RESUMEN
Activated neutrophil-derived exosomes reportedly contribute to the proliferation of airway smooth muscle cells (ASMCs), thereby aggravating the airway wall remodeling during asthma; however, the specific mechanism remains unclear. Lipopolysaccharide (LPS)-EXO and si-CRNDE-EXO were extracted from the media of human neutrophils treated with LPS and LPS + si-CRNDE (a siRNA targets long non-coding RNA CRNDE), respectively. Human ASMCs were co-cultured with LPS-EXO or si-CRNDE-EXO, and cell viability, proliferation and migration were measured. The interplay of colorectal neoplasia differentially expressed (CRNDE), inhibitor of nuclear factor kappa B kinase subunit beta (IKKß) and nuclear receptor subfamily 2 group C member 2 (TAK1) was explored using RNA immunoprecipitation (RIP) and Co-IP assays. A mouse model of asthma was induced using ovalbumin. CRNDE was upregulated in LPS-EXO and successfully transferred from LPS-treated neutrophils to ASMCs through exosome. Mechanically, CRNDE loaded in LPS-EXO reinforced TAK1-mediated IKKß phosphorylation, thereby activating the nuclear factor kappa B (NF-κB) pathway. Functionally, silencing CRNDE in LPS-EXO, an IKKß inhibitor, and an NF-κB inhibitor all removed the upregulation of cell viability, proliferation and migration induced by LPS-EXO in ASMCs. In the end, the in vivo experiment demonstrated that CRNDE knockdown in neutrophils effectively reduced the thickness of bronchial smooth muscle in a mouse model for asthma. Activated neutrophils-derived CRNDE was transferred to ASMCs through exosomes and activated the NF-κB pathway by enhancing IKKß phosphorylation. The latter promoted the proliferation and migration of ASMCs and then contributed to airway remodeling in asthma.
Asunto(s)
Asma , Neoplasias Colorrectales , ARN Largo no Codificante , Remodelación de las Vías Aéreas (Respiratorias) , Animales , Asma/genética , Proliferación Celular/genética , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Lipopolisacáridos/farmacología , Ratones , Miocitos del Músculo Liso/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Neutrófilos/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Bi/CeO2 (BC-x) photocatalysts are successfully prepared by solvothermal loading Bi nanoparticles and Bi-doped CeO2 derived by Ce-MOF (Ce-BTC). Formaldehyde gas (HCHO) and tetracycline hydrochloride (HTC) are used to evaluate the photocatalytic activity of the synthesized Bi/CeO2. For BC-1000 photocatalyst, the degradation of HTC by 420 nm < λ < 780 nm light reaches 91.89% for 90 min, and HCHO by 350 nm < λ < 780 nm light reaches 94.66% for 120 min. The photocatalytic cycle experiments prove that BC-1000 has good cyclic stability and repeatability. The results of photoluminescence spectra, fluorescence lifetime, photocurrent response, and electrochemical impedance spectroscopy showed that the SPR (Surface Plasmon Resonance) effect of Bi nanoparticles acted as a bridge and promoted electron transfer and enhanced the response-ability of Bi/CeO2 to visible light. Bi-doping produced more oxygen vacancies to provide adsorption sites for adsorbing oxygen and generated more ·O2 - thus promoting photocatalytic reactions. The mechanism of photocatalytic degradation is analyzed in detail utilizing active free radical capture experiments and electron paramagnetic resonance (EPR) characterization. The experimental results indicate that ·O2 - and h+ active free radicals significantly promote the degradation of pollutants.
RESUMEN
The Z-scheme MIL-88B/BiOBr (referred to as MxBy, whereas x and y are the mass of MIL-88B(Fe) and BiOBr) heterojunction photocatalysts are successfully prepared by a facile ball milling method. By adding low concentration H2O2 under visible light irradiation, the Z-scheme heterojunction and photocatalytic-Fenton-like reaction synergistically enhance the degradation and mineralization of ciprofloxacin (CIP). Among them, M50B150 showed efficient photodegradation efficiency and excellent cycling stability, with 94.6% removal of CIP (10 mg L-1) by M50B150 (0.2 g L-1) under 90 min of visible light. In the MxBy heterojunctions, the rapid transfer of photo-generated electrons not only directly decomposed H2O2 to generate ·OH, but also improved the cycle of Fe3+/Fe2+ pairs, which facilitated the reaction with H2O2 to generate ·OH and ·O2 - radicals. In addition, the effects of photocatalyst dosages, pH of CIP solution, and coexisting substances on CIP removal are systematically investigated. It is found that the photocatalytic- Fenton-like reaction can be carried out at a pH close to neutral conditions. Finally, the charge transfer mechanism of the Z-scheme is verified by electron spin resonance (ESR) signals. The ecotoxicity of CIP degradation products is estimated by the T.E.S.T tool, indicating that the constructed photocatalysis-Fenton-like system is a green wastewater treatment technology.
Asunto(s)
Bismuto , Ciprofloxacina , Peróxido de Hidrógeno , Hierro , Ciprofloxacina/química , Catálisis , Bismuto/química , Peróxido de Hidrógeno/química , Hierro/química , Luz , Fotólisis , Estructuras Metalorgánicas/química , Contaminantes Químicos del Agua/química , Compuestos Férricos/químicaRESUMEN
2D transition metal carbides and nitrides, i.e., MXene, are recently attracting wide attentions and presenting competitive performances as adsorbents used in hemoperfusion. Nonetheless, the nonporous texture and easily restacking feature limit the efficient adsorption of toxin molecules inside MXene and between layers. To circumvent this concern, here a plerogyra sinuosa biomimetic porous titanium carbide MXene (P-Ti3C2) is reported. The hollow and hierarchically porous structure with large surface area benefits the maximum access of toxins as well as trapping them inside the spherical cavity. The cambered surface of P-Ti3C2 prevents layers restacking, thus affording better interlaminar adsorption. In addition to enhanced toxin removal ability, the P-Ti3C2 is found to selectively adsorb more middle and large toxin molecules than small toxin molecules. It possibly originates from the rich Ti-deficient vacancies in the P-MXene lattice that increases the affinity with middle/large toxin molecules. Also, the vacancies as active sites facilitate the production of reactive oxygen under NIR irradiation to promote the photodynamic antibacterial performance. Then, the versatility of P-MXene is validated by extension to niobium carbide (P-Nb2C). And the simulated hemoperfusion proves the practicability of the P-MXene as polymeric adhesives-free adsorbents to eliminate the broad-spectrum toxins.
RESUMEN
BACKGROUND: Metabolic reprogramming contributes to bladder cancer development. This study aimed to understand the role of SLC7A5 in bladder cancer. METHODS: We systematically analyzed the correlation between SLC7A5 and bladder cancer through various approaches, including bioinformatics, western blotting, cell cycle analysis, cell proliferation assays, and invasion experiments. We also investigated the immunological features within the tumor microenvironment (TME), encompassing cancer immune cycles, immune modulators, immune checkpoints, tumor-infiltrating immune cells (TIIC), T cell inflammation scores, and treatment responses. Additionally, for a comprehensive assessment of the expression patterns and immunological roles of SLC7A5, pan-cancer analysis was performed using cancer genomics datasets. RESULTS: SLC7A5 was associated with adverse prognosis in bladder cancer patients, activating the Wnt pathway and promoting bladder cancer cell cycle progression, proliferation, migration, and invasion. Based on the evidence that SLC7A5 positively correlated with immunomodulators, TIIC, the cancer immune cycle, immune checkpoint and T cell inflammation scores, we also found that SLC7A5 was associated with the inflammatory tumor immune microenvironment. EGFR-targeted therapy, cancer immunotherapy, and radiation therapy were effective for patients with high SLC7A5 expression in bladder cancer. Low SLC7A5 patients were, however, sensitive to targeted therapies and anti-angiogenic therapy, such as blocking ß-catenin network, PPAR-γ and FGFR3 signaling. Anti-SLC7A5 combined with cancer immunotherapy may have greater effectiveness than either therapy alone. Furthermore, we observed specific overexpression of SLC7A5 in TME of various cancers. CONCLUSION: SLC7A5 can predict therapeutic response to immunotherapy, radiotherapy and chemotherapy in bladder cancer patients. Targeting SLC7A5 in combination with immunotherapy may be a potentially appropriate treatment option.
RESUMEN
Cell transplantation is a promising treatment option for spinal cord injury (SCI). However, there is no consensus on the choice of carrier scaffolds to host the cells. This study aims to evaluate the efficacy of different material scaffold-mediated cell transplantation in treating SCI in rats. According to PRISMA's principle, Embase, PubMed, Web of Science, and Cochrane databases were searched, and relevant literature was referenced. Only original research on cell transplantation plus natural or synthetic scaffolds in SCI rats was included. Direct and indirect evidence for improving hind limb motor function was pooled through meta-analysis. A subgroup analysis of some factors that may affect the therapeutic effect was conducted to understand the results fully. In total, 25 studies met the inclusion criteria, in which 293 rats received sham surgery, 78 rats received synthetic material scaffolds, and 219 rats received natural materials scaffolds. The network meta-analysis demonstrated that although synthetic scaffolds were slightly inferior to natural scaffolds in terms of restoring motor function in cell transplantation of SCI rats, no statistical differences were observed between the two (MD: -0.35; 95% CI -2.6 to 1.9). Moreover, the subgroup analysis revealed that the type and number of cells may be important factors in therapeutic efficacy (P < 0.01). Natural scaffolds and synthetic scaffolds are equally effective in cell transplantation of SCI rats without significant differences. In the future, the findings need to be validated in multicenter, large-scale, randomized controlled trials in clinical practice. Trial registration: Registration ID CRD42024459674 (PROSPERO).
Asunto(s)
Trasplante de Células , Traumatismos de la Médula Espinal , Andamios del Tejido , Animales , Traumatismos de la Médula Espinal/terapia , Ratas , Andamios del Tejido/química , Trasplante de Células/métodos , Metaanálisis en Red , Resultado del Tratamiento , Recuperación de la FunciónRESUMEN
Aortic dissection (AD) is a fatal cardiovascular disease with limited pharmacotherapies. To discover novel therapeutic targets for AD, the present study was conducted on ascending aorta samples from AD patients versus those from control subjects using proteomic analysis. Integrated proteomic data analysis identified S100 calcium-binding proteins A8 and A9 (S100A8/A9) as new therapeutic targets for AD. As assessed by ELISA, the circulating levels of S100A8/A9 were elevated in AD patients. In addition, we validated the upregulation of S100A8/A9 in a mouse model of AD. In vitro and in vivo studies substantiated that S100A8/A9, as danger-associated molecular pattern molecules, promotes the smooth muscle cells phenotypic switch by inhibiting serum response factor (SRF) activity but elevating NF-κB dependent inflammatory response. Depletion of S100A8/A9 attenuates the occurrence and development of AD. As a proof of concept, we tested the safety and efficacy of pharmacological inhibition of S100A8/A9 by ABR-25757 (paquinimod) in a mouse model of AD. We observed that ABR-25757 ameliorated the incidence of rupture and improved elastin morphology associated with AD. Further single-cell RNA sequencing disclosed that the phenotypic switch of vascular smooth muscle cells (VSMCs) and inflammatory response pathways were responsible for ABR-25757-mediated protection against AD. Thus, this study reveals the regulatory mechanism of S100A8/A9 in AD and offers a potential therapeutic avenue to treat AD by targeting S100A8/A9.
Asunto(s)
Disección Aórtica , Proteoma , Ratones , Animales , Humanos , Proteínas de Unión al Calcio , Proteómica , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Modelos Animales de Enfermedad , Disección Aórtica/tratamiento farmacológicoRESUMEN
AIM: To investigate the effects of adenosine kinase (ADK), a key enzyme in determining intracellular adenosine levels, on ß cells, and their underlying mechanism. METHODS: Genetic animal models and transgenic immortalized cells were applied to study the effect of ADK on islet beta-cell proliferation and function. The beta-cell mass and response to glucose were measured in vivo using mice with beta-cell-specific ADK overexpression, and in vitro using ADK-overexpressed immortalized beta-cell. RESULTS: The expression of ADK in human islets at high abundance, especially in ß cells, was decreased during the process of ß-cell proliferation. Additionally, a transgenic mouse model (ADKtg/tg /Mip-Cre) was generated wherein the mouse Insulin1 gene promoter specifically overexpressed ADK in pancreatic ß cells. The ADKtg/tg /Mip-Cre model exhibited impaired glucose tolerance, decreased fasting plasma insulin, loss of ß-cell mass, and inhibited ß-cell proliferation. Proteomic analysis revealed that ADK overexpression inhibited the expression of several proteins that promote cell proliferation and insulin secretion. Upregulating ADK in the ß-cell line inhibited the expression of ß-cell related regulatory molecules, including FoxO1, Appl1, Pxn, Pdx-1, Creb and Slc16a3. Subsequent in vitro experiments indicated that the inhibition of ß-cell proliferation and the decreased expression of Pdx-1, Creb and Slc16a3 were rescued by DNA methyltransferase 3A (DNMT3A) knockdown in ß cells. CONCLUSION: In this study, we found that the overexpression of ADK decreased the expression of several genes that regulate ß cells, resulting in the inhibition of ß-cell proliferation and dysfunction by upregulating the expression of DNMT3A.
Asunto(s)
Adenosina Quinasa , Proliferación Celular , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Células Secretoras de Insulina , Ratones Transgénicos , Regulación hacia Arriba , Células Secretoras de Insulina/metabolismo , Animales , Ratones , Humanos , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Adenosina Quinasa/genética , Adenosina Quinasa/metabolismo , Masculino , Secreción de Insulina , Insulina/metabolismoRESUMEN
Two new porous three-dimensional cadmium(II) metal-organic frameworks (MOFs) containing thiophene-appended carboxylate acid ligands, formulated as [Cd(L1)(4,4'-Bipy)]n.2n(DMF) (1) and [Cd(L2)(4,4'-Bipy)]n.2n(DMF) (2) [where L1 = 5-{(thiophen-2-ylmethyl)amino}isophthalate, L2 = 5-{(thiophen-3-ylmethyl)amino}isophthalate, 4,4'-Bipy = 4,4'-bipyridine, and DMF = N,N'-dimethylformamide] have been synthesized and structurally characterized. The gas adsorption analysis of the activated MOFs shows that they specifically capture CO2 (uptake amount 4.36 mmol/g under 1 bar at 195 K) over N2 and CH4. Moreover, both MOFs show a gate-opening-closing phenomenon, which features the S-shaped isotherms with impressive hysteretic desorption during the CO2 adsorption-desorption process at 195 K. Ideal adsorbed solution theory (IAST) calculations of these MOFs displayed that the obtained selectivity values for CO2/CH4 (50:50) and CO2/N2 (15:85) are approximately 8.6-23 and 93-565, respectively. Configurational bias Monte Carlo simulation was performed to understand the mechanism behind the better CO2 adsorption by these MOFs. Catalytic activity of the MOFs for the CO2 fixation reactions with different epoxides to form cyclic carbonates were tested. These MOFs demonstrated a significantly high conversion (94-99%) of epichlorohydrin to the corresponding cyclic carbonate within 8 h of reaction time at 1 bar of CO2 pressure, at 70 °C, and they can be reused up to five cycles without losing considerably their activity.
RESUMEN
Diamines play important roles in synthetic organic chemistry and thus facilitate life and materials sciences. Herein we report a cobalt-catalyzed ring opening, nucleophilic amination of aziridines and azetidines with N-fluorosulfonamides toward a wide range of 1,2- and 1,3-diamine derivatives in moderate to good yields under mild conditions.
RESUMEN
INTRODUCTION: Mycoplasma pneumoniae (MP) is the most common pathogen of community-acquired pneumonia in children. However, the role of neutrophil extracellular traps (NETs) in the pathogenesis of MP is unclear. METHODS: Both the level of NETs were detected between the 60 MP pneumonia patients and 20 healthy controls, whose the clinical characteristics were compared. Additionally, NETs formation induced by community-acquired respiratory distress syndrome (CARDS) toxin was also analyzed through transcriptome sequencing. RESULTS: The levels of cell-free DNA, Cit-H3, and MPO-DNA complexes were significantly increased in the patients with MP pneumonia. Importantly, both cell-free DNA and LDH were higher in hospitalized patients with severity than those without severity. In addition, CARDS toxin induced the NETs formation in vitro and in vivo. Transcriptomics GO and KEGG pathway analysis indicate that NOD like receptor signaling pathway and Toll-like receptor signaling pathway are significantly enriched. Finally, we found that DNase I significantly attenuated the higher levels of Cit-H3, and up-regulation of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) by down-regulating the expression of NLRP3 and Caspase1(p20) in the lung tissues. DISCUSSION: These results indicate that inhibiting excessive activation of NLRP3 inflammasomes, and NETs formation may alleviate MP pneumonia.
Asunto(s)
Trampas Extracelulares , Inflamasomas , Mycoplasma pneumoniae , Proteína con Dominio Pirina 3 de la Familia NLR , Neumonía por Mycoplasma , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Inflamasomas/metabolismo , Inflamasomas/inmunología , Mycoplasma pneumoniae/inmunología , Neumonía por Mycoplasma/inmunología , Neumonía por Mycoplasma/metabolismo , Masculino , Femenino , Animales , Neutrófilos/inmunología , Neutrófilos/metabolismo , Proteínas Bacterianas/metabolismo , Ácidos Nucleicos Libres de Células , Ratones , Desoxirribonucleasa I/metabolismo , Niño , Transducción de Señal , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Toxinas BacterianasRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is closely associated with metabolic derangement. Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) exert anti-HFpEF effects, but the underlying mechanisms remain unclear. In this study, we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF. This model was established by high-fat diet (HFD) feeding plus Nω-nitro-L-arginine methyl ester (L-NAME) treatment. The mice were treated with empagliflozin (20 mg·kg-1·d-1, i.g.) or liraglutide (0.3 mg·kg-1·d-1, i.p.) or their combination for 4 weeks. At the end of the experimental protocol, cardiac function was measured using ultrasound, then mice were euthanized and heart, liver, and kidney tissues were collected. Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing (snRNA-seq). We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function, ameliorated cardiomyocyte hypertrophy and cardiac fibrosis, as well as exercise tolerance but no synergism was observed in the combination group. Furthermore, empagliflozin and/or liraglutide lowered body weight, improved glucose metabolism, lowered blood pressure, and improved liver and kidney function. After the withdrawal of empagliflozin or liraglutide for 1 week, these beneficial effects tended to diminish. The snRNA-seq analysis revealed a subcluster of myocytes, in which Erbb4 expression was down-regulated under HFpEF conditions, and restored by empagliflozin or liraglutide. Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions. In the HFpEF mouse model, both empagliflozin and liraglutide reversed Erbb4 down-regulation. In rat h9c2 cells, we showed that palmitic acid- or high glucose-induced changes in PKCα and/or ERK1/2 phosphorylation at least in part through Erbb4. Collectively, the single-cell atlas reveals the anti-HFpEF mechanism of empagliflozin and liraglutide, suggesting that Erbb4 pathway represents a new therapeutic target for HFpEF. Effects and mechanisms of action of empagliflozin and liraglutide in HFpEF mice. HFpEF was induced with a high-fat diet and L-NAME for 15 weeks, and treatment with empagliflozin and liraglutide improved the HFpEF phenotype. Single nucleus RNA sequencing (snRNA-seq) was used to reveal the underlying mechanism of action of empagliflozin and liraglutide.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Insuficiencia Cardíaca , Liraglutida , Ratones Endogámicos C57BL , Transducción de Señal , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Glucósidos/farmacología , Glucósidos/uso terapéutico , Liraglutida/farmacología , Liraglutida/uso terapéutico , Transducción de Señal/efectos de los fármacos , Masculino , Ratones , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Dieta Alta en Grasa , Volumen Sistólico/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Modelos Animales de EnfermedadRESUMEN
Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg-1·d-1) and fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.
Asunto(s)
Aterosclerosis , Modelos Animales de Enfermedad , Hiperlipidemia Familiar Combinada , Ratones Endogámicos C57BL , Ratones Transgénicos , Animales , Aterosclerosis/tratamiento farmacológico , Humanos , Ratones , Hiperlipidemia Familiar Combinada/tratamiento farmacológico , Hiperlipidemia Familiar Combinada/genética , Apolipoproteína C-III/genética , Masculino , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Hipolipemiantes/uso terapéutico , Hipolipemiantes/farmacología , Triglicéridos/sangre , Dieta Alta en Grasa , Atorvastatina/uso terapéutico , Atorvastatina/farmacologíaRESUMEN
Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.
RESUMEN
INTRODUCTION: Surgery is currently the only effective treatment for retroperitoneal tumors that do not involve any specific organ. The use of robots for removing both benign and malignant retroperitoneal tumors is considered safe and feasible. However, there is insufficient evidence to determine whether robotic retroperitoneal tumor resection (RMBRs) is superior to open retroperitoneal malignant resection (OMBRs). This study compares the short-term outcomes of robotic excision of benign and malignant retroperitoneal tumors with open excision of the same-sized tumors. METHODS: The study compared demographics and outcomes of patients who underwent robotic resection (n = 54) vs open resection (n = 54) of retroperitoneal tumors between March 2018 and December 2022. A 1:1 matching analysis was conducted to ensure a fair comparison. RESULTS: The study found that RBMRs resulted in reduced operative time (OT), estimated blood loss (EBM), and postoperative hospital stay (PSH) when compared to OBMRs. Additionally, RBMRs reduced EBL, PHS, and OT for patients with malignant tumor involvement in major vessels. No significant differences were found in tumor size, blood transfusion rate, and morbidity rate between the RBMRs and OBMRs groups. CONCLUSION: When comparing RMBRs to OMBRs, it was observed that RMBR was associated with lower (EBL), shorter postoperative hospital stays (PHS), and reduced operative time (OT) in a specific group of patients with both benign and malignant tumors.
Asunto(s)
Aorta Abdominal , Tiempo de Internación , Tempo Operativo , Neoplasias Retroperitoneales , Procedimientos Quirúrgicos Robotizados , Vena Cava Inferior , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Vena Cava Inferior/cirugía , Vena Cava Inferior/patología , Masculino , Femenino , Neoplasias Retroperitoneales/cirugía , Neoplasias Retroperitoneales/patología , Persona de Mediana Edad , Aorta Abdominal/cirugía , Tiempo de Internación/estadística & datos numéricos , Anciano , Estudios Retrospectivos , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Adulto , Resultado del Tratamiento , Riñón/cirugía , Riñón/patologíaRESUMEN
Integration of spirocycles with buckybowls is a promising strategy to construct three-dimensional (3D) curved π-systems and to endow distinctive physicochemical features arising from buckybowls. Herein, a series of carbon-bridged spiro-type heterosumanenes (spiro-HSEs) were synthesized by combining 9,9'-spirobifluorene and dichalcogenasumanenes (DCSs). It is found that spiro-conjugation plays an important role in the geometric and electronic structures of spiro-HSEs. The bowl depth of DCSs moiety becomes larger in the spiro-HSEs. Owing to the Jahn-Teller (J-T) effect, two DCSs segments of spiro-HSEs have different bowl depths accompanied with the unequal distribution of charge in radical cation state. Taking advantage of the typical reactions of DCSs, selective transformations of spiro-HSEs have been adopted in accordance to the nature of chalcogen atoms (S, Se, Te) to bestow the value-added functionalities. The emissive property is enhanced by converting the thiophene rings of S-doped spiro-HSE into thiophene S,S-dioxides. A chiroptical polycycle could be produced by ring-opening of the edge benzene of Se-doped spiro-HSE. The covalent adduct of Te-doped spiro-HSE with Br2 forms non-centrosymmetric halogen-bonded networks, resulting in the high performance second-order nonlinear optics (NLO).
RESUMEN
Improving the slow redox kinetics of sulfur species and shuttling issues of soluble intermediates induced from the multiphase sulfur redox reactions are crucial factors for developing the next-generation high-energy-density lithium-sulfur (Li-S) batteries. In this study, we successfully constructed a novel molecular electrocatalyst through in situ polymerization of bis(3,4-dibromobenzene)-18-crown-6 (BD18C6) with polysulfide anions on the cathode interface. The crown ether (CE)-based polymer acts as a spatial "fence" to precisely control the unique redox characteristics of sulfur species, which could confine sulfur substance within its interior and interact with lithium polysulfides (LiPSs) to optimize the reaction barrier of sulfur species. The "fence" structure and the double-sided Li+ penetrability of the CE molecule may also prevent the CE catalytic sites from being covered by sulfur during cycling. This new fence-type electrocatalyst mitigates the "shuttle effect", enhances the redox activity of sulfur species, and promotes the formation of three-dimensional stacked lithium sulfide (Li2S) simultaneously. It thus enables lithium-sulfur batteries to exhibit superior rate performance and cycle stability, which may also inspire development facing analogous multiphase electrochemical energy-efficient conversion process.
RESUMEN
BACKGROUND: Non-invasive risk stratification contributes to the precise treatment of prostate cancer (PCa). In previous studies, lymphocyte subsets were used to differentiate between low-/intermediate-risk and high-risk PCa, with limited clinical value and poor interpretability. Based on functional subsets of peripheral lymphocyte with the largest sample size to date, this study aims to construct an easy-to-use and robust nomogram to guide the tripartite risk stratifications for PCa. METHODS: We retrospectively collected data from 2039 PCa and benign prostate disease (BPD) patients with 42 clinical characteristics on functional subsets of peripheral lymphocyte. After quality control and feature selection, clinical data with the optimal feature subset were utilized for the 10-fold cross-validation of five Machine Learning (ML) models for the task of predicting low-, intermediate- and high-risk stratification of PCa. Then, a novel clinic-ML nomogram was constructed using probabilistic predictions of the trained ML models via the combination of a multivariable Ordinal Logistic Regression analysis and the proposed feature mapping algorithm. RESULTS: 197 PCa patients, including 56 BPD, were enrolled in the study. An optimal subset with nine clinical features was selected. Compared with the best ML model and the clinic nomogram, the clinic-ML nomogram achieved the superior performance with a sensitivity of 0.713 (95% CI 0.573-0.853), specificity of 0.869 (95% CI 0.764-0.974), F1 of 0.699 (95% CI 0.557-0.841), and AUC of 0.864 (95% CI 0.794-0.935). The calibration curve and Decision Curve Analysis (DCA) indicated the predictive capacity and net benefits of the clinic-ML nomogram were improved. CONCLUSION: Combining the interpretability and simplicity of a nomogram with the efficacy and robustness of ML models, the proposed clinic-ML nomogram can serve as an insight tool for preoperative assessment of PCa risk stratifications, and could provide essential information for the individual diagnosis and treatment in PCa patients.
Asunto(s)
Nomogramas , Neoplasias de la Próstata , Masculino , Humanos , Estudios Retrospectivos , Neoplasias de la Próstata/diagnóstico , Linfocitos , Aprendizaje Automático , Medición de RiesgoRESUMEN
BACKGROUND: Kidney cancer undergoes a dramatic metabolic shift and has demonstrated responsiveness to immunotherapeutic intervention. However, metabolic classification and the associations between metabolic alterations and immune infiltration in Renal cell carcinoma still remain elucidative. METHODS: Unsupervised consensus clustering was conducted on the TCGA cohorts for metabolic classification. GESA, mRNAsi, prognosis, clinical features, mutation load, immune infiltration and differentially expressed gene differences among different clusters were compared. The prognosis model and nomograms were constructed based on metabolic gene signatures and verified using external ICGC datasets. Immunohistochemical results from Human Protein Atlas database and Tongji hospital were used to validate gene expression levels in normal tissues and tumor samples. CCK8, apoptosis analysis, qPCR, subcutaneously implanted murine models and flowcytometry analysis were applied to investigate the roles of ACAA2 in tumor progression and anti-tumor immunity. RESULTS: Renal cell carcinoma was classified into 3 metabolic subclusters and the subcluster with low metabolic profiles displayed the poorest prognosis, highest invasiveness and AJCC grade, enhanced immune infiltration but suppressive immunophenotypes. ACAA2, ACAT1, ASRGL1, AKR1B10, ABCC2, ANGPTL4 were identified to construct the 6 gene-signature prognosis model and verified both internally and externally with ICGC cohorts. ACAA2 was demonstrated as a tumor suppressor and was associated with higher immune infiltration and elevated PD-1 expression of CD8+ T cells. CONCLUSIONS: Our research proposed a new metabolic classification method for RCC and revealed intrinsic associations between metabolic phenotypes and immune profiles. The identified gene signatures might serve as key factors bridging tumor metabolism and tumor immunity and warrant further in-depth investigations.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Animales , Ratones , Linfocitos T CD8-positivos , Apoptosis , Análisis por Conglomerados , Pronóstico , Microambiente TumoralRESUMEN
A number of substances released by the brain under physiological and pathological conditions exert effects on other organs. In turn, substances produced primarily by organs such as bone marrow, adipose tissue, or the heart may have an impact on the metabolism and function and metabolism of the healthy and diseased brain. Despite a mounting amount of evidence supports such bidirectional communication between the brain and other organs, research on the function of molecular mediators carried by extracellular vesicles (EVs) is in the early stages. In addition to being able to target or reach practically any organ, EVs have the ability to cross the blood-brain barrier to transport a range of substances (lipids, peptides, proteins, and nucleic acids) to recipient cells, exerting biological effects. Here, we review the function of EVs in bidirectional communication between the brain and other organs. In a small number of cases, the role has been explicitly proven; yet, in most cases, it relies on indirect evidence from EVs in cell culture or animal models. There is a dearth of research currently available on the function of EVs-carrying mediators in the bidirectional communication between the brain and bone marrow, adipose tissue, liver, heart, lungs, and gut. Therefore, more studies are needed to determine how EVs facilitate communication between the brain and other organs.