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Antibiotics are among the most used weapons in fighting microbial infections and have greatly improved the quality of human life. However, bacteria can eventually evolve to exhibit antibiotic resistance to almost all prescribed antibiotic drugs. Photodynamic therapy (PDT) develops little antibiotic resistance and has become a promising strategy in fighting bacterial infection. To augment the killing effect of PDT, the conventional strategy is introducing excess ROS in various ways, such as applying high light doses, high photosensitizer concentrations, and exogenous oxygen. In this study, we report a metallacage-based PDT strategy that minimizes the use of ROS by jointly using gallium-metal organic framework rods to inhibit the production of bacterial endogenous NO, amplify ROS stress, and enhance the killing effect. The augmented bactericidal effect was demonstrated both in vitro and in vivo. This proposed enhanced PDT strategy will provide a new option for bacterial ablation.
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Fotoquimioterapia , Humanos , Espécies Reativas de Oxigênio/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , BactériasRESUMO
The vaginal epithelium plays pivotal roles in host defense against pathogen invasion, contributing to the maintenance of an acidic microenvironment within the vaginal lumen through the activity of acid-base transport proteins. However, the precise defense mechanisms of the vaginal epithelium after a bacterial infection remain incompletely understood. This study showed that bacterial lipopolysaccharide (LPS) potentiated net proton efflux by up-regulating the expression of Na+-H+ exchanger 1 (NHE1) without affecting other acid-base transport proteins in vaginal epithelial cells. Pharmacologic inhibition or genetic knockdown of Toll-like receptor-4 and the extracellular signal-regulated protein kinase signaling pathway effectively counteracted the up-regulation of NHE1 and the enhanced proton efflux triggered by LPS in vaginal epithelial cells. In vivo studies revealed that LPS administration led to luminal acidification through the up-regulation of NHE1 expression in the rat vagina. Moreover, inhibition of NHE exhibited an impaired defense against acute bacterial infection in the rat vagina. These findings collectively indicate the active involvement of vaginal epithelial cells in facilitating luminal acidification during acute bacterial infection, offering potential insights into the treatment of bacterial vaginosis.
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CD4+ T-cell counts are increased and activated in patients with chronic heart failure (CHF), whereas regulatory T-cell (Treg) expansion is inhibited, probably due to aberrant T-cell receptor (TCR) signaling. TCR signaling is affected by protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in autoimmune disorders, but whether PTPN22 influences TCR signaling in CHF remains unclear. This observational case-control study included 45 patients with CHF [18 patients with ischemic heart failure versus 27 patients with nonischemic heart failure (NIHF)] and 16 non-CHF controls. We used flow cytometry to detect PTPN22 expression, tyrosine phosphorylation levels, zeta-chain-associated protein kinase, 70 kDa (ZAP-70) inhibitory residue tyrosine 292 and 319 phosphorylation levels, and CD4+ T cell and Treg proportions. We conducted lentivirus-mediated PTPN22 RNA silencing in isolated CD4+ T cells. PTPN22 expression increased in the CD4+ T cells of patients with CHF compared with that in controls. PTPN22 expression was positively correlated with left ventricular end-diastolic diameter and type B natriuretic peptide but negatively correlated with left ventricular ejection fraction in the NIHF group. ZAP-70 tyrosine 292 phosphorylation was decreased, which correlated positively with PTPN22 overexpression in patients with NIHF and promoted early TCR signaling. PTPN22 silencing induced Treg differentiation in CD4+ T cells from patients with CHF, which might account for the reduced frequency of peripheral Tregs in these patients. PTPN22 is a potent immunomodulator in CHF and might play an essential role in the development of CHF by promoting early TCR signaling and impairing Treg differentiation from CD4+ T cells.
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Insuficiência Cardíaca , Receptores de Antígenos de Linfócitos T , Humanos , Estudos de Casos e Controles , Volume Sistólico , Receptores de Antígenos de Linfócitos T/metabolismo , Função Ventricular Esquerda , Proteínas Tirosina Fosfatases , Linfócitos T Reguladores , Tirosina , Proteína Tirosina Fosfatase não Receptora Tipo 22/genéticaRESUMO
The axis of platelet-derived growth factor (PDGF) and PDGF receptor-beta (PDGFRß) plays prominent roles in cell growth and motility. In addition, PDGF-D enhances human natural killer (NK) cell effector functions when binding to the NKp44 receptor. Here, we report an additional but previously unknown role of PDGF-D, whereby it mediates interleukin-15 (IL-15)-induced human NK cell survival but not effector functions via its binding to PDGFRß but independent of its binding to NKp44. Resting NK cells express no PDGFRß and only a low level of PDGF-D, but both are significantly up-regulated by IL-15, via the nuclear factor κB signaling pathway, to promote cell survival in an autocrine manner. Both ectopic and IL-15-induced expression of PDGFRß improves NK cell survival in response to treatment with PDGF-D. Our results suggest that the PDGF-D-PDGFRß signaling pathway is a mechanism by which IL-15 selectively regulates the survival of human NK cells without modulating their effector functions.
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Interleucina-15/metabolismo , Células Matadoras Naturais/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Linfocinas , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Receptor 2 Desencadeador da Citotoxicidade Natural , Fator de Crescimento Derivado de Plaquetas/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genéticaRESUMO
Immune cell infiltration is a significant pathological process in abdominal aortic aneurysms (AAA). T cells, particularly CD4+ T cells, are essential immune cells responsible for substantial infiltration of the aorta. Regulatory T cells (Tregs) in AAA have been identified as tissue-specific; however, the time, location, and mechanism of acquiring the tissue-specific phenotype are still unknown. Using single-cell RNA sequencing (scRNA-seq) on CD4+ T cells from the AAA aorta and spleen, we discovered heterogeneity among CD4+ T cells and identified activated, proliferating and developed aorta Tregs. These Tregs originate in the peripheral tissues and acquire the tissue-specific phenotype in the aorta. The identification of precursors for Tregs in AAA provides new insight into the pathogenesis of AAA.
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Aneurisma da Aorta Abdominal , Análise de Célula Única , Linfócitos T Reguladores , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Linfócitos T Reguladores/imunologia , Humanos , Animais , Masculino , Linfócitos T CD4-Positivos/imunologia , Camundongos , Análise de Sequência de RNA , Baço/imunologia , Ativação Linfocitária , Camundongos Endogâmicos C57BLRESUMO
Paclitaxel and its derivates are the first-line chemotherapeutic agents of breast cancer, which also showed tremendous clinical value in many other diseases including ovarian cancer, lung cancer etc. However, there are many drawbacks for almost all paclitaxel or its derivates, including extremely short half-life, poor solubility and adverse events, which significantly limits their clinical applications. In this work, we designed and constructed a bispecific hydrolysis PAP-SS-PTX (term as PDC), consisting with pro-apoptosis peptide (PAP) and paclitaxel (PTX) that were conjugated together via disulfide and ester bonds. On the one hand, PAP could improve the solubility of PTX and promote cellular uptake for drugs. On the other hand, it was able to prolong the PTX half-life. We performed series of chemo-dynamical assays and showed that PDC would release active drug molecules under micro-acidic and reduction circumstance. The further assays elucidated that PDC could interrupt DNA synthesis and arrest cell division through downregulating CDK4/6 and Histone methylation that inhibit tumor growth inâ vitro. What's more, it could not only inhibit 4T1 breast tumor growth, but also prolong the survival time of mice and exert antitumor efficacy inâ vivo. It may provide a new research idea for cancer therapies via controlled release strategy in tumor microenvironment.
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Metasurface zone plates exhibit stronger optical control capabilities than traditional Fresnel zone plates, especially in polarization transformation and multiplexing. However, there are still few studies on metasurface zone plates that can be used for simultaneous control of forward and backward waves. In this work, we propose what is to our knowledge a new scheme that utilizes metasurface zone plates for orthogonal linear polarization separation and wavefront manipulation at the same time. We demonstrate the separation of linearly polarized components and transmission-reflection focusing by using the destructive and constructive interference between different meta-atoms in the super-cell, as well as the phase difference between the super-cells. The metasurface not only needs a simple binary phase design but also shows a working bandwidth more than 30â nm with a central wavelength of 875â nm. This scheme can be extended to other electromagnetic bands such as visible and terahertz ones, providing an important way for the multi-dimensional light field manipulations.
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Circular dichroism (CD) spectrum and optical rotation (OR) spectrum, crucial for understanding molecular properties and configurations, present challenges due to limited testing methods and equipment accuracy in the ultraviolet (UV) region. This study proposes a weak measurement system for chiral signals in varying concentrations in the ultraviolet range, optimized using a deep neural network (DNN) model. Introducing different post-selections to detect the circular dichroism spectrum and optical rotation spectrum separately, with contrast as a probe, it achieves a detection resolution of up to 10-6 rad. Moreover, the fitted value of the training data can reach 0.9989, enhancing the prediction accuracy of chiral molecule concentrations. This method exhibits considerable promise for applications in chiral measurement and sensor technologies.
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With the rapid development of 5G communication technology, microwave dielectric ceramics with high dielectric constants are very conducive to the miniaturization of passive devices. Here, Ba3Ti4-x(Ni1/3Nb2/3)xNb4O21 (BTN â¼ NN, 0.03 ≤ x ≤ 0.15) ceramics with hexagonal phases are synthesized via the solid-phase route. The composite (Ni1/3Nb2/3)4+ ion substitution strategy can substantially improve the microwave dielectric properties of the Ba3Ti4Nb4O21 (BTN) ceramic. The εr and Q × f values depend on the ionicity (Nb-O bonds) and lattice energies (Nb(1)-O3 and Nb(1)-O2(1) bonds). The microwave dielectric properties of the BTN â¼ NN (x = 0.09) ceramic sintered at 1250 °C are εr = 60.3, Q × f = 22073 GHz, and τf = 78.1 ppm/°C. A miniaturized all-ceramic radome (@400 mm × 400 mm × 8 mm) for 5G beam-splitting function is designed and demonstrated using this ceramic. Compared to other radomes designed for other work utilizing low εr, the size of this radome has been reduced by 3/7. The reflection coefficients of the beam splitting function are all 0.73, and the phase shifts are all 360°. This work contributes to the development of miniaturized passive devices from a materials point of view.
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BACKGROUND: Previous studies of singletons evaluating prenatal phthalate exposure and early neurodevelopment reported mixed results and the associations could be biased by parental, obstetrical, and genetic factors. METHODS: A co-twin control design was employed to test whether prenatal phthalate exposure was associated with children's neurocognitive development. We collected information from 97 mother-twin pairs enrolled in the Wuhan Twin Birth Cohort between March 2016 and October 2018. Fourteen phthalate metabolites were measured in maternal urine collected at each trimester. Neurodevelopmental differences in twins at the age of two were examined as the outcome of interest. Multiple informant model was used to examine the covariate-adjusted associations of prenatal phthalate exposure with mental development index (MDI) and psychomotor development index (PDI) scores assessed at 2 years of age based on Bayley Scales of Infant Development (Second Edition). This model also helps to identify the exposure window of susceptibility. RESULTS: Maternal urinary levels of mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (ß = 1.91, 95% CI: 0.43, 3.39), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (ß = 1.56, 95% CI: 0.33, 2.79), and the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) (ß = 1.85, 95% CI: 0.39, 3.31) during the first trimester showed the strongest and significant positive associations with intra-twin MDI difference. When stratified with twin chorionicity, the positive associations of monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), individual DEHP metabolites, and ∑DEHP exposure during pregnancy with intra-twin neurodevelopmental differences were more significant in monochorionic diamniotic (MCDA) twins than those in dichorionic diamniotic (DCDA) twins. CONCLUSIONS: Neurodevelopmental differences in MCDA twins were strongly associated with prenatal phthalate exposure. Our findings warrant further confirmation in longitudinal studies with larger sample sizes.
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Poluentes Ambientais , Ácidos Ftálicos , Criança , Lactente , Gravidez , Feminino , Humanos , Ácidos Ftálicos/toxicidade , Estudos Longitudinais , Trimestres da Gravidez , Primeiro Trimestre da Gravidez , Mães , Exposição Ambiental , Poluentes Ambientais/toxicidade , Exposição Materna/efeitos adversosRESUMO
BACKGROUND: Abdominal distension is a relatively common complication in postoperative lung cancer patients, which affects patients' early postoperative recovery to varying degrees. However, the current status of the incidence of abdominal distension in postoperative lung cancer patients and the affecting factors are not well understood. This study aims at exploring the incidence of abdominal distension in postoperative lung cancer patients in ICU based on real-world data and analyzing its influencing factors. METHODS: A retrospective cohort study was conducted, encompassing patients who underwent lung cancer resections in the Lung Cancer Center of West China Hospital of Sichuan University from April 2020 to April 2021. Nevertheless, patients younger than 18 years and those whose information was limited in medical records were excluded. All data were obtained from the hospital HIS system. In this study, the influencing factors of abdominal distension were analyzed by univariate analysis and multiple logistic regression methods. RESULTS: A total of 1317 patients met eligibility criteria, and were divided into the abdominal distended group and the non-distended group according to whether abdominal distension occurred after surgery. Abdominal distension occurred in a total of 182 cases(13.8%). The results of the univariate analysis showed that, compared with the non-distended group, the abdominal distended group had these features as follows: more women (P = 0.021), older (P = 0.000), lower BMI (P = 0.000), longer operation duration (P = 0.031), more patients with open thoracotomy (P = 0.000), more patients with pneumonectomy (p = 0.002), more patients with neoadjuvant chemotherapy (P = 0.000), more days of hospitalization on average (P = 0.000), and higher costs of hospitalization on average (P = 0.032). Multifactor logistic regression analysis showed that sex (OR = 0.526; 95% CI = 0.378 ~0.731), age (OR = 1.154; 95%CI = 1.022 ~1.304) and surgical approach (OR = 4.010; 95%CI = 2.781 ~5.781) were independent influencing factors for the occurrence of abdominal distension in patients after lung cancer surgery in ICU. CONCLUSIONS: The incidence of abdominal distension was high in postoperative lung cancer patients in ICU, and female, older and patients with open thoracotomy were more likely to experience abdominal distension. TRIAL REGISTRATION: The study was approved by the Chinese Clinical Trials Registry (registration number was ChiCTR2200061370).
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Neoplasias Pulmonares , Feminino , Humanos , Incidência , Unidades de Terapia Intensiva , Neoplasias Pulmonares/cirurgia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , MasculinoRESUMO
BACKGROUND: Both the crystalline and soluble forms of cholesterol increase macrophage secretion of interleukin 1ß (IL-1ß), aggravating the inflammatory response in atherosclerosis (AS). However, the link between cholesterol and regulatory T cells (Tregs) remains unclear. This study aimed to investigate the effect of cholesterol treatment on Tregs. METHODS: Differentiation of induced Tregs (iTregs) was analyzed using flow cytometry. The expression of hypoxia-inducible factor-1a (HIF-1a) and its target genes was measured by western blotting and/or RT-qPCR. Two reporter jurkat cell lines were constructed by lentiviral transfection. Mitochondrial function and the structure of natural Tregs (nTregs) were determined by tetramethylrhodamine (TMRM) and mitoSOX staining, Seahorse assay, and electron microscopy. The immunoregulatory function of nTregs was determined by nTreg-macrophage co-culture assay and ELISA. RESULTS: Cholesterol treatment suppressed iTreg differentiation and impaired nTreg function. Mechanistically, cholesterol induced the production of mitochondrial reactive oxygen species (mtROS) in naïve T cells, inhibiting the degradation of HIF-1α and unleashing its inhibitory effects on iTreg differentiation. Furthermore, cholesterol-induced mitochondrial oxidative damage impaired the immunosuppressive function of nTregs. Mixed lymphocyte reaction and nTreg-macrophage co-culture assays revealed that cholesterol treatment compromised the ability of nTregs to inhibit pro-inflammatory conventional T cell proliferation and promote the anti-inflammatory functions of macrophages. Finally, mitoTEMPO (MT), a specific mtROS scavenger, restored iTreg differentiation and protected nTreg from further deterioration. CONCLUSION: Our findings suggest that cholesterol may aggravate inflammation within AS plaques by acting on both iTregs and nTregs, and that MT may be a promising anti-atherogenic drug.
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Inflamação , Linfócitos T Reguladores , Humanos , Diferenciação Celular , Inflamação/metabolismo , Mitocôndrias/metabolismo , Técnicas de Cocultura , Fatores de Transcrição Forkhead/metabolismoRESUMO
In this paper, we propose a precision method to measure the chiroptical signal of Artemisinin solutions using the photonic spin Hall effect (PSHE) on the Ce:YIG-YIG-SiO2 structure as a probe. The effects of transmission distance, incident angles, applied magnetic fields of different directions, and beam waist of light on the weak measurement system are analytically investigated through simulations. It is found that decreasing the beam waist of the incident spot, increasing the incident angle, increasing the transmission distance, and adding a longitudinal magnetic field is conducive to enhancing the amplification transverse shift of PSHE, thus the measurement sensitivity is greatly improved. Based on the optimal weak measurement scheme, the detection limit for concentration measurement of artemisinin based on optical rotatory (OR) was reduced to 0.05 mg/ml. The measurement precision of the OR angle has been improved to 10-7rad.
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Traditional grating lenses can accumulate phase for adjusting wavefronts, and plasmonic resonances can be excited in metasurfaces with discrete structures for optical field modulation. Diffractive and plasma optics have been developing in parallel, with easy processing, small size, and dynamic control advantages. Due to theoretical hybridization, structural design can combine advantages and show great potential value. Changing the shape and size of the flat metasurface can easily produce light field reflections, but changes in height are rarely cross-explored. We propose a graded metasurface with a single-structure periodic arrangement, which can mix the effects of plasmonic resonance and grating diffraction. As for solvents of different polarities, strong polarization-dependent beam reflections are produced, enabling versatile beam convergence and deflection. Dielectric/metal nanostructures with selective hydrophobic/hydrophilic properties can be arranged by the structural material specification to selectively settle the location of the solution in a liquid environment. Furthermore, the wetted metasurface is actively triggered to achieve spectral control and initiate polarization-dependent beam steering in the broadband visible light region. Actively reconfigurable polarization-dependent beam steering has potential applications in tunable optical displays, directional emission, beam manipulation and processing, and sensing technologies.
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BACKGROUND: The NLRP3/IL-1ß/IL-6 pathway plays a key role in mediating inflammatory responses after ST-elevation myocardial infarction (STEMI). However, the clinical benefits of inhibiting this pathway in STEMI are uncertain. We aimed to evaluate the efficacy and safety of inhibiting the NLRP3/IL-1ß/IL-6 pathway in STEMI patients. METHODS: This study followed PRISMA guidelines. PubMed, Embase, CENTRAL and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) of inhibiting the NLRP3/IL-1ß/IL-6 pathway in STEMI patients within 7 days of symptom onset. The efficacy outcomes included all-cause death, cardiovascular death, recurrent MI, new-onset or worsening heart failure (HF) and stroke. The safety outcomes were serious infection, gastrointestinal adverse events and injection site reactions. RESULTS: Of 316 screened records, nine trials with 1211 patients were included in the meta-analysis. Colchicine reduced the risk of recurrent MI (RR 0.28, 95% CI 0.10-0.74; I2 = 0.0%). Anakinra was associated with reduced risk of new-onset or worsening HF (RR 0.32, 95% CI 0.13-0.77; I2 = 0.0%) and decreased C-reactive protein levels (SMD -1.34, 95% CI -2.04 to -0.65; I2 = 0.0%). Colchicine and anakinra increased the risk of gastrointestinal adverse events (RR 4.43, 95% CI 2.75-7.13; I2 = 38.1%) and injection site reactions (RR 4.52, 95% CI 1.32-15.49; I2 = 0.8%), respectively. None of the three medications affected the risks of all-cause death, cardiovascular death, stroke and serious infection. CONCLUSIONS: There is still no large-scale RCT evidence on the efficacy and safety of inhibiting the NLRP3/IL-1ß/IL-6 pathway for the treatment of STEMI. Preliminary results from the available RCTs suggest colchicine and anakinra may respectively reduce the risks of recurrent MI and new-onset or worsening HF. The available RCTs in this meta-analysis lack power to determine any differences on mortality.
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The properties of traditional Fresnel zone plates have been greatly enhanced by metasurfaces, which allow the control of polarization, orbital angular momentum, or other parameters on the basis of focusing. In this Letter, a new, to the best of our knowledge, method for circularly polarized wave manipulation based on a zone plate is proposed. Chiral meta-atoms and binary geometric phase are used for the simultaneous focusing of reflected and transmitted terahertz waves. The silicon-based dielectric chiral units, which show great performance of spin-selective transmission near 0.54 THz, separate the orthogonal circularly polarized components. A binary Pancharatnam-Berry (P-B) phase gradient is obtained by rotating the unit 90 degrees, then the phase zone plate can be easily designed. The simulation results show that the proposed chiral metasurface zone plate has the function of reflection-transmission separation and focusing for the circularly polarized terahertz waves. In addition, we also demonstrate the possibility of using a 1064-nm continuous infrared laser to adjust the intensity of our devices, based on photo-generated carriers in silicon. The design principle of the chiral metasurface zone plates can be extended to other wavelengths, providing new ideas for the regulation of circularly polarized light.
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Abdominal aortic aneurysms (AAAs) elicit massive inflammatory leukocyte recruitment to the aorta. CD4+ T cells, which include regulatory T cells (Tregs) and conventional T cells (Tconvs), are involved in the progression of AAA. Tregs have been reported to limit AAA formation. However, the function and phenotype of the Tconvs found in AAAs remain poorly understood. We characterized aortic Tconvs by bulk RNA sequencing and discovered that Tconvs in aortic aneurysm highly expressed Cxcr6 and Csf2. Herein, we determined that the CXCR6/CXCL16 signaling axis controlled the recruitment of Tconvs to aortic aneurysms. Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF), encoded by Csf2, markedly inhibited AAA formation and led to a decrease of inflammatory monocytes, due to a reduction of CCL2 expression. Conversely, the exogenous administration of GM-CSF exacerbated inflammatory monocyte infiltration by upregulating CCL2 expression, resulting in worsened AAA formation. Mechanistically, GM-CSF upregulated the expression of interferon regulatory factor 5 to promote M1-like macrophage differentiation in aortic aneurysms. Importantly, we also demonstrated that the GM-CSF produced by Tconvs enhanced the polarization of M1-like macrophages and exacerbated AAA formation. Our findings revealed that GM-CSF, which was predominantly derived from Tconvs in aortic aneurysms, played a pathogenic role in the progression of AAAs and may represent a potential target for AAA treatment.
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Aneurisma da Aorta Abdominal/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Macrófagos/imunologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson's disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 µM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.
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Doença de Parkinson , Receptores de Grelina , Animais , Camundongos , Receptores de Grelina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Grelina/farmacologia , Dopamina/metabolismo , Quimpirol/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Substância Negra/metabolismo , Substância Negra/patologia , Modelos Animais de DoençasRESUMO
Enantiomeric separation of furanocoumarins and dihydroflavones compounds were systematically studied in the normal-phase mode using four different polysaccharide-type chiral stationary phases, namely, Chiralpak IA, Chiralpak IC, Chiralpak IG, and Chiralpak IK-3 by high-performance liquid chromatography. The effect of alcohol modifiers and alcohol content on enantiomeric separation was evaluated for the separation of furanocoumarins and dihydroflavones. All the eight compounds have achieved baseline separation with the resolutions ranging between 1.52 and 23.11. For a better insight into the enantiorecognition mechanisms, thermodynamic analysis was carried out. The mechanisms of chiral recognition have been discussed. Among four chiral columns, Chiralpak IG exhibited the most universal and the best enantioseparation ability toward furanocoumarins and dihydroflavones when used n-hexane-isopropanol and n-hexane-ethanol as mobile phase, respectively. The steric hindrance, hydrogen bonding, and π-π interaction played major roles in chiral recognition on Chiralpak IG. By comparing four chiral columns, this work systematically analyzed the separation methods of furanocoumarins and dihydroflavones for the first time and reported some active chiral ingredients of traditional Chinese medicine that have never been separated, which provided a further insight into the enantioseparation of furanocoumarins and dihydroflavones on chiral stationary phases.
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Furocumarinas , Polissacarídeos/química , Hexanos , Cromatografia Líquida de Alta Pressão/métodos , Etanol , EstereoisomerismoRESUMO
Our earlier work in Nguyen et al. (Maximizing metapopulation growth rate and biomass in stream networks. arXiv preprint arXiv:2306.05555 , 2023) shows that concentrating resources on the upstream end tends to maximize the total biomass in a metapopulation model for a stream species. In this paper, we continue our research direction by further considering a Lotka-Volterra competition patch model for two stream species. We show that the species whose resource allocations maximize the total biomass has the competitive advantage.