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1.
Immunity ; 56(2): 320-335.e9, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36693372

RESUMO

Neuronal signals have emerged as pivotal regulators of group 2 innate lymphoid cells (ILC2s) that regulate tissue homeostasis and allergic inflammation. The molecular pathways underlying the neuronal regulation of ILC2 responses in lungs remain to be fully elucidated. Here, we found that the abundance of neurotransmitter dopamine was negatively correlated with circulating ILC2 numbers and positively associated with pulmonary function in humans. Dopamine potently suppressed lung ILC2 responses in a DRD1-receptor-dependent manner. Genetic deletion of Drd1 or local ablation of dopaminergic neurons augmented ILC2 responses and allergic lung inflammation. Transcriptome and metabolic analyses revealed that dopamine impaired the mitochondrial oxidative phosphorylation (OXPHOS) pathway in ILC2s. Augmentation of OXPHOS activity with oltipraz antagonized the inhibitory effect of dopamine. Local administration of dopamine alleviated allergen-induced ILC2 responses and airway inflammation. These findings demonstrate that dopamine represents an inhibitory regulator of ILC2 responses in allergic airway inflammation.


Assuntos
Imunidade Inata , Pneumonia , Humanos , Dopamina/metabolismo , Linfócitos , Pulmão/metabolismo , Pneumonia/metabolismo , Inflamação/metabolismo , Interleucina-33/metabolismo
3.
J Biol Chem ; 300(8): 107516, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38960036

RESUMO

Focal segmental glomerulosclerosis (FSGS), a common cause of primary glomerulonephritis, has a poor prognosis and is pathologically featured by tubulointerstitial injury. Thrombospondin-1 (TSP-1) is an extracellular matrix protein that acts in combination with different receptors in the kidney. Here, we analyzed the tubular expression of TSP-1 and its receptor integrin ß3 (ITGB3) in FSGS. Previously the renal interstitial chip analysis of FSGS patients with tubular interstitial injury showed that the expression of TSP-1 and ITGB3 were upregulated. We found that the expression of TSP-1 and ITGB3 increased in the tubular cells of FSGS patients. The plasma level of TSP-1 increased and was correlated to the degree of tubulointerstitial lesions in FSGS patients. TSP-1/ITGB3 signaling induced renal tubular injury in HK-2 cells exposure to bovine serum albumin and the adriamycin (ADR)-induced nephropathy model. THBS1 KO ameliorated tubular injury and renal fibrosis in ADR-treated mice. THBS1 knockdown decreased the expression of KIM-1 and caspase 3 in the HK-2 cells treated with bovine serum albumin, while THBS1 overexpression could induce tubular injury. In vivo, we identified cyclo-RGDfK as an agent to block the binding of TSP-1 to ITGB3. Cyclo-RGDfK treatment could alleviate ADR-induced renal tubular injury and interstitial fibrosis in mice. Moreover, TSP-1 and ITGB3 were colocalized in tubular cells of FSGS patients and ADR-treated mice. Taken together, our data showed that TSP-1/ITGB3 signaling contributed to the development of renal tubulointerstitial injury in FSGS, potentially identifying a new therapeutic target for FSGS.


Assuntos
Glomerulosclerose Segmentar e Focal , Integrina beta3 , Trombospondina 1 , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Linhagem Celular , Doxorrubicina/farmacologia , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Glomerulosclerose Segmentar e Focal/genética , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Receptor Celular 1 do Vírus da Hepatite A/genética , Integrina beta3/metabolismo , Integrina beta3/genética , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Camundongos Knockout , Transdução de Sinais , Trombospondina 1/metabolismo , Trombospondina 1/genética
4.
Lancet ; 403(10445): 2720-2731, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38824941

RESUMO

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Anticorpos Monoclonais Humanizados , Quimiorradioterapia , Quimioterapia de Indução , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/tratamento farmacológico , Adulto , China/epidemiologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/terapia , Quimiorradioterapia/métodos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Idoso , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gencitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Adulto Jovem , Adolescente , Intervalo Livre de Progressão
5.
Brief Bioinform ; 24(5)2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37615358

RESUMO

Non-coding RNA (ncRNA) plays a critical role in biology. ncRNAs from the same family usually have similar functions, as a result, it is essential to predict ncRNA families before identifying their functions. There are two primary methods for predicting ncRNA families, namely, traditional biological methods and computational methods. In traditional biological methods, a lot of manpower and resources are required to predict ncRNA families. Therefore, this paper proposed a new ncRNA family prediction method called MFPred based on computational methods. MFPred identified ncRNA families by extracting sequence features of ncRNAs, and it possessed three primary modules, including (1) four ncRNA sequences encoding and feature extraction module, which encoded ncRNA sequences and extracted four different features of ncRNA sequences, (2) dynamic Bi_GRU and feature fusion module, which extracted contextual information features of the ncRNA sequence and (3) ResNet_SE module that extracted local information features of the ncRNA sequence. In this study, MFPred was compared with the previously proposed ncRNA family prediction methods using two frequently used public ncRNA datasets, NCY and nRC. The results showed that MFPred outperformed other prediction methods in the two datasets.


Assuntos
Biologia Computacional , RNA não Traduzido , Humanos , Biologia Computacional/métodos , RNA não Traduzido/genética
6.
Nature ; 567(7747): 257-261, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30814741

RESUMO

Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia1. Although surgical treatment may be effective in the early stages, the five-year overall rate of survival after developing this cancer is only 50-70%2. Here, using proteomic and phospho-proteomic profiling, we characterize 110 paired tumour and non-tumour tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. Our quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma: we used this to stratify the cohort into the subtypes S-I, S-II and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)-high expression of which is a signature specific to the S-III subtype-alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. The proteomic stratification of early-stage hepatocellular carcinoma presented in this study provides insight into the tumour biology of this cancer, and suggests opportunities for personalized therapies that target it.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Terapia de Alvo Molecular/tendências , Proteômica , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Processos de Crescimento Celular , Movimento Celular , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Estadiamento de Neoplasias , Prognóstico , Esterol O-Aciltransferase/genética
7.
Nano Lett ; 24(2): 748-756, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38166417

RESUMO

The electrochemical N2 reduction reaction (NRR) is a green and energy-saving sustainable technology for NH3 production. However, high activity and high selectivity can hardly be achieved in the same catalyst, which severely restricts the development of the electrochemical NRR. In2Se3 with partially occupied p-orbitals can suppress the H2 evolution reaction (HER), which shows excellent selectivity in the electrochemical NRR. The presence of VIn can simultaneously provide active sites and confine Re clusters through strong charge transfer. Additionally, well-isolated Re clusters stabilized on In2Se3 by the confinement effect of VIn result in Re-VIn active sites with maximum availability. By combining Re clusters and VIn as dual sites for spontaneous N2 adsorption and activation, the electrochemical NRR performance is enhanced significantly. As a result, the Re-In2Se3-VIn/CC catalyst delivers a high NH3 yield rate (26.63 µg h-1 cm-2) and high FEs (30.8%) at -0.5 V vs RHE.

8.
J Hepatol ; 81(1): 93-107, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38403027

RESUMO

BACKGROUND & AIMS: The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain elusive. We aimed to identify the role of CT10 regulator of kinase-like (CRKL) in resistance to anti-PD-1 therapy in HCC. METHODS: Gene expression in HCC specimens from 10 patients receiving anti-PD-1 therapy was identified by RNA-sequencing. A total of 404 HCC samples from tissue microarrays were analyzed by immunohistochemistry. Transgenic mice (Alb-Cre/Trp53fl/fl) received hydrodynamic tail vein injections of a CRKL-overexpressing vector. Mass cytometry by time of flight was used to profile the proportion and status of different immune cell lineages in the mouse tumor tissues. RESULTS: CRKL was identified as a candidate anti-PD-1-resistance gene using a pooled genetic screen. CRKL overexpression nullifies anti-PD-1 treatment efficacy by mobilizing tumor-associated neutrophils (TANs), which block the infiltration and function of CD8+ T cells. PD-L1+ TANs were found to be an essential subset of TANs that were regulated by CRKL expression and display an immunosuppressive phenotype. Mechanistically, CRKL inhibits APC (adenomatous polyposis coli)-mediated proteasomal degradation of ß-catenin by competitively decreasing Axin1 binding, and thus promotes VEGFα and CXCL1 expression. Using human HCC samples, we verified the positive correlations of CRKL/ß-catenin/VEGFα and CXCL1. Targeting CRKL using CRISPR-Cas9 gene editing (CRKL knockout) or its downstream regulators effectively restored the efficacy of anti-PD-1 therapy in an orthotopic mouse model and a patient-derived organotypic tumor spheroid model. CONCLUSIONS: Activation of the CRKL/ß-catenin/VEGFα and CXCL1 axis is a critical obstacle to successful anti-PD-1 therapy. Therefore, CRKL inhibitors combined with anti-PD-1 could be useful for the treatment of HCC. IMPACT AND IMPLICATIONS: Here, we found that CRKL was overexpressed in anti-PD-1-resistant hepatocellular carcinoma (HCC) and that CRKL upregulation promotes anti-PD-1 resistance in HCC. We identified that upregulation of the CRKL/ß-catenin/VEGFα and CXCL1 axis contributes to anti-PD-1 tolerance by promoting infiltration of tumor-associated neutrophils. These findings support the strategy of bevacizumab-based immune checkpoint inhibitor combination therapy, and CRKL inhibitors combined with anti-PD-1 therapy may be developed for the treatment of HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Carcinoma Hepatocelular , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Infiltração de Neutrófilos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Humanos , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Camundongos Transgênicos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Masculino , Quimiocina CXCL1/metabolismo , Quimiocina CXCL1/genética
9.
Oncologist ; 29(4): e487-e497, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-37874924

RESUMO

BACKGROUND: The difference in the prognoses between treatment with surgical therapy and continuation of local-plus-systemic therapy following successful down-staging of intermediate-advanced hepatocellular carcinoma (HCC) remains unclear. METHODS: Data of 405 patients with intermediate-advanced HCC treated at 30 hospitals across China from January 2017 to July 2022 were retrospectively reviewed. All patients received local-plus-systemic therapy and were divided into the surgical (n = 100) and nonsurgical groups (n = 305) according to whether they received surgical therapy. The differences between long-term prognoses of the 2 groups were compared. Subgroup analysis was performed in 173 HCC patients who met the criteria for surgical resection following down-staging. RESULTS: Multivariable analysis of all patients showed that surgical therapy, hazard ratio (HR): 0.289, 95% confidence interval, CI, 0.136-0.613) was a protective factor for overall survival (OS), but not for event-free survival (EFS). Multivariable analysis of 173 intermediate-advanced HCC patients who met the criteria for surgical resection after conversion therapy showed that surgical therapy (HR: 0.282, 95% CI, 0.121-0.655) was a protective factor for OS, but not for EFS. Similar results were obtained after propensity score matching. For patients with Barcelona Clinic Liver Cancer stage B (HR: 0.171, 95% CI, 0.039-0.751) and C (HR: 0.269, 95% CI, 0.085-0.854), surgical therapy was also a protective factor for OS. CONCLUSIONS: Overall, for patients with intermediate-advanced HCC who underwent local-plus-systemic therapies, surgical therapy is a protective factor for long-term prognosis and can prolong OS, and for those who met the surgical resection criteria after conversion therapy, surgical therapy is recommended.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Estadiamento de Neoplasias , Prognóstico , Hepatectomia
10.
Cancer Immunol Immunother ; 73(11): 226, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39237636

RESUMO

BACKGROUND: Treatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood-brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival. METHODS: In this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher's exact test, and survival curves were estimated with the Kaplan-Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk. RESULTS: From an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43-0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18-0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683). CONCLUSION: Our study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population.


Assuntos
Inibidores da Angiogênese , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos Retrospectivos , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/tratamento farmacológico , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Inibidores da Angiogênese/uso terapêutico , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto
11.
Small ; : e2407153, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39410725

RESUMO

Dendrite growth and interfacial side reactions on Zn anode seriously affect the safety and service life of Zn ions batteries. Interface engineering is an effective way to solve these problems. Here, a liquid metal-ZnO composite coating with high ionic conductivity is creatively designed, which not only reduces the Zn2+ diffusion barrier but also increases the hydrogen evolution overpotential, thereby eliminating dendrite growth behavior and corrosion on the modified Zn anode. Moreover, its unique structure induces Zn deposition into the inner of coating, which can effectively avoid the volume expansion in the deposit layer of Zn anode. Therefore, it can cycle for 3 000 h at an ultra-small polarization of 28 mV at 1 mA cm-2, and the microbattery assembled in combination with the MnO2 cathode also maintains 2 000 cycles with high Coulomb efficiency, providing a general idea for the development of the next generation of rechargeable metal batteries.

12.
Small ; 20(22): e2309448, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38362699

RESUMO

Hydrogen peroxide (H2O2) is a highly value-added and environmental-friendly chemical with various applications. The production of H2O2 by electrocatalytic 2e- oxygen reduction reaction (ORR) has emerged as a promising alternative to the energy-intensive anthraquinone process. High selectivity Catalysts combining with superior activity are critical for the efficient electrosynthesis of H2O2. Earth-abundant transition metal selenides (TMSs) being discovered as a classic of stable, low-cost, highly active and selective catalysts for electrochemical 2e- ORR. These features come from the relatively large atomic radius of selenium element, the metal-like properties and the abundant reserves. Moreover, compared with the advanced noble metal or single-atom catalysts, the kinetic current density of TMSs for H2O2 generation is higher in acidic solution, which enable them to become suitable catalyst candidates. Herein, the recent progress of TMSs for ORR to H2O2 is systematically reviewed. The effects of TMSs electrocatalysts on the activity, selectivity and stability of ORR to H2O2 are summarized. It is intended to provide an insight from catalyst design and corresponding reaction mechanisms to the device setup, and to discuss the relationship between structure and activity.

13.
Small ; : e2401655, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38966887

RESUMO

Despite the advantages of high tissue penetration depth, selectivity, and non-invasiveness of photothermal therapy for cancer treatment, developing NIR-II photothermal agents with desirable photothermal performance and advanced theranostics ability remains a key challenge. Herein, a universal surface modification strategy is proposed to effectively improve the photothermal performance of vanadium carbide MXene nanosheets (L-V2C) with the removal of surface impurity ions and generation of mesopores. Subsequently, MnOx coating capable of T1-weighted magnetic resonance imaging can be in situ formed through surface redox reaction on L-V2C, and then, stable nanoplatforms (LVM-PEG) under physiological conditions can be obtained after further PEGylation. In the tumor microenvironment irradiated by NIR-II laser, multivalent Mn ions released from LVM-PEG, as a reversible electronic station, can consume the overexpression of glutathione and catalyze a Fenton-like reaction to produce ·OH, resulting in synchronous cellular oxidative damage. Efficient synergistic therapy promotes immunogenic cell death, improving tumor-related immune microenvironment and immunomodulation, and thus, LVM-PEG can demonstrate high accuracy and excellent anticancer efficiency guided by multimodal imaging. As a result, this study provides a new approach for the customization of 2D surface strategies and the study of synergistic therapy mechanisms, highlighting the application of MXene-based materials in the biomedical field.

14.
Am J Kidney Dis ; 84(4): 447-456.e1, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38750878

RESUMO

RATIONALE & OBJECTIVE: Light and heavy chain deposition disease (LHCDD) is a rare form of monoclonal immunoglobulin (Ig) deposition disease, and limited clinical data are available characterizing this condition. Here we describe the clinicopathological characteristics and outcomes of LHCDD. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 13 patients with biopsy-proven LHCDD diagnosed between January 2008 and December 2022 at one of 2 Chinese medical centers. FINDINGS: Among the 13 patients described, 6 were men and 7 were women, with a mean age of 52.6±8.0 years. Patients presented with hypertension (76.9%), anemia (84.6%), increased serum creatinine concentrations (84.6%; median, 1.7mg/dL), proteinuria (100%; average urine protein, 3.0g/24h), nephrotic syndrome (30.8%), and microscopic hematuria (76.9%). Serum immunofixation electrophoresis showed monoclonal Ig for 11 patients (84.6%). Serum free light chain ratios were abnormal in 11 patients (84.6%), and heavy/light chain ratios were abnormal in 9 of 10 patients (90%) with available data. Five patients were diagnosed with multiple myeloma. A histological diagnosis of nodular mesangial sclerosis was made in 10 patients (76.9%). Immunofluorescence demonstrated deposits of IgG subclass in 7 patients (γ-κ, n=4; γ-λ, n=3) and IgA in 5 patients (α-κ, n=2; α-λ, n=3). Six patients underwent IgG subclass staining (γ1, n=3; γ2, n=2; γ3, n=1). The deposits of IgD-κ were confirmed by mass spectrometry in 1 patient. Among 12 patients for whom data were available during a median of 26.5 months, 11 received chemotherapy and 1 received conservative treatment. One patient died, and disease progressed to kidney failure in 3 (25%). Among the 9 patients evaluable for hematological and kidney disease progression, 5 (56%) had a hematologic response and 1 (11%) exhibited improvement in kidney disease. LIMITATIONS: Retrospective descriptive study, limited number of patients, urine protein electrophoresis or immunofixation electrophoresis test results missing for most patients. CONCLUSIONS: In this case series of LHCDD, light and heavy chain deposition in kidney tissues were most frequent with monoclonal IgG1-κ. Among patients with evaluable data, more than half had a hematologic response, but a kidney response was uncommon.


Assuntos
Cadeias Pesadas de Imunoglobulinas , Cadeias Leves de Imunoglobulina , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Cadeias Leves de Imunoglobulina/análise , Cadeias Leves de Imunoglobulina/urina , Paraproteinemias/diagnóstico , Paraproteinemias/patologia , Paraproteinemias/complicações , Estudos Retrospectivos , Doença das Cadeias Pesadas/patologia , Doença das Cadeias Pesadas/diagnóstico , Idoso
15.
Amino Acids ; 56(1): 48, 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39060743

RESUMO

Sepsis is characterized by a metabolic disorder of amino acid occurs in the early stage; however, the profile of serum amino acids and their alterations associated with the onset of sepsis remain unclear. Thus, our objective is to identify the specific kinds of amino acids as diagnostic biomarkers in pediatric patients with sepsis. Serum samples were collected from patients with sepsis admitted to the pediatric intensive care unit (PICU) between January 2019 and December 2019 on the 1st, 3rd and 7th day following admission. Demographic and laboratory variables were also retrieved from the medical records specified times. Serum amino acid concentrations were detected by UPLC-MS/MS system. PLS-DA (VIP > 1.0) and Kruskal-Wallis test (p < 0.05) were employed to identify potential biomarkers. Spearman's rank correlation analysis was conducted to find the potential association between amino acid levels and clinical features. The diagnostic utility for pediatric sepsis was assessed using receiver operating characteristic (ROC) curve analysis. Most of amino acid contents in serum were significantly decreased in patients with sepsis, but approached normal levels by the seventh day post-diagnosis. Threonine (THR), lysine (LYS), valine (VAL) and alanine (ALA) emerged as potential biomarkers related for sepsis occurrence, though they were not associated with PELOD/PELOD-2 scores. Moreover, alterations in serum THR, LYS and ALA were linked to complications of brain injury, and serum ALA levels were also related to sepsis-associated acute kidney injury. Further analysis revealed that ALA was significantly correlated with the Glasgow score, serum lactate and glucose levels, C-reactive protein (CRP), and other indicators for liver or kidney dysfunction. Notably, the area under the ROC curve (AUC) for ALA in distinguishing sepsis from healthy controls was 0.977 (95% CI: 0.925-1.000). The serum amino acid profile of children with sepsis is significantly altered compared to that of healthy controls. Notably, ALA shows promise as a potential biomarker for the early diagnosis in septic children.


Assuntos
Alanina , Biomarcadores , Unidades de Terapia Intensiva Pediátrica , Sepse , Humanos , Sepse/sangue , Sepse/diagnóstico , Biomarcadores/sangue , Masculino , Projetos Piloto , Feminino , Pré-Escolar , Alanina/sangue , Criança , Lactente , Curva ROC , Aminoácidos/sangue , Espectrometria de Massas em Tandem
16.
Langmuir ; 40(42): 22409-22416, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39375876

RESUMO

The phenomenon of multicolor afterglow emission has attracted considerable attention in information encryption, bioimaging, and sensing. Consequently, there is a growing demand for the development of multicolor afterglow and phosphorescence switching methods utilizing carbon dot (CD) materials. Herein, multicolor room-temperature phosphorescence (RTP) emission in CD-based materials (PM-CD@BA composite) was achieved by developing multiple emission centers and tuning the excitation wavelength. The color of the afterglow observed in this composite covered from the deep-blue to the green region. The experimental results reveal that under heating treatment, the CDs embedded in inorganic boric acid/B2O3 matrix materials and a rigid framework generated in the composite system effectively suppressed the nonradiative transition and promoted the RTP emission. Finally, high-resolution multilevel RTP 2D code data encryption was realized by inkjet printing technology. The developed concepts of information encryption and anticounterfeiting exhibit the significant potential of CD-based afterglow materials applied in advanced optical applications.

17.
Clin Nephrol ; 102(5): 273-284, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39099383

RESUMO

BACKGROUND: Membranous nephropathy (MN) is an immune complex-mediated disease. Massive proteinuria can lead to Fanconi syndrome, clinically manifesting as renal glycosuria. The prevalence and prognosis of M-type phospholipase A2 receptor (PLA2R)-related MN with renal glycosuria remain unknown. MATERIALS AND METHODS: Patients diagnosed with PLA2R-related MN with renal glycosuria were reviewed, and the control group comprised patients with MN without renal glycosuria who were randomly selected at a ratio of 1 : 3. RESULTS: 50 patients diagnosed with PLA2R-related MN with renal glycosuria from January 2015 to January 2020 were included, with a prevalence of 2.3%. Compared with patients without renal glycosuria, those with renal glycosuria exhibited greater proteinuria, lower estimated glomerular filtration rate (eGFR), and higher use of diuretics, anticoagulants, antibiotics, traditional Chinese medicine, and tacrolimus within 3 months prior to renal biopsy (all p < 0.05). Histologically, patients with renal glycosuria exhibited more severe pathological stages, acute/chronic tubulointerstitial lesions, and tubulointerstitial inflammation (all p < 0.05). Of the 10 patients treated with rituximab (RTX), proteinuria remission was maintained in 6 (60%) patients, and urine glucose remission was achieved in 5 of these 6 patients (83.3%). Multivariate Cox regression analysis showed that renal glycosuria and age > 50 years were independent risk factors for end-stage renal disease (ESRD) or a 30% reduction in the eGFR in patients with PLA2R-related MN. CONCLUSION: PLA2R-related MN patients with renal glycosuria presented with more severe clinicopathological manifestations and worse prognoses. Nephrotoxic drugs should be administered rationally, and RTX should be considered as a promising treatment option.


Assuntos
Glomerulonefrite Membranosa , Glicosúria , Receptores da Fosfolipase A2 , Rituximab , Humanos , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/complicações , Masculino , Feminino , Receptores da Fosfolipase A2/imunologia , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Rituximab/uso terapêutico , Proteinúria/etiologia , Taxa de Filtração Glomerular , Resultado do Tratamento , Rim/patologia , Fatores de Risco , Prognóstico , Prevalência
18.
J Neuroeng Rehabil ; 21(1): 166, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39300485

RESUMO

BACKGROUND: The loss of gait automaticity is a key cause of motor deficits in Parkinson's disease (PD) patients, even at the early stage of the disease. Action observation training (AOT) shows promise in enhancing gait automaticity. However, effective assessment methods are lacking. We aimed to propose a novel gait normalcy index based on dual task cost (NIDTC) and evaluate its validity and responsiveness for early-stage PD rehabilitation. METHODS: Thirty early-stage PD patients were recruited and randomly assigned to the AOT or active control (CON) group. The proposed NIDTC during straight walking and turning tasks and clinical scale scores were measured before and after 12 weeks of rehabilitation. The correlations between the NIDTCs and clinical scores were analyzed with Pearson correlation coefficient analysis to evaluate the construct validity. The rehabilitative changes were assessed using repeated-measures ANOVA, while the responsiveness of NIDTC was further compared by t tests. RESULTS: The turning-based NIDTC was significantly correlated with multiple clinical scales. Significant group-time interactions were observed for the turning-based NIDTC (F = 4.669, p = 0.042), BBS (F = 6.050, p = 0.022) and PDQ-39 (F = 7.772, p = 0.011) tests. The turning-based NIDTC reflected different rehabilitation effects between the AOT and CON groups, with the largest effect size (p = 0.020, Cohen's d = 0.933). CONCLUSION: The turning-based NIDTC exhibited the highest responsiveness for identifying gait automaticity improvement by providing a comprehensive representation of motor ability during dual tasks. It has great potential as a valid measure for early-stage PD diagnosis and rehabilitation assessment. Trial registration Chinese Clinical Trial Registry: ChiCTR2300067657.


Assuntos
Marcha , Doença de Parkinson , Humanos , Doença de Parkinson/reabilitação , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Marcha/fisiologia , Transtornos Neurológicos da Marcha/reabilitação , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/diagnóstico
19.
Environ Toxicol ; 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39041630

RESUMO

Asparagus officinalis (ASP) has antioxidation, anti-inflammatory, antiaging, and immune system-enhancing effects. We explored the preventive and therapeutic consequences of ASP on the brain damage elicited by fluorosis through network pharmacology and in vivo experimental validation. We ascertained the pharmaceutically active ingredients and drug targets of ASP from the Traditional Chinese Medicine Systems Pharmacology database, predicted the disease targets of fluorosis-induced brain injury using GeneCards and Online Mendelian Inheritance in Man databases, obtained target protein-protein interaction networks in the Search Tool for the Retrieval of Interacting Genes/Proteins database, used Cytoscape to obtain key targets and active ingredients, and conducted enrichment analyses of key targets in the Database for Annotation, Visualization and Integrated Discovery. Enrichment analyses showed that "mitogen-activated protein kinase" (MAPK), "phosphoinositide 3-kinase/protein kinase B" (PI3K-Akt), "nuclear factor-kappa B" (NF-κB), and the "neurotrophin signaling pathway" were the most enriched biological processes and signaling pathways. ASP could alleviate fluorosis-based injury, improve brain-tissue damage, increase urinary fluoride content, and improve oxidation levels and inflammatory-factor levels in the body. ASP could also reduce dental fluorosis, bone damage, fluoride concentrations in blood and bone, and accumulation of lipid peroxide. Upon ASP treatment, expression of silent information regulator (SIRT)1, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), MAPK, NF-κB, PI3K, Akt, and B-cell lymphoma-2 in rat brain tissue increased gradually, whereas that of Bax, caspase-3, and p53 decreased gradually. We demonstrated that ASP could regulate the brain damage caused by fluorosis through the SIRT1/BDNF/TrkB signaling pathway, and reported the possible part played by ASP in preventing and treating fluorosis.

20.
Mikrochim Acta ; 191(10): 588, 2024 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256210

RESUMO

Different morphological Cu2O nanoparticles including cube, truncated cube, and octahedron were successfully prepared by a selective surface stabilization strategy. The prepared cube Cu2O exhibited superior peroxidase-like activity over the other two morphological Cu2O nanoparticles, which can readily oxidize 3,3',5,5'-tetramethylbenzidine (TMB) to form visually recognizable color signals. Consequently, a sensitive and simple colorimetric biosensor was proposed for deoxynivalenol (DON) detection. In this biosensor, the uniform cube Cu2O was employed as the vehicle to label the antibody for the recognition of immunoreaction. The sensing strategy showed a detection limit as low as 0.01 ng/mL, and a wide linear range from 2 to 100 ng/mL. Concurrently, the approximate DON concentration can be immediately and conveniently observed by the vivid color changes. Benefiting from the high sensitivity and selectivity of the designed biosensor, the detection of DON in wheat, corn, and tap water samples was achieved, suggesting the bright prospect of the biosensor for the convenient and intuitive detection of DON in actual samples.


Assuntos
Benzidinas , Técnicas Biossensoriais , Colorimetria , Cobre , Limite de Detecção , Nanopartículas Metálicas , Tricotecenos , Zea mays , Tricotecenos/análise , Tricotecenos/imunologia , Colorimetria/métodos , Cobre/química , Técnicas Biossensoriais/métodos , Benzidinas/química , Zea mays/química , Nanopartículas Metálicas/química , Triticum/química , Peroxidase/química , Anticorpos Imobilizados/imunologia , Contaminação de Alimentos/análise
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