA. Nevertheless, their involvement, especially the interaction in RA osteoclastogenesis remains elusive. In this study, our results revealed a marked expansion of MDSCs in RA patients, and importantly, their abundance was positively correlated with radiographic damage evaluated by the Sharp/van der Heijde score. Notably, MDSCs derived from both RA patients and arthritic mice exhibited a heightened propensity to differentiate into osteoclasts compared with those from healthy individuals. Intriguingly, we observed that B cells from RA patients could augment the osteoclastogenic potential of MDSCs, which was also observed in arthritic mice. The impact of B cells on MDSC-mediated osteoclastogenesis was found to be most pronounced in switched memory B cells, followed by CD21low B cells and naïve B cells. MDSCs from B-cell-deficient mice exhibited diminished capacity to differentiate into osteoclasts, accompanied by distinct gene expression profiles associated with osteoclastogenesis. Taken together, our findings suggested that MDSCs were important osteoclast precursors primed by B cells in RA, serving as novel therapeutic targets for the persistent disease.
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In this study, a novel array electrospinning collector was devised to generate two distinct regenerated silk fibroin (SF) fibrous membranes: ordered and disordered. Leveraging electrostatic forces during the electrospinning process allowed precise control over the orientation of SF fiber, resulting in the creation of membranes comprising both aligned and randomly arranged fiber layers. This innovative approach resulted in the development of large-area membranes featuring exceptional stability due to their alternating patterned structure, achievable through expansion using the collector, and improving the aligned fiber membrane mechanical properties. The study delved into exploring the potential of these membranes in augmenting wound healing efficiency. Conducting in vitro toxicity assays with adipose tissue-derived mesenchymal stem cells (AD-MSCs) and normal human dermal fibroblasts (NHDFs) confirmed the biocompatibility of the SF membranes. We use dual perspectives on exploring the effects of different conditioned mediums produced by cells and structural cues of materials on NHDFs migration. The nanofibers providing the microenvironment can directly guide NHDFs migration and also affect the AD-MSCs and NHDFs paracrine effects, which can improve the chemotaxis of NHDFs migration. The ordered membrane, in particular, exhibited pronounced effectiveness in guiding directional cell migration. This research underscores the revelation that customizable microenvironments facilitated by SF membranes optimize the paracrine products of mesenchymal stem cells and offer valuable physical cues, presenting novel prospects for enhancing wound healing efficiency.
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Cell-laden bioprinting is a promising biofabrication strategy for regenerating bioactive transplants to address organ donor shortages. However, there has been little success in reproducing transplantable artificial organs with multiple distinctive cell types and physiologically relevant architecture. In this study, an omnidirectional printing embedded network (OPEN) is presented as a support medium for embedded 3D printing. The medium is state-of-the-art due to its one-step preparation, fast removal, and versatile ink compatibility. To test the feasibility of OPEN, exceptional primary mouse hepatocytes (PMHs) and endothelial cell line-C166, were used to print hepatospheroid-encapsulated-artificial livers (HEALs) with vein structures following predesigned anatomy-based printing paths in OPEN. PMHs self-organized into hepatocyte spheroids within the ink matrix, whereas the entire cross-linked structure remained intact for a minimum of ten days of cultivation. Cultivated HEALs maintained mature hepatic functions and marker gene expression at a higher level than conventional 2D and 3D conditions in vitro. HEALs with C166-laden vein structures promoted endogenous neovascularization in vivo compared with hepatospheroid-only liver prints within two weeks of transplantation. Collectively, the proposed platform enables the manufacture of bioactive tissues or organs resembling anatomical architecture, and has broad implications for liver function replacement in clinical applications.
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Bioimpressão , Veias Hepáticas , Hepatócitos , Fígado , Neovascularização Fisiológica , Impressão Tridimensional , Esferoides Celulares , Animais , Bioimpressão/métodos , Hepatócitos/citologia , Camundongos , Esferoides Celulares/citologia , Fígado/citologia , Transplante de Fígado , Fígado Artificial , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Linhagem Celular , Camundongos Endogâmicos C57BL , MasculinoRESUMO
BACKGROUND/AIM: Depression is associated with metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms underlying the interaction between them are still poorly known. MATERIALS AND METHODS: In this study, mice on a choline deficiency, L-amino acid-defined, high-fat diet (CDAHFD) developing steatosis were challenged with chronic restraint stress (CRS), a protocol widely used to induce depression. The development of depression and steatosis was evaluated using histopathology analysis, ELISA, q-PCR and Western Blot. RESULTS: The contribution of the activated HPA axis to hepatic steatosis progress was fully established, which was validated using a hepatocyte model. Histopathological and biochemical analysis indicated that steatosis was exacerbated by CRS challenge, and behavioral tests indicated that the mice developed depression. Among the screened endocrinal pathways, the hypothalamic-pituitary-adrenal (HPA) axis was significantly activated and the synergistic effect of CDAHFD and CRS in activating the HPA axis was observed. In the hypothalamus, expression of corticotropin-releasing hormone (CRH) was increased by 86% and the protein levels of hypothalamic CRH were upregulated by 25% to 33% by CRS treatment. Plasma CRH levels were elevated by 45-56% and plasma adrenocorticotropic hormone (ACTH) levels were elevated by 29-58% by CRS treatment. In the liver, target genes of the HPA axis were activated, accompanied by disruption of the lipid metabolism and progression of steatohepatitis. The lipid metabolism in the Hepa1-6 cell line treated with endogenous corticosterone (CORT) was in accordance with the aforementioned in vivo responses. CONCLUSION: Depression aggravated hepatic steatosis in CDAHFD-fed mice by activating the HPA axis. The risk of NAFLD development should be fully considered in depressive patients and improvement of psychotic disorders could be an etiological treatment strategy for them.
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Depressão , Modelos Animais de Doenças , Sistema Hipotálamo-Hipofisário , Hepatopatia Gordurosa não Alcoólica , Sistema Hipófise-Suprarrenal , Animais , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Camundongos , Depressão/metabolismo , Depressão/etiologia , Depressão/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Masculino , Camundongos Endogâmicos C57BL , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/genética , Dieta Hiperlipídica/efeitos adversos , Hormônio Adrenocorticotrópico/sangue , Fígado/metabolismo , Fígado/patologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Corticosterona/sangueRESUMO
Background: Autoantibodies targeting tumor-associated antigens (TAAbs) have emerged as promising biomarkers for early cancer detection. This research aimed to assess the diagnostic capacity of anti-BIRC5 autoantibody in detecting AFP-negative hepatocellular carcinoma (ANHCC). Methods: This research was carried out in three stages (discovery phase, validation phase, and evaluation phase) and included a total of 744 participants. Firstly, the anti-BIRC5 autoantibody was discovered using protein microarray, exhibiting a higher positive rate in ANHCC samples (ANHCCs) compared to normal control samples (NCs). Secondly, the anti-BIRC5 autoantibody was validated through enzyme-linked immunosorbent assay (ELISA) in 85 ANHCCs and 85 NCs from two clinical centers (Zhengzhou and Nanchang). Lastly, the diagnostic usefulness of the anti-BIRC5 autoantibody for hepatocellular carcinoma (HCC) was evaluated by ELISA in a cohort consisting of an additional 149 AFP-positive hepatocellular carcinoma samples (APHCCs), 95 ANHCCs and 244 NCs. The association of elevated autoantibody to high expression of BIRC5 in HCC was further explored by the database from prognosis, immune infiltration, DNA methylation, and gene mutation level. Results: In the validation phase, the area under the ROC curve (AUC) of anti-BIRC5 autoantibody to distinguish ANHCCs from NCs in Zhengzhou and Nanchang centers was 0.733 and 0.745, respectively. In the evaluation phase, the AUCs of anti-BIRC5 autoantibody for identifying ANHCCs and HCCs from NCs were 0.738 and 0.726, respectively. Furthermore, when combined with AFP, the AUC for identifying HCCs from NCs increased to 0.914 with a sensitivity of 77.5% and specificity of 91.8%. High expression of BIRC5 gene is not only correlated with poor prognosis of HCCs, but also significantly associated with infiltration of immune cells, DNA methylation, and gene mutation. Conclusion: The findings suggest that the anti-BIRC5 autoantibody could serve as a potential biomarker for ANHCC, in addition to its supplementary role alongside AFP in the diagnosis of HCC. Next, we can carry out specific verification and explore the function of anti-BIRC5 autoantibody in the occurrence and development of HCC.
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Autoanticorpos , Biomarcadores Tumorais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Survivina , alfa-Fetoproteínas , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Autoanticorpos/sangue , Autoanticorpos/imunologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/genética , Masculino , Feminino , Pessoa de Meia-Idade , Survivina/genética , Survivina/imunologia , alfa-Fetoproteínas/imunologia , alfa-Fetoproteínas/análise , Ensaio de Imunoadsorção Enzimática , AdultoRESUMO
Reduction of carbon dioxide (CO2) by renewable electricity to produce multicarbon chemicals, such as ethylene (C2H4), continues to be a challenge because of insufficient Faradaic efficiency, low production rates, and complex mechanistic pathways. Here, we report that the rate-determining steps (RDS) on common copper (Cu) surfaces diverge in CO2 electroreduction, leading to distinct catalytic performances. Through a combination of experimental and computational studies, we reveal that CâC bond-making is the RDS on Cu(100), whereas the protonation of *CO with adsorbed water becomes rate-limiting on Cu(111) with a higher energy barrier. On an oxide-derived Cu(100)-dominant Cu catalyst, we reach a high C2H4 Faradaic efficiency of 72%, partial current density of 359 mA cm-2, and long-term stability exceeding 100 h at 500 mA cm-2, greatly outperforming its Cu(111)-rich counterpart. We further demonstrate constant C2H4 selectivity of >60% over 70 h in a membrane electrode assembly electrolyzer with a full-cell energy efficiency of 23.4%.
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BACKGROUND: Although normal acute phase reactants (APRs) play an important role in assessing disease activity of rheumatoid arthritis (RA), some studies pointed out the discordance between disease activity and APR level. Neutrophil-to-lymphocyte ratios (NLRs), platelet-to-lymphocyte ratios (PLRs) and lymphocyte-to-monocyte ratios (LMRs) have been reported to be sensitive measures of inflammatory reaction. This study aims to explore the value of these haematological makers in assessment of APR-negative RA patients. METHODS: Out of a cohort of 418 consecutive patients with RA, we enrolled 135 patients with normal APR for this study. We performed ultrasound assessments to evaluate synovitis and bone erosion in the affected joints. Synovitis was evaluated by ultrasound grey scale (GS) and power Doppler (PD) with semi-quantitative scoring (0-3). Demographic, clinical and laboratory data were collected from the patients. Disease Activity Score-28 joints (DAS28), NLR, MLR and PLR were calculated. RESULTS: In RA patients with normal APR, PLR exhibited a positive correlation with ultrasound-detected synovitis and bone erosion, whereas NLR, MLR showed no significant correlation with ultrasonography parameters. The area under the ROC curve (AUC) for identifying synovitis with a GS grade ≥2 based on a PLR cutoff value of ≥159.6 was 0.7868 (sensitivity: 80.95%, specificity: 74.24%). For synovitis with a PD grade ≥2, the AUC was 0.7690, using a PLR cutoff value of ≥166.1 (sensitivity: 68.0%, specificity: 83.87%). CONCLUSIONS: Our findings suggested that PLR might be a reliable and cost-effective marker for identifying moderate-to-severe synovitis in RA patients with normal APR.
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Artrite Reumatoide , Biomarcadores , Linfócitos , Sinovite , Humanos , Sinovite/diagnóstico por imagem , Sinovite/sangue , Sinovite/diagnóstico , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Adulto , Plaquetas , Proteínas de Fase Aguda/análise , Idoso , Índice de Gravidade de Doença , Contagem de Plaquetas , Curva ROC , Contagem de Linfócitos , NeutrófilosRESUMO
Environmental lipids are essential for fueling tumor energetics, but whether these exogenous lipids transported into cancer cells facilitate immune escape remains unclear. Here, we find that CD36, a transporter for exogenous lipids, promotes acute myeloid leukemia (AML) immune evasion. We show that, separately from its established role in lipid oxidation, CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway, and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MYD88 palmitoylation. Subsequently, NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably, high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling, leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression.