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Amino acids are essential for cell growth and metabolism. Amino acid and growth factor signaling pathways coordinately regulate the mechanistic target of rapamycin complex 1 (mTORC1) kinase in cell growth and organ development. While major components of amino acid signaling mechanisms have been identified, their biological functions in organ development are unclear. We aimed to understand the functions of the critically positioned amino acid signaling complex GAP activity towards Rags 2 (GATOR2) in brain development. GATOR2 mediates amino acid signaling to mTORC1 by directly linking the amino acid sensors for arginine and leucine to downstream signaling complexes. Now, we report a role of GATOR2 in oligodendrocyte myelination in postnatal brain development. We show that the disruption of GATOR2 complex by genetic deletion of meiosis regulator for oocyte development (Mios, encoding a component of GATOR2) selectively impairs the formation of myelinating oligodendrocytes, thus brain myelination, without apparent effects on the formation of neurons and astrocytes. The loss of Mios impairs cell cycle progression of oligodendrocyte precursor cells, leading to their reduced proliferation and differentiation. Mios deletion manifests a cell type-dependent effect on mTORC1 in the brain, with oligodendroglial mTORC1 selectively affected. However, the role of Mios/GATOR2 in oligodendrocyte formation and myelination involves mTORC1-independent function. This study suggests that GATOR2 coordinates amino acid and growth factor signaling to regulate oligodendrocyte myelination.
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Aminoácidos/metabolismo , Encéfalo/metabolismo , Complexos Multiproteicos/metabolismo , Bainha de Mielina/metabolismo , Transdução de Sinais , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Deleção de Genes , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Modelos Biológicos , Células-Tronco Neurais/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , TransgenesRESUMO
Light presents substantial potential in disease treatment, where the development of efficient photocatalysts could enhance the utilization of photocatalytic systems in biomedicine. Here, we devised a novel approach to designing and synthesizing photocatalysts of conjugated polymers for photocatalytic CO2 reduction, relying on a multiple linear regression model built with theoretically calculated descriptors. We established a logarithmic relationship between molecular structure and CO yield and identified the poly(fluorene-co-thiophene) deviant (PFT) as the optimal one. PFT excited a CO regeneration ratio of 231 nmol h-1 in acetonitrile and 46 nmol h-1 in an aqueous solution with a reaction selectivity of 88%. Further advancements were made through the development of liposomes encapsulating PFT for targeted macrophage delivery. By distributing PFT on the liposome membranes, our constructed photocatalytic system efficiently generated CO in situ from surrounding CO2. This localized CO production served as an endogenous signaling molecule, promoting the desirable polarization of macrophages from the M1 to M2 phenotype. Consequently, the M2 cells reduced the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß). We also demonstrated the efficacy of our system in treating lipopolysaccharide-induced inflammation of cardiomyocytes under white light irradiation. Moreover, our research provides a comprehensive understanding of the intricate processes involved in CO2 reduction by a combination of theoretical calculations and experimental techniques including transient absorption, femtosecond ultrafast spectroscopy, and in situ infrared spectroscopy. These findings pave the way for further advancements of conjugated polymers and photocatalytic systems in biomedical investigation.
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N6-methyladenosine (m6A) is important in regulating mRNA stability, splicing, and translation, and it also contributes to tumor development. However, there is still limited understanding of the comprehensive effects of m6A modification patterns on the tumor immune microenvironment, metabolism, and drug resistance in hepatocellular carcinoma (HCC). In this study, we utilized unsupervised clustering based on the expression of 23 m6A regulators to identify m6A clusters. We identified differential m6A modification patterns and characterized m6A-gene-cluster A, which exhibited poorer survival rates, a higher abundance of Treg cells, and increased expression of TGFß in the tumor microenvironment (TME). Additionally, m6A-gene-cluster A demonstrated higher levels of glycolysis activity, cholesterol metabolism, and fatty acid biosynthesis. We also found that the m6A score was associated with prognosis and drug resistance. Patients with a low m6A score experienced worse prognoses, which were linked to an abundance of Treg cells, upregulation of TGFß, and increased metabolic activity. HCC patients with a higher m6A score showed improved prognosis following sorafenib treatment and immunotherapy. In conclusion, we reveals the association between m6A modification patterns and the tumor immune microenvironment, metabolism, and drug resistance in HCC. Furthermore, the m6A score holds potential as a predictive factor for the efficacy of targeted therapy and immunotherapy in HCC.
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Despite the advances of multistep enzymatic cascade reactions, their incorporation with abiotic reactions in living organisms remains challenging in synthetic biology. Herein, we combined microbial metabolic pathways and Pd-catalyzed processes for in-situ generation of bioactive conjugated oligomers. Our biocompatible one-pot coupling reaction utilized the fermentation process of engineered E. coli that converted glucose to styrene, which participated in the Pd-catalyzed Heck reaction for in-situ synthesis of conjugated oligomers. This process serves a great interest in understanding resistance evolution by utilizing the inhibitory activity of the synthesized conjugated oligomers. The approach allows for the in-situ combination of biological metabolism and CC coupling reactions, opening up new possibilities for the biosynthesis of unnatural molecules and enabling the in-situ regulation of the bioactivity of the obtained products.
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Escherichia coli , Paládio , Escherichia coli/metabolismo , Catálise , FermentaçãoRESUMO
AIM: To investigate whether oral microbiome diversity is associated with all-cause mortality in the general US population and in individuals with chronic diseases. MATERIALS AND METHODS: We included 8224 individuals with oral microbiome diversity data from the National Health and Nutrition Examination Survey (2009-2012), representing 164,000,205 US adults, using a survey-weighted analysis method. Cox regression analyses were performed to identify the association between oral microbiome diversity and all-cause mortality. RESULTS: During a survey-weighted mean follow-up period of 8.86 years, 429 all-cause deaths (survey-weighted number: 7,124,920) occurred in 8224 participants. Cox regression analysis revealed that higher oral microbiome diversity was significantly associated with a lower all-cause mortality risk. Significant differences in all-cause mortality risk were observed among the different clusters based on oral microbiome ß-diversity (log-rank p < 0.001). Subgroup analyses revealed that the oral microbiome diversity was independently associated with all-cause mortality in individuals with diabetes mellitus and hypertension. A multivariate logistic regression model showed that current smoking and antibiotic use were significantly associated with lower oral microbiome α diversity. CONCLUSIONS: Higher oral microbiome diversity was significantly associated with a lower all-cause mortality risk in the general US population and in individuals with diabetes mellitus and hypertension.
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Herein, activated red mud particles are used as adsorbents for phosphorus adsorption. HCl solutions with different concentrations and deionized water are employed for desorption tests, and the desorption mechanism under the following optimal conditions is investigated: HCl concentration = 0.2 mol/L, desorbent dosage = 0.15 L/g, desorption temperature = 35 °C, and desorption time = 12 h. Under these conditions, the phosphate desorption rate and amount reach 99.11% and 11.29 mg/g, respectively. Notably, the Langmuir isothermal and pseudo-second-order kinetic linear models exhibit consistent results: monomolecular-layer surface desorption is dominant, and chemical desorption limits the rate of surface desorption. Thermodynamic analysis indicates that phosphorus desorption by the desorbents is spontaneous and that high temperatures promote such desorption. Moreover, an intraparticle diffusion model demonstrates that the removal of phosphorus in the form of precipitation from the surface of an activated hematite particle adsorbent primarily occurs via a chemical reaction, and surface micromorphological analysis indicates that desorption is primarily accompanied by Ca dissolution, followed by Al and Fe dissolutions. The desorbents react with the active elements in red mud, and the vibrations of the [SiO4]4- functional groups of calcium-iron garnet and calcite or aragonite disappear. Further, in Fourier-transform infrared spectra, the intensities of the peaks corresponding to the PO43- group considerably decrease. Thus, desorption primarily involves monomolecular-layer chemical desorption.
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Engineered nanomaterials hold great promise to improve the specificity of disease treatment. Herein, a fully protein-based material is obtained from nonpathogenic Escherichia coli (E. coli), which is capable of morphological transformation from globular to fibrous in situ for inducing tumor cell apoptosis. The protein-based material P1 is comprised of a ß-sheet-forming peptide KLVFF, pro-apoptotic protein BAK, and GFP along with targeting moieties. The self-assembled nanoparticles of P1 transform into nanofibers in situ in the presence of cathepsin B, and the generated nanofibrils favor the dimerization of functional BH3 domain of BAK on the mitochondrial outer membrane, leading to efficient anticancer activity both in vitro and in vivo via mitochondria-dependent apoptosis through Bcl-2 pathway. To precisely manipulate the morphological transformation of biosynthetic molecules in living cells, a spatiotemporally controllable anticancer system is constructed by coating P1-expressing E. coli with cationic conjugated polyelectrolytes to release the peptides in situ under light irradiation. The biosynthetic peptide-based enzyme-catalytic transformation strategy in vivo would offer a novel perspective for targeted delivery and shows great potential in precision disease therapeutics.
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Escherichia coli , Proteínas Proto-Oncogênicas c-bcl-2 , Escherichia coli/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismoRESUMO
BACKGROUND: Pulmonary cavities caused by Legionella occur mainly in immunocompromised patients, and clinical information in patients with normal immune function is therefore limited. METHODS: We report a 64-year-old female who developed a Legionella pulmonary cavity without any immunological abnormality. RESULTS: She suffered severe pneumonia complicated by acute respiratory failure and acute renal insufficiency. Despite long-term antibiotic therapy, she showed signs of a life-threatening infection and a progressive pulmonary cavity. CONCLUSIONS: Our case report provided clinical data regarding the diagnosis and therapy of patients who develop Legionella pulmonary cavities without any underlying disease.
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Legionella pneumophila , Doença dos Legionários , Pneumonia , Síndrome do Desconforto Respiratório , Feminino , Humanos , Pessoa de Meia-Idade , Doença dos Legionários/complicações , Doença dos Legionários/diagnóstico , Doença dos Legionários/tratamento farmacológico , Pneumonia/complicações , Antibacterianos/uso terapêutico , Síndrome do Desconforto Respiratório/complicaçõesRESUMO
BACKGROUND: Carbapenem-resistant gram-negative bacteria pose a serious threat worldwide, and some patients even have rapidly aggravated life-threatening infection. However, as a result of the complexities of clinical therapy, antibiotic options against carbapenem-resistant pathogens have not yet been fully standardized. It should be individualized to control carbapenem-resistant pathogens in accordance with the different region. METHODS: In this study, we conducted a retrospective study in 65,000 inpatients over a 2-year period that involved a total of 86 patients from whom carbapenem-resistant gram-negative bacteria were isolated. RESULTS: Monotherapy using trimethoprim/sulfamethoxazole, amikacin, meropenem, and/or doxycycline in our hospital exhibited a clinical success rate of 83.3% for carbapenem-resistant Klebsiella pneumoniae, monotherapy using moxifloxacin, piperacillin/tazobactam, cefepime, and/or ceftazidime for carbapenem-resistant Pseudomonas aeruginosa exhibited a clinical success rate of 77.7%, and monotherapy using cefoperazone/sulbactam or combination therapy with tigecycline and cefoperazone/sulbactam for carbapenem-resistant Acinetobacter baumannii exhibited a clinical success rate of 62.1%. CONCLUSIONS: Taken together, our findings highlight the clinical strategies used in our hospital to successfully treat carbapenem-resistant gram-negative bacterial infections.
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Carbapenêmicos , Cefoperazona , Humanos , Estudos Retrospectivos , Sulbactam , ChinaRESUMO
Gastric cancer (GC) is one of the most prevalent malignancies of the digestive tract. Ginsenoside Rh1 was reported to exert effects on GC. The current study set out to explore the mechanism underlying Ginsenoside Rh1 effects on GC. With oxaliplatin (OXA) serving as the positive control, human GC cells AGS were treated with 0, 10, 25, 50, 74, or 100 µM of ginsenoside Rh1 for 48 h. Proliferation, migration, invasion, and apoptosis were subsequently assessed by means of MTT, scratch test, Transwell, and TUNEL, respectively. AGS cells were further jointly treated with Rh1 and the TGF-ß/Smad pathway activator Kartogenin, followed by detection of TGF-ß/Smad pathway effects on AGS biological behaviours. Moreover, TGF-ß/Smad pathway activation was detected with a Western blot assay. Furthermore, xenograft tumour models were established and tumour growth was recorded. Ki-67 expression patterns and apoptosis were detected with immunohistochemistry and TUNEL, respectively. In vitro, Ginsenoside Rh1 repressed AGS cell proliferation, migration, and invasion, and further promoted apoptosis, with a concentration of 50 µM Rh1 exerting the equivalent effects as OXA. In vivo, Ginsenoside Rh1 inhibited GC proliferation and induced tumour cell apoptosis. Mechanistically, Ginsenoside Rh1 reduced TGF-ß1 and TGF-ß2 levels and Smad2 and Smad3 phosphorylation levels. Collectively, our findings highlighted that ginsenoside Rh1 inhibited GC cell growth and tumour growth in xenograft tumour models via inhibition of the TGF-ß/Smad pathway.
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Ginsenosídeos , Neoplasias Gástricas , Animais , Humanos , Camundongos , Movimento Celular , Ginsenosídeos/farmacologia , Camundongos Nus , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Smad/metabolismoRESUMO
As compared to conventional diesel heavy-duty vehicles, natural gas vehicles have been proved to be more eco-friendly due to their lower production of greenhouse gas and pollutant emissions, which are causing enormous adverse effects on global warming and air pollution. However, natural gas vehicles were rarely studied before, especially through on-road measurements. In this study, a portable emission measurement system (PEMS) was employed to investigate the real-world emissions of nitrogen oxides (NOx) (nitrogen monoxide (NO), nitrogen dioxide (NO2)), total hydrocarbons (THC), carbon monoxide (CO), and carbon dioxide (CO2) from two liquified natural gas (LNG) China V heavy-duty cleaning sanitation trucks with different weight. Associated with the more aggressive driving behaviors, the vehicle with lower weight exhibited higher CO2 (3%) but lower NOx (48.3%) (NO2 (78.2%) and NO (29.4%)), CO (44.8%), and THC (3.7%) emission factors. Aggressive driving behaviors were also favorable to the production of THC, especially those in the medium-speed range but significantly negative to the production of CO and NO2, especially those in the low-speed range with high engine load. In particular, the emission rate ratio of NO2/NO decreased with the increase of speed/scaled tractive power in different speed ranges.
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Poluentes Atmosféricos , Gás Natural , Poluentes Atmosféricos/análise , Monitoramento Ambiental , Gases , Gasolina/análise , Veículos Automotores , Saneamento , Emissões de Veículos/análiseRESUMO
The electrocatalytic CO2 reduction reaction (ECO2 RR) is one promising method for storing intermittent clean energy in chemical bonds and producing fuels. Among various kinds of catalysts for ECO2 RR, molecular metal complexes with well-defined structures are convenient for studies of their rational design, structure-reactivity relationships, and mechanisms. In this Review, we summarize the molecular engineering of several N-based metal complexes including Re/Mn bipyridine compounds and metal macrocycles, concluding with general modification strategies to devise novel molecular catalysts with high intrinsic activity. Through physical adsorption, covalent linking, and formation of a periodic backbone, these active molecules can be heterogenized into immobilized catalysts with more practical prospects. Finally, significant challenges and opportunities based on molecular catalysts are discussed.
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Inside living cells, regulation of catalytic activity of artificial enzymes remains challenging due to issues such as biocompatibility, efficiency, and stability of the catalyst, by which the practical applications of artificial enzymes have been severely hindered. Here, an artificial enzyme, PTT-SGH, with responsiveness to reactive oxygen species (ROS), was obtained by introducing a catalytic histidine residue to pentaerythritol tetra(3-mercaptopropionate) (PTT). The artificial enzyme formed large aggregates in cells via the intracellular ROS-mediated oxidation of thiol groups. The process was significantly facilitated in tumor cells because of the higher ROS concentration in the tumor microenvironment. The catalytic activity of this artificial enzyme was intensively enhanced through deprotonation of cross-linked PTT-SGH, which showed typical esterase activities. Selective fluorescence imaging of tumor cells was achieved using the artificial enzyme to trigger the cleavage of the ester bond of the caged fluorophore inside living cells.
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Neoplasias , Imagem Óptica , Catálise , Neoplasias/diagnóstico por imagem , Espécies Reativas de Oxigênio , Compostos de Sulfidrila , Microambiente TumoralRESUMO
The photocatalytic reduction of CO2 into fuels offers the prospect for creating a new CO2 economy. Harnessing visible light-driven CO2 -to-CO reduction mediated by the long-lived triplet excited state of rhenium(I) tricarbonyl complexes is a challenging approach. We here develop a series of new mononuclear rhenium(I) tricarbonyl complexes (Re-1-Re-4) based on the imidazole-pyridine skeleton for photo-driven CO2 reduction. These catalysts are featured by combining pyridyl-imidazole with the aromatic ring and different pendant organic groups onto the N1 position of 1,3-imidazole unit, which display phosphorescence under Ar-saturated solution even at ambient conditions. By contrast, {Re[9-(pyren-1-yl)-10-(pyridin-2-yl)-9H-pyreno[4,5-d]imidazole)](CO)3 Cl} (Re-4) by introducing pyrene ring at the N1 position of pyrene-fused imidazole unit exhibits superior catalytic performance with a higher turnover number for CO (TONCO =124) and >99.9 % selectivity, primarily ascribed to the strong visible light-harvesting ability, long-lived triplet lifetimes (164.2â µs) and large reductive quenching constant. Moreover, the rhenium(I) tricarbonyl complexes derived from π-extended pyrene chromophore exhibit a long lifetime corresponding to its ligand-localized triplet state (3 IL) evidenced from spectroscopic investigations and DFT calculations.
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Many bone diseases result from abnormal bone resorption by osteoclasts (OCs). Studying OC related regulatory genes is necessary for the development of new therapeutic strategies. Rho GTPases have been proven to regulate OC differentiation and function and only mature OCs can carry out bone resorption. Here we demonstrate that Rac1 and Cdc42 exchange factor Triple functional domain (Trio) is critical for bone resorption caused by OCs. In this study, we created LysM-Cre;Triofl/fl conditional knockout mice in which Trio was conditionally ablated in monocytes. LysM-Cre;Triofl/fl mice showed increased bone mass due to impaired bone resorption caused by OCs. Furthermore, our in vitro analysis indicated that Trio conditional deficiency significantly suppressed OC differentiation and function. At the molecular level, Trio deficiency significantly inhibited the expression of genes critical for osteoclastogenesis and OC function. Mechanistically, our researches suggested that perturbed Rac1/Cdc42-PAK1-ERK/p38 signaling could be used to explain the lower ability of bone resorption in CKO mice. Taken together, this study indicates that Trio is a regulator of OCs. Studying the role of Trio in OCs provides a potential new insight for the treatment of OC related bone diseases.
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Reabsorção Óssea/genética , Fêmur/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Neuropeptídeos/genética , Osteoclastos/metabolismo , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Proteína cdc42 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/genética , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Fêmur/citologia , Fêmur/efeitos dos fármacos , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fator Estimulador de Colônias de Macrófagos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neuropeptídeos/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Fosfoproteínas/deficiência , Proteínas Serina-Treonina Quinases/deficiência , Ligante RANK/farmacologia , Transdução de Sinais , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
BACKGROUND AND AIMS: Whether surgical resection or repeated ablation should be recommended for intrahepatic recurrent hepatocellular carcinoma (HCC) conforming to the Milan criteria after initial ablation remains unclear. In this study, we compared the outcomes of patients who underwent surgical resection with those who underwent re-ablation for recurrent HCC after initial curative-intent ablation. METHODS: The data of 28 and 98 patients who underwent surgical resection and re-ablation, respectively, for recurrent HCC after initial ablation between January 2003 and 2017 were analyzed using propensity score matching. RESULTS: Before matching, the 1-, 3-, and 5-year overall survival (OS) rates were 95.7, 83.0, and 74.4% for the ablation group, compared to 92.9, 89.1, and 70.9% for the resection group (p = 0.490). The corresponding disease-free survival (DFS) rates were 67.5, 40.1, and 25.6% for the ablation group and were 85.4, 59.9, and 53.3% for the resection group (p = 0.018). After matching, the 1-, 3-, and 5-year OS rates for the ablation and resection group were 95.2, 85.5 and 81.8% versus 96.0, 96.0, and 76.4%, respectively (p = 0.550). The 1-, 3-, and 5-year DFS rates were 58.0, 39.5, and 29.9% for the ablation group and were 95.8, 67.2, and 59.8% for the resection group (p = 0.004). Cox proportional hazards model identified surgical resection as the only significant prognostic factor for DFS but not for OS. CONCLUSION: For intrahepatic recurrent HCC patients after initial ablation, surgical resection could provide better DFS than re-ablation, while no difference in OS was observed between the 2 treatment groups.
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Técnicas de Ablação , Carcinoma Hepatocelular/cirurgia , Hepatectomia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Adulto , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Micro-Ondas/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Ablação por Radiofrequência , Reoperação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Neutrophils play a critical role in innate immune defense and directly contribute to infectious and autoimmune ailments. Great efforts are underway to better understand the nature of neutrophilic inflammation. Of note, CARD9, a myeloid cell-specific signaling protein that mainly expresses in macrophages and dendritic cells, is also present in neutrophils, emerging as a critical mediator for intercellular communication. CARD9-deficiency neutrophils display an increased susceptibility to fungal infection that primarily localize to the central nervous system, subcutaneous, and skin tissue. Additionally, CARD9-deficiency neutrophils are associated with some autoimmune diseases and even provide protection against a few bacteria. Here, the review summarizes recent preclinical and clinical advances that have provided a novel insight into the pathogenesis of CARD9 deficiency in neutrophils.
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Proteínas Adaptadoras de Sinalização CARD/metabolismo , Neutrófilos/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Humanos , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
The widespread application of cadmium-free CuInS2/ZnS QDs has raised great concern regarding their potential toxicity to humans. To date, toxicological data related to CuInS2/ZnS QDs are scarce. Neurons play extraordinary roles in regulating the activities of organs and systems, and serious consequences occur when neurons are damaged. Currently, the potential toxicity of CuInS2/ZnS QDs on neurons has not been fully elucidated. Here, we investigate the neurotoxicity of PEGylated CuInS2/ZnS (CuInS2/ZnS-PEG) QDs on neuron-like PC12 cells. We found that CuInS2/ZnS-PEG QDs were taken up by PC12 cells, but at a concentration range from 0 to 100 µg/mL, they did not affect the survival rate of the PC12 cells. In addition, we found that CuInS2/ZnS-PEG QDs significantly inhibited neurite outgrowth from and the differentiation of PC12 cells in the presence of NGF, while COOH-modified CuInS2/ZnS QDs or free PEG did not have a similar effect. Further studies showed that CuInS2/ZnS-PEG QDs obviously downregulated the expression of low-affinity NGF receptor (p75NTR) and subsequently negatively regulated the downstream MAPK cascade by dephosphorylating ERK1/2 and AKT. Taken together, these results suggest that CuInS2/ZnS-PEG QDs disturb NGF signal transduction from external stimuli to relevant internal signals, thus affecting normal biological processes such as neurite outgrowth and cell differentiation.
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Crescimento Neuronal/efeitos dos fármacos , Pontos Quânticos/toxicidade , Animais , Cádmio/farmacologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Proteína Quinase 3 Ativada por Mitógeno , Fator de Crescimento Neural , Proteínas do Tecido Nervoso , Células PC12 , Ratos , Receptores de Fator de Crescimento Neural , Transdução de Sinais/efeitos dos fármacos , Sulfetos , Testes de Toxicidade , Compostos de ZincoRESUMO
Increased applications of quantum dots (QDs) in the biomedical field have aroused attention for their potential toxicological effects. Although numerous studies have been carried out on the toxicity of QDs, their effects on reproductive and development are still unclear. In this study, we systematically evaluated the male reproductive toxicity and developmental toxicity of CdSe/ZnS QDs in BALB/c mice. The male mice were injected intravenously with CdSe/ZnS QDs at the dosage of 2.5 mg/kg BW or 25 mg/kg BW, respectively, and the survival status, biodistribution of QDs in testes, serum sex hormone levels, histopathology, sperm motility and acrosome integrity was measured on Day 1, 7, 14, 28 and 42 after injection. On Day 35 after treatment, male mice were housed with non-exposed female mice, and then offspring number, body weight, organ index and histopathology of major organs, blood routine and biochemical tests of offspring were measured to evaluate the fertility and offspring health. The results showed that CdSe/ZnS QDs could rapidly distribute in the testis, and the fluorescence of QDs could still be detected on Day 42 post-injection. QDs had no adverse effect on the structure of testis and epididymis, but high-dose QDs could induce apoptosis of Leydig cells in testis at an early stage. No significant differences in survival of state, body weight organ index of testis and epididymis, sex hormones levels, sperm quality, sperm acrosome integrity and fertility of male mice were observed in QDs exposed groups. However, the development of offspring was obviously influenced, which was mainly manifested in the slow growth of offspring, changes in organ index of main organs, and the abnormality of liver and kidney function parameters. Our findings revealed that CdSe/ZnS QDs were able to cross the blood-testis barrier (BTB), produce no discernible toxic effects on the male reproductive system, but could affect the healthy growth of future generations to some extent. In view of the broad application prospect of QDs in biomedical fields, our findings might provide insight into the biological safety evaluation of the reproductive health of QDs.
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Pontos Quânticos/toxicidade , Acrossomo , Animais , Compostos de Cádmio/química , Compostos de Cádmio/toxicidade , Epididimo , Feminino , Fertilidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pontos Quânticos/química , Reprodução , Compostos de Selênio/farmacologia , Motilidade dos Espermatozoides , Espermatozoides , Sulfetos/toxicidade , Testículo , Distribuição Tecidual , Testes de Toxicidade , Compostos de Zinco/toxicidadeRESUMO
Inflammatory bowel disease (IBD) involves a dysregulated immune response to the gut microbiota. Emerging evidence has demonstrated that dysfunctions in caspase recruitment domain-containing protein 9 (CARD9) may contribute to the pathogenesis of IBD. Interestingly, an allelic series of Card9 variants have both a common predisposing and rare protective function in IBD patients. In this review, we provide mechanistic insights into the role of the CARD9 adaptor molecule in intestinal inflammation and determine a potential CARD9-targeting therapeutic approach against IBD.