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Metal-organic framework (MOF) materials are three-dimensional structures formed by the combination of metal ions and organic ligands. So far, various typical metal organic framework materials have emerged, such as ZIF-8, MOF-5, UIO-66, etc. These traditional MOF materials have the advantages of simple synthesis, high porosity, and high stability, and have great research potential in the field of fluorescence sensing. However, MOF materials with excellent luminescent properties often involve fine regulation of organic ligands to ensure that fluorescence emission can be achieved between metal ions and organic ligands through energy transfer and photo induced electron transfer. The long synthesis cycle and cumbersome preparation process pose challenges for the research of fluorescent MOF materials. Combining MOF materials with luminescent guests is an effective way to prepare simple fluorescent chemical sensors. These luminescent guests include quantum dots, organic dyes, fluorescent nanoparticles, etc. They have the characteristic of high luminescence quantum yield, but high concentrations often lead to aggregation and collision, which in turn cause emission quenching. MOF materials with excellent porosity and specific surface area can serve as an ideal platform for encapsulating luminescent guests and preventing their aggregation. The preparation of MOF@luminescent guest composite material (MOF@LG) is easy to synthesize, which not only effectively improves the poor fluorescence performance of MOFs themselves, but also preserves the excellent fluorescence performance of luminescent guests. Composite materials often have excellent solid-state luminescence performance, making them a good choice for constructing a simple fluorescence sensing platform.
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Background/Objectives: Breast cancer is diagnosed in 2.3 million women each year and kills 685,000 (~30% of patients) worldwide. The prognosis for many breast cancer subtypes has improved due to treatments targeting the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In contrast, patients with triple-negative breast cancer (TNBC) tumors, which lack all three commonly targeted membrane markers, more frequently relapse and have lower survival rates due to a lack of tumor-selective TNBC treatments. We aim to investigate TNBC mechanistic markers that could be targeted for treatment. Methods: We performed a secondary TNBC analysis of 196 samples across 10 publicly available bulk RNA-sequencing studies to better understand the molecular mechanism(s) of disease and predict robust mechanistic markers that could be used to improve the mechanistic understanding of and diagnostic capabilities for TNBC. Results: Our analysis identified ~12,500 significant differentially expressed genes (FDR-adjusted p-value < 0.05), including KIF14 and ELMOD3, and two significantly modulated pathways. Additionally, our novel findings include highly accurate mechanistic markers identified using machine learning methods, including CIDEC (97.1% accuracy alone), CD300LG, ASPM, and RGS1 (98.9% combined accuracy), as well as TNBC subtype-differentiating mechanistic markers, including the targets PDE3B, CFD, IFNG, and ADM, which have associated therapeutics that can potentially be repurposed to improve treatment options. We then experimentally and computationally validated a subset of these findings. Conclusions: The results of our analyses can be used to better understand the mechanism(s) of disease and contribute to the development of improved diagnostics and/or treatments for TNBC.
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Despite an increase in the promotion of equal opportunities at work, there is still persistent discrimination against lesbian and gay (LG) workers. In this vein, this study aimed to systematically review the research investigating the peculiarities of the work experience of LG people, particularly considering the theoretical frameworks in the approach to sexual minorities' work-related issues, as well as individual and contextual variables influencing the work experience and the impact they may have on health and well-being. We explored the PsycArticles, EMBASE, Scopus, and Web of Science electronic databases and the EBSCOHost (PsycInfo, Psychology and Behavioral Sciences Collection) scholarly search engine, between 01/01/2013 to 01/03/2023, with regards to the search terms "lgb*", "gay*", "lesbian*", "homosexual*", and "sexual minorit*", associated with "employee*", "personnel", "worker*", and "staff", and with "workplace", "work", "job", "occupation", "employment", and "career". Data were narratively synthesized and critically discussed. Of the 1584 potentially eligible articles, 140 papers contributed to this systematic review. Five main theoretical frameworks were identified: (a) minority stress, (b) sexual prejudice and stigma, (c) queer and Foucauldian paradigms, (d) social identity theories, and (e) intersectionality. Furthermore, significant individual (e.g., outness, disclosure, and work-family conflict) and contextual (e.g., heterosexist and heteronormative workplace climate and culture) variables influencing LG people's work experience were identified. This review highlights the need to develop a unified theoretical model for the construction of specific measurement tools to assess the work experience of LG people and for the implementation of interventions aimed at minimizing the effects of stigma in work contexts.
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Minorias Sexuais e de Gênero , Humanos , Minorias Sexuais e de Gênero/psicologia , Feminino , Masculino , Local de Trabalho/psicologia , Emprego/psicologiaRESUMO
Recombinant adeno-associated viruses (rAAV) are promising for applications in many genome editing techniques through their effectiveness as carriers of DNA homologous donors into primary hematopoietic stem and progenitor cells (HSPCs), but they have many outstanding concerns. Specifically, their biomanufacturing and the variety of factors that influence the quality and consistency of rAAV preps are in question. During the process of rAAV packaging, a cell line is transfected with several DNA plasmids that collectively encode all the necessary information to allow for viral packaging. Ideally, this process results in the packaging of complete viral particles only containing rAAV genomes; however, this is not the case. Through this study, we were able to leverage single-stranded virus (SSV) sequencing, a next-generation sequencing-based method to quantify all DNA species present within rAAV preps. From this, it was determined that much of the DNA within some rAAV preps is not vector-genome derived, and there is wide variability in the contamination by DNA across various preps. Furthermore, we demonstrate that transducing CD34+ HSPCs with preps with higher contaminating DNA resulted in decreased clonogenic potential, altered transcriptomic profiles, and decreased genomic editing. Collectively, this study characterized the effects of DNA contamination within rAAV preps on CD34+ HSPC cellular potential.
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PURPOSE: To evaluate the efficacy and safety of UGN-102 chemoablation for the primary treatment of patients with recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: ENVISION is an ongoing, multinational, single-arm, Phase 3 study in patients with a biopsy-proven recurrence of untreated low-grade intermediate-risk nonmuscle-invasive bladder cancer. Patients received 6 weekly intravesical instillations of UGN-102 (mitomycin; outpatient setting) and were evaluated at 3 months. Patients achieving complete response (CR) (negative cystoscopic examination, cytology, and for-cause biopsy) were surveilled regularly until recurrence, progression, or death. Patients who remain disease-free will be followed up to 5 years, and further results will be reported in the future. RESULTS: Of 240 patients enrolled, 228 (95%) received all 6 planned doses; 191 (79.6%; 95% CI: 73.9, 84.5) achieved CR at 3 months, with an 82.3% (95% CI: 75.9, 87.1) probability of response 12 months later. Median duration of response was not estimable over a median 13.9-month follow-up period. The most common adverse events (≥5.0% of patients) were dysuria, hematuria, urinary tract infection, pollakiuria, fatigue, and urinary retention; generally mild/moderate and resolved/resolving. Serious adverse events were observed in 29/240 (12.1%), 2 were treatment-related (urinary retention/urethral stenosis), both resolved. CONCLUSIONS: Primary chemoablation with UGN-102 in patients with recurrent low-grade-intermediate-risk-nonmuscle-invasive bladder cancer resulted in a 79.6% CR rate. Patients achieving a CR had an 82.3% likelihood of remaining disease-free 1 year later. The benefit-risk profile was favorable, supporting UGN-102 as a non-surgical alternative for transurethral resection of bladder tumors in this patient population. Limitations of this study included lack of tumor sizing after the diagnostic biopsy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05243550.
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OBJECTIVES: To evaluate the long-term effectiveness of weekly vs. daily growth hormone (GH) administration in children with GH deficiency. METHODS: This study, part of the "LG Growth Study", included a total of 996 children with GH deficiency (773 receiving daily GH and 193 receiving weekly GH). Anthropometric data were collected at baseline and every 12 months; clinical and laboratory data were collected at baseline and throughout the study. RESULTS: At baseline, the weekly GH group was older, shorter in mid-parental height (MPH), and had more pubertal boys compared to the daily GH group (age: 8.46 ± 3.44 vs. 7.46 ± 2.89 years, p<0.001; MPH: -0.88 ± 0.73 SD vs. -1.02 ± 0.84 SD, p=0.044; pubertal boys: 34.0 vs. 16.9â¯%, p=0.006). Height velocity and change in height SDS during the first 12 months were higher in the daily GH group (height velocity: 9.06 ± 1.72 vs. 8.67 ± 1.98â¯cm/year, p=0.028; height SDS change: 0.78 ± 0.39 vs. 0.61 ± 0.41, p<0.001). However, height SDS at 24 and 48 months were similar between groups. No significant differences in overall height velocity, annualized treatment continuation rate, and safety profile were observed over 48 months. CONCLUSIONS: Weekly GH therapy appears to be an effective and safe alternative to daily GH treatment in children with GH deficiency over a 4-year period. Further research with larger sample sizes and longer follow-up is needed to confirm these findings and assess the extended safety and effectiveness of LAGH.
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Quantum entanglement is essential in performing many quantum information tasks. Here, we theoretically investigate the stationary entanglement between a Laguerre-Gaussian (LG) cavity field and a rotating end mirror in an LG-cavity optorotational system with a nonlinear cross-Kerr (CK) interaction and a degenerate optical parametric amplifier (OPA). We calculate the logarithmic negativity of the system to quantify the stationary entanglement. We examine the influence of various system parameters such as the cavity detuning, the strength of the nonlinear CK interaction, the parametric gain and phase of the OPA, the power of the input Gaussian laser, the topological charge of the LG-cavity field, the mass of the rotating end mirror, and the ambient temperature on the stationary entanglement. Under the combined effect of the nonlinear CK interaction and the OPA, we find that the stationary entanglement can be substantially enhanced at lower Gaussian laser powers, smaller topological charges of the LG-cavity field, and larger masses of the rotating end mirror. We show that the combination of the nonlinear CK interaction and the OPA can make the stationary entanglement more robust against the ambient temperature.
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According to a central tenet of classical immune theory, a healthy immune system must avoid self-reactive lymphocyte clones but we now know that B cells repertoire exhibit some level of autoreactivity. These autoreactive B cells are thought to rely on self-ligands for their clonal selection and survival. Here, we confirm that healthy mice exhibit self-reactive B cell clones that can be stimulated in vitro by agonists of toll-like receptor (TLR) 1/2, TLR4, TLR7 and TLR9 to secrete anti-LG3/perlecan. LG3/perlecan is an antigen packaged in exosome-like structures released by apoptotic endothelial cells (ApoExos) upon vascular injury. We demonstrate that the injection of ApoExos in healthy animals activates the IL-23/IL-17 pro-inflammatory and autoimmune axis, and produces several autoantibodies, including anti-LG3 autoantibodies and hallmark autoantibodies found in systemic lupus erythematosus. We also identify γδT cells as key mediators of the maturation of ApoExos-induced autoantibodies in healthy mice. Altogether we show that ApoExos released by apoptotic endothelial cells display immune-mediating functions that can stimulate the B cells in the normal repertoire to produce autoantibodies. Our work also identifies TLR activation and γδT cells as important modulators of the humoral autoimmune response induced by ApoExos.
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PURPOSE: This study aims to develop a novel serum-free culture strategy containing only two small molecules, Y27632 and SB431542 (2C), for in vitro expansion of mouse lacrimal gland epithelial cells (LGECs) and investigate an innovative therapeutic approach for lacrimal gland (LG) injury. METHODS: LGECs proliferative capacity was assessed by cell counting, crystal violet staining, qRT-PCR and immunofluorescence. Cell differentiation was achieved by manipulating culture conditions and assessed by qRT-PCR and AQP5 immunofluorescence. LGECs were seeded in Matrigel for three-dimensional culture and assessed by qRT-PCR and immunofluorescence. Secretory function of the cultures was assayed by ELISA. In vivo, 2C injection verified its reparative capacity in a mouse LG injury model. Corneal fluorescein staining, phenol red cotton thread, H&E, immunofluorescence and Western blot were used to assess LG injury repair. RESULTS: LGECs cultured with 2C exhibited high expression of stemness/proliferation markers and maintained morphology and proliferative capacity even after the tenth passage. Removal of 2C was efficacious in achieving LGECs differentiation, characterized by the increased AQP5 expression and LTF secretion. 3D spheroids cultured with 2C demonstrated differentiation potential, forming microglandular structures containing multiple LG cell types with secretory functions after 2C removal. In vivo, 2C improved the structural integrity and function of the injured LG. CONCLUSIONS: We present a small molecule combination, 2C, that promotes LGECs expansion and differentiation in vitro and accelerates LG injury repair in vivo. This approach has potential applications for providing a stable source of seed cells for tissue engineering applications, providing new sights for LG-related diseases treatment.
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Corn leaf aphids (Rhopalosiphum maidis) are highly destructive pests of maize (Zea mays) that threaten growth and seed yield, but resources for aphid resistance are scarce. Here, we identified an aphid-resistant maize mutant, resistance to aphids 1 (rta1), which is allelic to LIGULELESS1 (LG1). We confirmed LG1's role in aphid resistance using the independent allele lg1-2, allelism tests and LG1 overexpression lines. LG1 interacts with, and increases the stability of ZINC-FINGER PROTEIN EXPRESSED IN INFLORESCENCE MERISTEM (ZIM1), a central component of the jasmonic acid (JA) signalling pathway, by disturbing its interaction with the F-box protein CORONATINE INSENSITIVE 1a (COI1a). Natural variation in the LG1 promoter was associated with aphid resistance among inbred lines. Moreover, a loss-of-function mutant in the LG1-related gene SPL8 in the dicot Arabidopsis thaliana conferred aphid resistance. This study revealed the aphid resistance mechanism of lg1, providing a theoretical basis and germplasm for breeding aphid-resistant crops.
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Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer (THCA) and shows a better prognosis than other types. However, further research is needed to determine the risk of PTC. We herein used the CIBERSORT algorithm to analyze the gene-expression profile obtained from TCGA, estimated the infiltration ratio of 22 immune cell types in tumor tissues and normal tissues, analyzed the differential expression of immune-related genes, and identified immune cells and immune-related genes related to clinical progress and prognosis. We uncovered 12 immune cell types and nine immune-related genes that were closely correlated with TNM staging, and two immune cell types (activated NK cells and γδT cells) and one immune-related gene (CD40LG) that were associated with prognosis. After evaluation, four immune cell types could be used to determine low-risk PTC, with six immune cell types and six immune-related genes closely associated with high-risk PTC. The type and quantity of infiltrating immune cells in the microenvironment of PTC, as well as immune-related genes, appear to be closely related to tumor progression and can therefore be used as important indicators for the evaluation of patient prognosis. We posit that the study of immune cells and immune-related genes in the tumor microenvironment will facilitate the determination of low-risk PTC more accurately, and that this will greatly promote the development of high-risk PTC immunotherapy.
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Imunoterapia , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/imunologia , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/terapia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Imunoterapia/métodos , Prognóstico , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica , Biomarcadores Tumorais/genética , MasculinoRESUMO
Garviecin LG34 produced by Lactococcus garvieae LG34 exhibits wide-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria. This work aimed at clarifying the antibacterial mode of action of garviecin LG34 against Gram-negative bacterium Salmonella typhimurium. To determine the concentration for the bacteriocin antimicrobial mode experiments, the minimum inhibitory concentration of garviecin LG34 against S. typhimurium CICC21484 was determined as 0.25 mg/ml. Garviecin LG34 decreased the viable count of S. typhimurium CICC21484 and its antibacterial activity was the dose and time dependant. Garviecin LG34 led to the dissipation of transmembrane potential, the rise in the extracellular conductivity, UV-absorbing material at 260 nm, and LDH level of S. typhimurium CICC21484. Scanning electron micrographs results shown that garviecin LG34 cause dramatic deformation and fragmentation including the flagellum shedding, pores formation in surface, and even completely breakage of S. typhimurium cell. Moreover, garviecin LG34 decreased the intracellular ATP level. The results of this study demonstrated that garviecin LG34 can destroy cell structure, increase membrane permeability of S. typhimurium, thereby might be used as biopreservative for treating food borne and salmonellosis resulting from Gram-negative bacterium S. typhimurium.
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Antibacterianos , Testes de Sensibilidade Microbiana , Salmonella typhimurium , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/crescimento & desenvolvimento , Antibacterianos/farmacologia , Antibacterianos/química , Bacteriocinas/farmacologia , Lactococcus/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Potenciais da Membrana/efeitos dos fármacosRESUMO
Despite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. Here, we investigate the efficacy of long-term oral K3Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K3Citrate successfully reduced the incidence of disc calcification in LG/J mice without deleterious effects on vertebral bone structure, plasma chemistry, and locomotion. Notably, a positive effect on grip strength was evident in treated mice. Spectroscopic investigation of the persisting calcified nodules indicated K3Citrate did not alter the mineral composition and revealed that reactivation of an endochondral differentiation program in endplates may drive LG/J disc calcification. Importantly, K3Citrate reduced calcification incidence without altering the pathological endplate chondrocyte hypertrophy, suggesting mitigation of disc calcification primarily occurred through Ca2+ chelation, a conclusion supported by chondrogenic differentiation and Seahorse metabolic assays. Overall, this study underscores the therapeutic potential of K3Citrate as a systemic intervention strategy for disc calcification.
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Bovine leukemia virus (BLV) is a widespread virus that decreases milk production and quality in dairy cows. As crucial components of BLV, BLV-encoded microRNAs (BLV-miRNAs) affect BLV replication and may impact the synthesis of Lactoferrin (LTF), Lactoperoxidase (LPO), Alpha-lactalbumin (alpha-LA), and Beta-lactoglobulin (beta-LG). In this study, we investigated the targeting relationship between BLV-miRNAs and LTF, LPO, alpha-LA, and beta-LG in cow's milk. Additionally, we investigated the possible mechanisms by which BLV reduces milk quality. The results showed that cow's milk had significantly lower levels of LTF, LPO, and alpha-LA proteins in BLV-positive cows than in BLV-negative cows. BLV-â³miRNAs (miRNA-deleted BLV) enhanced the reduction of LPO, alpha-LA, and beta-LG protein levels caused by BLV infection. Multiple BLV-miRNAs have binding sites with LTF and LPO mRNA; however, only BLV-miR-B1-5â¯P has a targeting relationship with LPO mRNA. The results revealed that BLV-miR-B1-5â¯P inhibits LPO protein expression by targeting LPO mRNA. However, BLV does not directly regulate the expression of LTF, alpha-LA, or beta-LG proteins through BLV-miRNAs.
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Lactalbumina , Lactoferrina , Lactoglobulinas , Lactoperoxidase , Vírus da Leucemia Bovina , MicroRNAs , Leite , Animais , Lactoferrina/genética , Lactoferrina/metabolismo , Lactoperoxidase/metabolismo , Lactoperoxidase/genética , Lactalbumina/genética , Lactalbumina/metabolismo , Bovinos , Lactoglobulinas/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Vírus da Leucemia Bovina/genética , Feminino , Leucose Enzoótica Bovina/virologia , Leucose Enzoótica Bovina/genéticaRESUMO
ß-lactoglobulin (ß-Lg) is a major food allergen, there is an urgent need to develop a rapid method for detecting ß-Lg in order to avoid contact or ingestion by allergic patients. Peptide aptamers have high affinity, specificity, and stability, and have broad prospects in the field of rapid detection. Using ß-Lg as the target, this study screened 11 peptides (P1-11) from a phage display library. Using molecular docking technology to predict binding energy and binding mode of proteins and peptides. Select the peptides with the best binding ability to ß-Lg (P5, P7, P8) through ELISA. Combining them with whey protein, casein, and bovine serum protein, it was found that P7 has the best specificity for ß-Lg, with an inhibition rate of 87.99%. Verified by molecular dynamics that P7 binds well with ß-Lg. Therefore, this peptide can be used for the recognition of ß-Lg, becoming a new recognition element for detecting ß-Lg.
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Lactoglobulinas , Simulação de Acoplamento Molecular , Peptídeos , Lactoglobulinas/química , Peptídeos/química , Animais , Ligação Proteica , Biblioteca de Peptídeos , Bovinos , Técnicas de Visualização da Superfície Celular , Ensaio de Imunoadsorção Enzimática , Alérgenos/química , Alérgenos/imunologia , HumanosRESUMO
FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.
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Células Matadoras Naturais , Proteínas de Membrana , Animais , Feminino , Humanos , Masculino , Camundongos , Linfócitos B/metabolismo , Linfócitos B/citologia , Medula Óssea/metabolismo , Linhagem da Célula , Células Dendríticas/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/imunologia , Células de Langerhans/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Monócitos/metabolismo , Pele/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Shewanella putrefaciens Pdp11 (SpPdp11) is a probiotic strain assayed in aquaculture; however, its postbiotic potential is unknown. Postbiotics are bacterial metabolites, including extracellular products (ECPs) that improve host physiology and immunity. Their production and composition can be affected by different factors such as the growing conditions of the probiotics. Photobacterium damselae subsp. piscicida strain Lg 41/01 (Phdp) is one of the most important pathogens in marine aquaculture. The major virulent factor of this bacterium is the exotoxin aip56, responsible for inducing apoptosis of fish leucocytes. Viable SpPdp11 cells have been reported to increase resistance to challenges with Phdp. This work aimed to evaluate the effect of two ECPs, T2348-ECP and FM1548-ECP, obtained from SpPdp11 grown under different culture conditions that previously demonstrated to exert different degradative and non-cytotoxic activities, as well as the effect on pathogens biofilm formation. These SpPdp11-ECPs were then analyzed by their effect on the viability, phagocytosis, respiratory burst and apoptogenic activity against European sea bass leucocytes infected or not with Phdp supernatant. Both ECPs, T2348-ECP and FM1548-ECP, were not cytotoxic against leucocytes and significantly reduced their apoptosis. Phagocytosis and respiratory burst of leucocytes were significantly reduced by incubation with Phdp supernatant, and not influenced by incubation with T2348-ECP or FM1548-ECP. However, both activities were significantly increased after leucocyte incubation with combined T2348-ECP and FM1548-ECP with Phdp supernatant, compared to those incubated only with Phdp supernatant. Finally, both T2348-ECP and FM1548-ECP significantly reduced the relative in vitro expression of the Phdp aip56 encoding gene.
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Psoriasis is a common chronic inflammatory skin disease characterized by aberrant proliferation of keratinocytes and infiltration of immune cells. We previously found that GPR15LG protein is highly expressed in psoriasis lesional skin and it positively regulates psoriatic keratinocyte proliferation. Our data also showed that GPR15LG could regulate the activity of NF-κB pathway, which is associated with psoriatic inflammation. In the present study, we demonstrated that Gpr15lg (ortholog of GPR15LG) knockdown attenuated the severity of imiquimod (IMQ)-induced psoriasis-like inflammation in mice. Such an effect was achieved by down-regulating the expression of inflammatory cytokines interleukin (IL)-1α, IL-1ß, tumor necrosis factor (TNF)-α and S100A7. Consistently, GPR15LG knockdown in vitro significantly downgraded the expression of inflammatory factors in the cellular model of psoriasis. These results suggested that GPR15LG could be involved in the development of psoriasis by regulating inflammation.
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Imiquimode , Interleucina-1alfa , Queratinócitos , Psoríase , Receptores Acoplados a Proteínas G , Animais , Humanos , Masculino , Camundongos , Modelos Animais de Doenças , Regulação para Baixo , Células HaCaT , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1alfa/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Psoríase/genética , Psoríase/metabolismo , Psoríase/patologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteína A7 Ligante de Cálcio S100/metabolismo , Proteína A7 Ligante de Cálcio S100/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
CD8+ T cells are critical for host antitumor responses, whereas persistent antigenic stimulation and excessive inflammatory signals lead to T cell dysfunction or exhaustion. Increasing early memory T cells can improve T cell persistence and empower T cell-mediated tumor eradication, especially for adoptive cancer immunotherapy. Here, it is reported that tumor-associated monocytes (TAMos) are highly correlated with the accumulation of CD8+ memory T cells in human cancers. Further analysis identifies that TAMos selectively reprogram CD8+ T cells into T central memory-like (TCM-like) cells with enhanced recall responses. L-NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo-mediated inhibition of T cell proliferation without affecting TCM-like cell generation. Moreover, the modified T cells by TAMo exposure and L-NMMA treatment exhibit long-term persistence and elicit superior antitumor effects in vivo. Mechanistically, the transmembrane protein CD300LG is involved in TAMo-mediated TCM-like cell polarization in a cell-cell contact-dependent manner. Thus, the terminally differentiated TAMo subset (CD300LGhighACElow) mainly contributes to TCM-like cell development. Taken together, these findings establish the significance of TAMos in boosting T-cell antitumor immunity.