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Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets.
Assuntos
Hematopoese/imunologia , Macrófagos/imunologia , Receptores Nucleares Órfãos/imunologia , Baço/imunologia , Animais , Benzoatos/farmacologia , Benzilaminas/farmacologia , Diferenciação Celular/imunologia , Citometria de Fluxo , Imunidade Celular/imunologia , Imuno-Histoquímica , Receptores X do Fígado , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Fluorescência , Receptores Nucleares Órfãos/agonistas , Transdução de Sinais/imunologia , Organismos Livres de Patógenos Específicos , Baço/citologiaRESUMO
Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.
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Fator Neurotrófico Derivado de Linhagem de Célula Glial , Macrófagos , Microglia , Doença de Parkinson , Animais , Masculino , Camundongos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Exossomos/metabolismo , Terapia Genética/métodos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doença de Parkinson/terapia , Doença de Parkinson/metabolismo , Substância Negra/metabolismoRESUMO
Acetylene (C2 H2 ) monitoring in real time and online is essential for erasing transformer risks and guaranteeing normal equipment operation and operator safety. This study examines the direct fabrication of ultrathin SnO2 nanowalls on Ag-Pd substrates using a simple solvothermal method that doesn't demand the use of any additional motivators or templates. The thickness and shape of the nanowalls can be controlled by varying the cetyl trimethyl ammonium bromide (CTAB) concentration in the solvent. As observed, the gas sensor (SnO2 -3) fabricated by 2.4â g CTAB exhibits superior gas-sensing features. This is primarily due to the hollow structure constructed by the arrangement of nanowalls, which delivers not only enough gas diffusion pathways but also enough reaction sites during the gas sensing processes. The findings suggest that low-cost SnO2 nanowalls created using a straightforward procedure could be taken into consideration as prospective candidates for use in industrial C2 H2 sensing applications.
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Tacrolimus, one of the macrolide calcineurin inhibitors, is the most frequently used immunosuppressant after transplantation. Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism. In this study, we investigated the mode of action and underlying mechanisms of this adverse reaction. Mice were administered tacrolimus (2.5 mg·kg-1·d-1, i.g.) for 10 weeks, then euthanized; the blood samples and liver tissues were collected for analyses. We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver. Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus. We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids, but markedly decreased fatty acid oxidation (FAO) in AML12 cells. Furthermore, we showed that tacrolimus dramatically decreased the expression of HMGCS2, the rate-limiting enzyme of ketogenesis, with decreased ketogenesis in AML12 cells, which was responsible for lipid deposition in normal hepatocytes. Moreover, we revealed that tacrolimus inhibited forkhead box protein O1 (FoxO1) nuclear translocation by promoting FKBP51-FoxO1 complex formation, thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells. The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation, which promoted mitochondrial protein acetylation, thereby resulting in FAO function inhibition. Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition, thus removing the lipid deposition in hepatocytes. Collectively, this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus, resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition, providing an alternative target for reversing tacrolimus-induced adverse reaction.
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Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1-/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.
Assuntos
Proteínas de Membrana/antagonistas & inibidores , Nucleotídeos Cíclicos/metabolismo , Animais , Sítios de Ligação , Biotinilação , Morte Celular , Exodesoxirribonucleases/deficiência , Humanos , Inflamação/patologia , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Mutação/genética , Fosfoproteínas/deficiência , Domínios Proteicos , Transdução de SinaisRESUMO
Alkaline metal-air batteries are advantageous in high voltage, low cost, and high safety. However, metal anodes are heavily eroded in strong alkaline electrolytes, causing serious side reactions including dendrite growth, passivation, and hydrogen evolution. To address this limitation, we successfully synthesized an organic N-heterocycle compound (NHCC) to serve as an alternative anode. This compound not only exhibits remarkable stability but also possesses a low redox potential (-1.04â V vs. Hg/HgO) in alkaline environments. To effectively complement the low redox potential of the NHCC anode, we designed a dual-salt highly concentrated electrolyte (4.0â M KOH+10.0â M KCF3 SO3 ). This electrolyte expands the electrochemical stability window to 2.3â V through the robust interaction between the O atom in H2 O molecule with the K+ of KCF3 SO3 (H-Oâ â â KCF3 SO3 ). We further demonstrated the K+ uptaken/extraction storage mechanism of NHCC anodes. Consequently, the alkaline aqueous NHCC anode-air batteries delivers a high battery voltage of 1.6â V, high-rate performance (101.9â mAh g-1 at 100â A g-1 ) and long cycle ability (30,000â cycles). Our work offers a molecular engineering strategy for superior organic anode materials and develops a novel double superconcentrated conductive salt electrolyte for the construction of high-rate, long-cycle alkaline aqueous organic anode-air batteries.
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Pancreatic sympathetic innervation can directly affect the function of islet. The disorder of sympathetic innervation in islets during the occurrence of type 1 diabetes (T1D) has been reported to be controversial with the inducing factor unclarified. Several studies have uncovered the critical role that sympathetic signals play in controlling the local immune system. The survival and function of endocrine cells can be regulated by immune cell infiltration in islets. In the current review, we focused on the impact of sympathetic signals working on islets cell regulation, and discussed the potential factors that can induce the sympathetic innervation disorder in the islets. We also summarized the effect of interference with the islet sympathetic signals on the T1D occurrence. Overall, a comprehensive understanding of the regulatory effect of sympathetic signals on islet cells and local immune system could facilitate better strategies design to control inflammation and protect ß cells in T1D therapy.
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Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Humanos , InsulinaRESUMO
Cold tumor immune microenvironment (TIME) of pancreatic cancer (PC) with minimal dendritic cell (DC) and T cell infiltration can result in insufficient immunotherapy and chemotherapy. While gemcitabine (GEM) is a first-line chemotherapeutic drug for PC, its efficacy is reduced by immunosuppression and drug resistance. Ginsenoside Rh2 (Rh2) is known to have anti-cancer and immunomodulatory properties. Combining GEM with Rh2 may thus overcome immunosuppression and induce lasting anti-tumor immunity in PC. Here, we showed that after GEM-Rh2 therapy, there was significantly greater tumor infiltration by DCs. Caspase recruitment domain-containing protein 9 (CARD9), a central adaptor protein, was strongly up-regulated DCs with GEM-Rh2 therapy and promoted anti-tumor immune responses by DCs. CARD9 was found to be a critical target for Rh2 to enhance DC function. However, GEM-Rh2 treatment did not achieve the substantial anti-PC efficacy in CARD9-/- mice as in WT mice. The adoptive transfer of WT DCs to DC-depleted PC mice treated with GEM-Rh2 elicited strong anti-tumor immune responses, although CARD9-/- DCs were less effective than WT DCs. Our results showed that GEM-Rh2 may reverse cold TIME by enhancing tumor immunogenicity and decreasing the levels of immunosuppressive factors, reactivating DCs via the CARD9-BCL10-MALT1/ NF-κB pathway. Our findings suggest a potentially feasible and safe treatment strategy for PC, with a unique mechanism of action. Thus, Rh2 activation of DCs may remodel the cold TIME and optimize GEM chemotherapy for future therapeutic use.
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NF-kappa B , Neoplasias Pancreáticas , Animais , Camundongos , NF-kappa B/metabolismo , Gencitabina , Imunidade , Células Dendríticas , Linhagem Celular Tumoral , Microambiente Tumoral , Proteína 10 de Linfoma CCL de Células B , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Neoplasias PancreáticasRESUMO
Two-dimensional graphdiyne (GDY) formed by sp and sp2 hybridized carbon has been found to be an efficient toxic gas sensing material by density functional theory (DFT). However, little experimental research concerning its gas sensing capability has been reported owing to the complex preparation process and harsh experimental conditions. Herein, porous GDY nanosheets are successfully synthesized through a facile solvothermal synthesis technique by using CuO microspheres (MSs) as both template and source of catalyst. The porous GDY nanosheets exhibit a broadband optical absorption, rendering it suitable for the light-driven optoelectronic gas sensing applications. The GDY-based gas sensor was demonstrated to have excellent reversible to NO2 behaviors at 25 °C for the first time. More importantly, higher response value and faster response-recovery time once exposed to NO2 gas molecules are achieved by the illumination of UV light. In this way, our work paves the way for the exploration of GDY-based gas detection experimentally.
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Stimulator of interferon genes (STING, also known as MITA, ERIS, or MPYS) is essential for host immune responses triggered by microbial DNAs. However, the regulatory mechanisms underlying STING-mediated signaling are not fully understood. We report here that, upon cytoplasmic DNA stimulation, the endoplasmic reticulum (ER) protein AMFR was recruited to and interacted with STING in an insulin-induced gene 1 (INSIG1)-dependent manner. AMFR and INSIG1, an E3 ubiquitin ligase complex, then catalyzed the K27-linked polyubiquitination of STING. This modification served as an anchoring platform for recruiting TANK-binding kinase 1 (TBK1) and facilitating its translocation to the perinuclear microsomes. Depletion of AMFR or INSIG1 impaired STING-mediated antiviral gene induction. Consistently, myeloid-cell-specific Insig1(-/-) mice were more susceptible to herpes simplex virus 1 (HSV-1) infection than wild-type mice. This study uncovers an essential role of the ER proteins AMFR and INSIG1 in innate immunity, revealing an important missing link in the STING signaling pathway.
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Retículo Endoplasmático/metabolismo , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Microssomos/metabolismo , Células Mieloides/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores do Fator Autócrino de Motilidade/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Células Cultivadas , Ativação Enzimática/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Células Mieloides/virologia , Ligação Proteica/genética , Transporte Proteico/genética , Transdução de Sinais , Ubiquitinação/genéticaRESUMO
BACKGROUND AND STUDY AIMS: The optimal treatment for gastric varices (GVs) is a topic that remains definite for this study. This study compared the clinical outcomes of clip-assisted endoscopic cyanoacrylate injection (clip-ECI) to conventional endoscopic cyanoacrylate injection (con-ECI) for the treatment of GVs with a gastrorenal shunt. PATIENTS AND METHODS: Data were collected retrospectively in five medical centers from 2015 to 2020. The patients were treated with con-ECI (n = 126) or clip-ECI (n = 148). Clinical characteristics and procedural outcomes were compared. Patients were followed until death, liver transplantation or 6 months after the treatment. The primary outcome was rebleeding, and the secondary outcome was survival. RESULTS: There were no significant differences in age, sex, etiology, shunt diameter and Child-Pugh classification between the two groups. Fewer GVs obliteration sessions were required in the clip-ECI group than in the con-ECI group (p = 0.015). The cumulative 6-month rebleeding-free rates were 88.6% in the clip-ECI group and 73.7% in the con-ECI group (p = 0.002). The cumulative 6-month survival rates were 97.1% in the clip-ECI group and 94.8% in the con-ECI group (p = 0.378). CONCLUSIONS: Compared with con-ECI, clip-ECI appears more effective for the treatment of GVs with a gastrorenal shunt, which required less sessions and achieved a higher 6-month rebleeding-free rate.
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Cianoacrilatos , Varizes Esofágicas e Gástricas , Humanos , Cianoacrilatos/efeitos adversos , Varizes Esofágicas e Gástricas/complicações , Estudos Retrospectivos , Resultado do Tratamento , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Recidiva Local de Neoplasia , Instrumentos Cirúrgicos/efeitos adversos , RecidivaRESUMO
BACKGROUND: The combination of sorafenib and hepatic arterial infusion chemotherapy (HAIC) is expected to exert a synergistic anticancer effect. We conducted this systematic review to examine the efficacy and safety of sorafenib plus HAIC vs sorafenib alone for advanced hepatocellular carcinoma (HCC). METHODS: We systematically searched the PubMed, Embase, and Cochrane Library with the following search terms: "sorafenib," "hepatic arterial infusion chemotherapy," "HAIC," "advanced," "hepatocellular carcinoma," and "HCC." Pooled hazard ratios (HRs) and 95% CIs were calculated for overall survival (OS) and progression-free survival (PFS), and we calculated the pooled risk ratios (RRs) and 95% CIs for objective response rate (ORR) and adverse events (AEs). RESULTS: We found that sorafenib plus HAIC was associated with significantly better OS (HR, 0.56; 95% CI, 0.37-0.83; P < 0.01), PFS (HR, 0.44; 95% CI, 0.27-0.72; P < 0.01), and ORR (RR, 3.77; 95% CI, 1.87-7.58; P < 0.01) than sorafenib alone in advanced HCC. Grade 3/4 AEs were more frequent in the sorafenib plus HAIC group, including leukopenia (RR, 4.54; 95% CI, 1.77-11.64; P < 0.01), neutropenia (RR, 7.81; 95% CI, 3.36-18.16; P < 0.01), thrombocytopenia (RR, 2.97; 95% CI, 1.98-4.46; P < 0.01), anemia (RR, 2.24; 95% CI, 1.22-4.09; P < 0.01), anorexia (RR, 2.37; 95% CI, 1.07-5.27; P = 0.03), nausea (RR, 2.98; 95% CI, 1.19-7.42; P = 0.02), and vomiting (RR, 3.99; 95% CI, 1.14-14.01; P = 0.03). CONCLUSION: Sorafenib plus HAIC improved OS, PFS, and ORR compared with sorafenib alone in advanced HCC, with acceptable safety profile.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombocitopenia , Humanos , Sorafenibe/uso terapêutico , Neoplasias Hepáticas/patologia , Resultado do Tratamento , Infusões Intra-Arteriais , Trombocitopenia/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Due to the pivotal role of microfilament in cancer cells, targeting microfilaments with cytochalasins is considered a promising anticancer strategy. Here, we obtained cytochalasin Q (CQ) from Xylaria sp. DO1801, the endophytic fungi from the root of plant Damnacanthus officinarum, and discovered its anti-melanoma activity in vivo and in vitro attributing to microfilament depolymerization. Mechanistically, CQ directly bound to and inactivated creatine kinase B (CKB), an enzyme phosphorylating creatine to phosphocreatine (PCr) and regenerating ATP to cope with high energy demand, and then inhibited the creatine metabolism as well as cytosolic glycolysis in melanoma cells. Preloading PCr recovered ATP generation, reversed microfilament depolymerization and blunted anti-melanoma efficacy of CQ. Knockdown of CKB resulted in reduced ATP level, perturbed microfilament, inhibited proliferation and induced apoptosis, and manifested lower sensitivity to CQ. Further, we found that either CQ or CKB depletion suppressed the PI3K/AKT/FoxO1 pathway, whereas 740Y-P, a PI3K agonist, elevated protein expression of CKB suppressed by CQ. Taken together, our study highlights the significant anti-melanoma effect and proposes a PI3K/AKT/FoxO1/ CKB feedback circuit for the activity of CQ, opening new opportunities for current chemotherapy.
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Melanoma , Proteínas Proto-Oncogênicas c-akt , Trifosfato de Adenosina , Creatina , Creatina Quinase , Citocalasinas , Humanos , Melanoma/tratamento farmacológico , Fosfatidilinositol 3-QuinasesRESUMO
Currently, little is known about the function of L-arginine in the homeostasis of intestinal lipid metabolism. This study was conducted to test the hypothesis that dietary L-arginine supplementation may alter intestinal microbiota and lipid metabolism in tilapia. Tilapia were fed a basal diet (containing 16.9 g L-arginine per kilogram diets) or the basal diet supplemented with 1% or 2% L-arginine for 8 wks. In the present study, we found that dietary supplementation with 1% or 2% L-arginine induced a shift in the community structure of gut microbiota, as showed by increased (p < 0.05) α-diversity, altered (p < 0.05) ß-diversity and function profile. This finding coincided with decreased lipid accretion in the intestine of tilapia, which was associated with an enhancement in mRNA levels for peroxisome proliferator-activated receptor α (Pparα), acyl-coenzyme a oxidase 1 (Acox1), and peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α). Using intestinal epithelial cell culture, we demonstrated that the lipid-lowering effect of L-arginine was mainly mediated by activating the AMP-activated protein kinase (AMPK) signaling pathway, carnitine palmitoyltransferase 1 (CPT1), and PPARα, as well as mRNA levels for Acox1 and Acox2. Collectively, our results suggest that dietary L-arginine supplementation of tilapia changed the intestinal microbiota and activated intestinal fatty acid oxidation. However, future studies are warranted to determine the relationship between microbiota and lipid metabolism in the intestine.
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Ciclídeos , Tilápia , Animais , Arginina/metabolismo , Arginina/farmacologia , Ciclídeos/genética , Ciclídeos/metabolismo , Suplementos Nutricionais , Ácidos Graxos/metabolismo , Intestinos , Metabolismo dos Lipídeos , Tilápia/metabolismoRESUMO
Kinsenoside (KD) exhibits anti-inflammatory and immunosuppressive effects. Dendritic cells (DCs) are critical regulators of the pathologic inflammatory milieu in liver fibrosis (LF). Herein, we explored whether and how KD repressed development of LF via DC regulation and verified the pathway involved in the process. Given our analysis, both KD and adoptive transfer of KD-conditioned DCs conspicuously reduced hepatic histopathological damage, proinflammatory cytokine release and extracellular matrix deposition in CCl4-induced LF mice. Of note, KD restrained the LF-driven rise in CD86, MHC-II, and CCR7 levels and, simultaneously, upregulated PD-L1 expression on DCs specifically, which blocked CD8+T cell activation. Additionally, KD reduced DC glycolysis, maintained DCs immature, accompanied by IL-12 decrease in DCs. Inhibiting DC function by KD disturbed the communication of DCs and HSCs with the expression or secretion of α-SMA and Col-I declined in the liver. Mechanistically, KD suppressed the phosphorylation of PI3K-AKT driven by LF or PI3K agonist, followed by enhanced nuclear transport of FoxO1 and upregulated interaction of FoxO1 with the PD-L1 promoter in DCs. PI3K inhibitor or si-IL-12 acting on DC could relieve LF, HSC activation and diminish the effect of KD. In conclusion, KD suppressed DC maturation with promoted PD-L1 expression via PI3K-AKT-FoxO1 and decreased IL-12 secretion, which blocked activation of CD8+T cells and HSCs, thereby alleviating liver injury and fibro-inflammation in LF.
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Hepatite , Fosfatidilinositol 3-Quinases , 4-Butirolactona/análogos & derivados , Animais , Antígeno B7-H1 , Células Dendríticas/metabolismo , Proteína Forkhead Box O1 , Inflamação/tratamento farmacológico , Interleucina-12 , Camundongos , Monossacarídeos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Few prognostic risk scores (PRSs) have been routinely used in acute decompensated heart failure (ADHF). We, therefore, externally validated three published PRSs (3A3B, AHEAD, and OPTIME-CHF) and derived a new PRS to predict the short-term prognosis in ADHF. METHODS: A total of 4550 patients from the Heb-ADHF registry in China were randomly divided into the derivation and validation cohorts (3:2). Discrimination of each PRS was assessed by the area under the receiver operating characteristic curve (AUROC). Logistic regression was exploited to select the predictors and create the new PRS. The Hosmer-Lemeshow goodness-of-fit test was used to assess the calibration of the new PRS. RESULTS: The AUROCs of the 3A3B, AHEAD, and OPTIME-CHF score in the derivation cohort were 0.55 (95% CI 0.53-0.57), 0.54 (95% CI 0.53-0.56), and 0.56 (95% CI 0.54-0.57), respectively. After logistic regression analysis, the new PRS computed as 1 × (diastolic blood pressure < 80 mmHg) + 2 × (lymphocyte > 1.11 × 109/L) + 1 × (creatinine > 80 µmol/L) + 2 × (blood urea nitrogen > 21 mg/dL) + 1 × [BNP 500 to < 1500 pg/mL (NT-proBNP 2500 to < 7500 pg/mL)] or 3 × [BNP ≥ 1500 (NT-proBNP ≥ 7500) pg/mL] + 3 × (QRS fraction of electrocardiogram < 55%) + 4 × (ACEI/ARB not used) + 1 × (rhBNP used), with a better AUROC of 0.67 (95% CI 0.64-0.70) and a good calibration (Hosmer-Lemeshow χ2 = 3.366, P = 0.186). The results in validation cohort verified these findings. CONCLUSIONS: The short-term prognostic values of 3A3B, AHEAD, and OPTIME-CHF score in ADHF patients were all poor, while the new PRS exhibited potential predictive ability. We demonstrated the QRS fraction of electrocardiogram as a novel predictor for the short-term outcomes of ADHF for the first time. Our findings might help to recognize high-risk ADHF patients.
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Insuficiência Cardíaca , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Prognóstico , Fatores de RiscoRESUMO
Tea contains high levels of the compound epigallocatechin gallate (EGCG). It is considered an important functional component in tea and has anti-cancer, antioxidant, and anti-inflammatory effects. The eight phenolic hydroxyl groups in EGCG's chemical structure are the basis for EGCG's multiple biological effects. At the same time, it also leads to poor chemical stability, rendering EGCG prone to oxidation and isomerization reactions that change its original structure and biological activity. Learning how to maintain the activity of EGCG has become an important goal in understanding the biological activity of EGCG and the research and development of tea-related products. Metal-organic frameworks (MOFs) are porous materials with a three-dimensional network structure that are composed of inorganic metals or metal clusters together with organic complexes. MOFs exploit the porous nature of the material itself. When a drug is an appropriate size, it can be wrapped into the pores by physical or chemical methods; this allows the drug to be released slowly, and MOFs can also reduce drug toxicity. In this study, we used MOF Zn(BTC)4 materials to load EGCG and investigated the sustained release effect of EGCG@MOF Zn(BTC)4 and the biological effects on wound healing in a diabetic mouse model.
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Catequina , Diabetes Mellitus , Animais , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Camundongos , Chá/química , Cicatrização , ZincoRESUMO
Long noncoding RNAs (lncRNAs) play important roles in various biological activities as vital regulators. However, no study has focused on the lncRNA regulation of Outer membrane protein (OMP) immunization against aquatic bacterial infection. In this study, we examined the genome-wide expression of lncRNAs in the liver of European eel (Anguilla anguilla, Aa) administrated by a recombinant OmpA (rOmpA) from Edwardsiella anguillarum (Ea) to elucidate the functions of lncRNAs in the process of Ea infection and Aa anti-Ea infection using strand specific RNA-seq. Eels were challenged by Ea at 28 d post the immunization (dpi) of OmpA, and the result showed, compared to uninfected livers in the PBS group (Con group), the infected livers in the PBS group (Con_inf group) showed severe bleeding, hepatocyte atrophy and thrombi formed in the hepatic vessels; livers in the OmpA group (OmpA_inf) also formed slight thrombi in the hepatic vessels. The relative percent survival of eels in OmpA_inf vs Con_inf was 78.6%. Using high-throughput transcriptomics, we found 13405 lncRNAs in 3 compares of Con_inf vs Con, OmpA_inf vs Con and OmpA_inf vs Con_inf, of which 111, 129 and 158 DE-lncRNAs were ascertained. GO analysis of the DE-lncRNAs revealed the targeting DEGs were mainly involved in single-organism process, signaling, biological process and response to stimulus in BP, component of membrane in CC and binding in MF; KEGG pathways showed that the targeting DEGs in co-expression and co-location enriched in cell adhesion molecules. Finally, 54 DE-lncRNAs targeting 1675 DEGs were involved in an interaction network of 21692 co-expression and 483 co-location related links, of which 18 DE-lncRNAs appear to play crucial roles in anti-Ea infection. Thus, the interaction networks revealed crucial DE-lncRNAs underlying the process of Ea infection and Aa anti-Ea infection pre and post the immunization of OmpA.
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Anguilla , Doenças dos Peixes , RNA Longo não Codificante , Aeromonas hydrophila/imunologia , Anguilla/imunologia , Animais , Edwardsiella , Imunização , RNA-Seq , TranscriptomaRESUMO
BACKGROUND: The isolated superior mesenteric artery dissection (SMAD) is a rare and sporadic cause of acute abdominal pain. It most frequently affects male patients in their fifth to sixth decades, while our patient was a young woman who delivered a baby before the onset of abdominal pain. Possible risk factors for SMAD include hypertension, arteriosclerosis, abnormalities in elastic fibres, trauma, and pregnancy. In our case, delivery was suggested as a risk factor, which has not been reported previously. CASE PRESENTATION: A 27-year-old woman complained of acute severe upper abdominal pain and vomiting for 2 days after delivery. The patient had no significant medical history. Physical examination revealed epigastric mild tenderness. All routine blood tests, blood coagulation analysis, liver function tests and abdomen computed tomography showed no remarkable findings. Computed tomography angiography revealed a marked dissection 3.5 cm below the superior mesenteric artery ostium. Since distal blood flow existed and the patient was in a puerperal state with no evidences of mesenteric ischemia, she was managed conservatively, including intestinal rest by fasting, parenteral nutritional support and antibioticis, without anticoagulants or antiplatelet agents. Fortunately, she recovered smoothly and had no recurrence. CONCLUSIONS: SMAD is a rare and sporadic cause of acute abdominal pain that occurs in young women after delivery.
Assuntos
Dissecção Aórtica , Isquemia Mesentérica , Dor Abdominal/etiologia , Adulto , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/etiologia , Dissecação , Feminino , Humanos , Masculino , Artéria Mesentérica Superior/diagnóstico por imagem , GravidezRESUMO
Heat stress due to global warming exerts deleterious effects on both humans and animals. However, nutritional strategies to reduce heat stress-induced intestinal mucosal barrier dysfunction and the underlying mechanisms remain largely unknown. In the present study, 240 tilapia were distributed into four treatment groups that were fed a basal diet supplemented with or without 0.1% Yucca schidigera extract under normal (28 °C) temperature or heat stress (36 °C) conditions for 2 weeks. Our results showed that tilapia exposed to heat stress resulted in growth arrest, intestinal dysfunction, oxidative damage, endoplasmic reticulum stress, and pro-inflammatory response, which were significantly relieved by yucca supplementation. The alleviative effect of Yucca schidigera extract was related to the down-regulation of mRNA expression of ubiquitin-proteasome system (Polyubiquitin, Proteasome 26S, Proteasome α5, Proteasome ß3, and Ubiquitin-like 3) and inflammatory factors (tumor necrosis factor α, interleukin 1ß, and interleukin 8), as well as the improved histological structure and activation of Hsp70, nuclear factor erythroid 2-related factor 2 signaling, interleukin 10, lysozyme, complement 3, and acid phosphatase in the intestine of tilapia. Collectively, these results indicated that heat stress-induced growth arrest, intestinal dysfunction, and oxidative damage were alleviated by dietary supplementation with Yucca schidigera extract. This offers a nutritional way of improving the growth and intestinal health of tilapia exposed to a hot environment.