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1.
Chem Sci ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39309089

RESUMO

The helical structure is often the key factor for forming and enhancing chiroptical properties, such as circular dichroism (CD) and circular polarized luminescence (CPL) effects. However, no matter whether helical molecules or helical aggregates, they usually display modest chiroptical signals, which limits their practical applications. Herein, chiral tetraphenylethylene (TPE) bimacrocycles prepared in almost quantitative yield show strong and repeatable CD signals up to more than 7000 mdeg, which is very rare for general organic compounds, besides emitting very strong CPL light with an absolute g lum value up to 6.2 × 10-2. It is found that the superhelices formed by self-inclusion between the cavity and outward cyclohexyl ring of TPE bimacrocycles in crystal state are the key factor for highly enhanced chiroptical effect, and the self-inclusion superhelices in assemblies are confirmed by High Resolution Transmission Electron Microscopy (HR-TEM), Powder X-ray Diffraction (XRD) and Fourier Transform Infrared Spectrometry (FT-IR) data. Furthermore, the chiral TPE bimacrocycle shows great potential in chiral recognition and chiral analysis not only for chiral acids but also for chiral amines, chiral amino acids, and neutral chiral alcohol. Using self-inclusion helical nanocrystals of chiral macrocycles, this work provides a new strategy for chiroptical materials with excellent chiroptical properties.

2.
J Pharm Anal ; 14(9): 100978, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39315124

RESUMO

Jumonji domain-containing protein D3 (JMJD3) is a 2-oxoglutarate-dependent dioxygenase that specifically removes transcriptional repression marks di- and tri-methylated groups from lysine 27 on histone 3 (H3K27me2/3). The erasure of these marks leads to the activation of some associated genes, thereby influencing various biological processes, such as development, differentiation, and immune response. However, comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking. Here, we provide a comprehensive overview of JMJD3, including its structure, functions, and involvement in inflammatory pathways. In addition, we summarize the evidence supporting JMJD3's role in several inflammatory diseases, as well as the potential therapeutic applications of JMJD3 inhibitors. Additionally, we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases.

3.
Chemosphere ; 365: 143394, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39307469

RESUMO

The discharge of metal nanoparticles into the water inevitably poses a threat to aquatic organisms and the balance of the aquatic ecosystem. Photoperiod is one of the most important ecological factors for the development of cladocerans. In addition, different light conditions can also affect the toxicity of metal nanoparticles. In this study, we studied the effects of four photoperiods (8L/16D, 10L/14D, 14L/10D, and 16L/8D) combined with three concentrations of ZnO NPs (0 mg L-1, 0.05 mg L-1, and 0.10 mg L-1) on the growth and reproduction of Daphnia pulex. With the increase of photoperiod, the maternal body size and growth rate increased first and then decreased; the first time to reproduction was advanced, and broods and the total offspring also increased. Under the influence of ZnO NPs, growth rate and reproductive capacity were inhibited. The photoperiod 8L/16D and 16L/8D interacted with ZnO NPs on the growth of D. pulex, which significantly decreased the growth rate. Besides, the interaction between photoperiod 8L/16D and ZnO NPs decreased the reproduction ability of D. pulex. These results suggest that the effects of zinc oxide nanoparticles on the growth and reproduction of D. pulex is photoperiod dependent, which is useful for assessing the risk of pollutants to cladoceras under different light conditions.

4.
Int J Biol Macromol ; 279(Pt 4): 135381, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39244132

RESUMO

The majority of natural fungal ß-glucans exhibit diverse biological functionalities, such as immunomodulation and anti-inflammatory effects, attributed to their distinctive helix or highly branched conformation This study utilized ß-glucan with helix conformation and high-viscosity extracted from Hericium erinaceus, employing freeze-thaw and solvent exchange strategies to induce multiple hydrogen bonding between molecules, thereby initiating the self-assembly process of ß-glucan from random coil to stable helix conformation without chemical modifications. Subsequently, the natural bioactive compound tannic acid was introduced through physical entanglement, imparting exceptional antioxidant properties to the hydrogel. The HEBG/TA hydrogel exhibited injectable properties, appropriate mechanical characteristics, degradability, temperature-responsive tannic acid release, antioxidant activity, and hemostatic potential. In vivo experiments using skin full-thickness defect and deep second-degree burn wound models demonstrated significant therapeutic efficacy, including neovascularization, and tissue regeneration. Moreover, the HEBG/TA hydrogel demonstrated its ability to regulate cytokines by effectively inhibiting the production of inflammatory mediators (TNF-α, IL-6), while simultaneously enhancing the expression of cell proliferation factor KI-67 and markers associated with angiogenesis such as CD31 and α-SMA. This study highlights the potential of combining natural ß-glucan with bioactive molecules for skin repair.

5.
J Ethnopharmacol ; 337(Pt 1): 118783, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39244175

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxyli Radix (ZR), the dry root of Zanthoxylum nitidum (Roxb.) DC (ZN) is known as Liang Mian Zhen in China and has been the preferred Chinese medicine for the treatment of inflammation and cancer disease at home and abroad. ZR has been used as the core ingredient in anti-inflammatory traditional medicines, such as Sanjiuweitai granules and Jinji tablets, etc. AIM OF THE WORK: This review aimed to provide a comprehensive overview of ZR in terms of traditional uses, quality control, botany, phytochemistry, pharmacology, toxicology, and pharmacokinetics. Meanwhile, the anti-inflammatory substances and mechanism of ZR were emphasized, to offer new perspectives and broad scopes for future studies. MATERIALS AND METHODS: The information was retrieved from Web of Science, Researchgate, Google Scholar, SciFinder, X-MOL, PubMed, China National Knowledge Infrastructure (CNKI), Chinese Masters and Doctoral Dissertations, and Elsevier between 1984 and 2024. RESULTS: Till now, a total of 184 chemical components have been identified in ZR, including 91 alkaloids, 22 lignans, 4 flavonoids, 19 coumarins, 17 terpenoids, and 31 other types. Pharmacological studies have proved that ZR had a variety of biological activities, such as anti-tumour, antibacterial, antioxidant and other activities, particularly in anti-inflammation. ZR exerts anti-inflammatory disease effects by modulating various signaling pathways, including MAPK, NF-κB, P13/AKT and JAK/STAT. Pharmacokinetic studies have shown that ZR exhibits low absorption rates, broad distribution, and rapid metabolism. Additionally, this review also revealed the shortcomings of current research on ZR and possible future research directions. CONCLUSION: Extensive literature analysis indicates that ZR and its bioactive constituents possess diverse pharmacological activities, especially anti-inflammation. Moreover, in order to promote the safety and adaptability of ZR in clinical application, it is also strongly recommended that further research should focus on toxicity studies, pharmacokinetic studies of herb-drug interactions, and quality control.

6.
Hum Genomics ; 18(1): 98, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39256828

RESUMO

This study aims to assess the effect of familial structures on the still-missing heritability estimate and prediction accuracy of Type 2 Diabetes (T2D) using pedigree estimated risk values (ERV) and genomic ERV. We used 11,818 individuals (T2D cases: 2,210) with genotype (649,932 SNPs) and pedigree information from the ongoing periodic cohort study of the Iranian population project. We considered three different familial structure scenarios, including (i) all families, (ii) all families with ≥ 1 generation, and (iii) families with ≥ 1 generation in which both case and control individuals are presented. Comprehensive simulation strategies were implemented to quantify the difference between estimates of [Formula: see text] and [Formula: see text]. A proportion of still-missing heritability in T2D could be explained by overestimation of pedigree-based heritability due to the presence of families with individuals having only one of the two disease statuses. Our research findings underscore the significance of including families with only case/control individuals in cohort studies. The presence of such family structures (as observed in scenarios i and ii) contributes to a more accurate estimation of disease heritability, addressing the underestimation that was previously overlooked in prior research. However, when predicting disease risk, the absence of these families (as seen in scenario iii) can yield the highest prediction accuracy and the strongest correlation with Polygenic Risk Scores. Our findings represent the first evidence of the important contribution of familial structure for heritability estimations and genomic prediction studies in T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Predisposição Genética para Doença , Linhagem , Polimorfismo de Nucleotídeo Único , Humanos , Diabetes Mellitus Tipo 2/genética , Feminino , Polimorfismo de Nucleotídeo Único/genética , Masculino , Genômica/métodos , Irã (Geográfico) , Modelos Genéticos , Estudos de Coortes , Estudo de Associação Genômica Ampla , Genótipo , Estudos de Casos e Controles , Pessoa de Meia-Idade , Família , Estrutura Familiar
7.
Cell Signal ; 124: 111376, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39236836

RESUMO

While certain members of ubiquitin-coupled enzymes (E2s) have garnered attention as potential therapeutic targets across diverse diseases, research progress on Ubiquitin-Conjugating Enzyme 5 (UBC5)-a pivotal member of the E2s family involved in crucial cellular processes such as apoptosis, DNA repair, and signal transduction-has been relatively sluggish. Previous findings suggest that UBC5 plays a vital role in the ubiquitination of various target proteins implicated in diseases and homeostasis, particularly in various cancer types. This review comprehensively introduces the structure and biological functions of UBC5, with a specific focus on its contributions to the onset and advancement of diverse diseases. It suggests that targeting UBC5 holds promise as a therapeutic approach for disease therapy. Recent discoveries highlighting the high homology between UBC5, UBC1, and UBC4 have provided insight into the mechanism of UBC5 in protein degradation and the regulation of cellular functions. As our comprehension of the structural distinctions among UBC5 and its homologues, namely UBC1 and UBC4, advances, our understanding of UBC5's functional significance also expands.

8.
J Am Heart Assoc ; 13(18): e034870, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39248255

RESUMO

BACKGROUND: The prognostic implication of mildly reduced ejection fraction (mrEF) after acute myocardial infarction has not been clearly demonstrated. We investigated the long-term risk of cardiovascular death and its predictors in patients with mrEF following acute myocardial infarction. METHODS AND RESULTS: A total of 18 668 patients who presented with acute myocardial infarction were included in 2 prospective, multicenter registries. The incidence of adverse cardiovascular events according to the left ventricular ejection fraction (EF) strata at index admission were evaluated. A score system consisting of clinical variables were developed to predict long-term cardiovascular death in the mrEF group. There were 2548 patients with reduced EF (EF ≤40%), 4266 patients with mrEF (EF 41%-49%), and 11 854 patients with preserved EF (EF ≥50%). During a median follow-up period of 37.9 months, the cardiovascular death rate was 22.3% in the reduced EF group, 10.3% in the mrEF group, and 7.3% in the preserved EF group (P<0.001). In the mrEF group, age>65 years, hypertension, stroke, severe renal insufficiency, and Killip class ≥3 were independent predictors for cardiovascular death. Presence of >2 predictors best discriminated the high-risk patients for cardiovascular death with an area under the curve of 0.746. Incidence of cardiovascular death in the high-risk mrEF group was comparable with the rEF group, while it was lower in the low-risk mrEF group than in the pEF group. CONCLUSIONS: Patients with mrEF after acute myocardial infarction had a modest risk of cardiovascular death. Clinical predictors could help discriminate a high-risk subpopulation with cardiovascular death risks comparable with those in the reduced EF group.


Assuntos
Infarto do Miocárdio , Sistema de Registros , Volume Sistólico , Função Ventricular Esquerda , Humanos , Masculino , Feminino , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Volume Sistólico/fisiologia , Idoso , Estudos Prospectivos , Pessoa de Meia-Idade , Medição de Risco/métodos , Prognóstico , Fatores de Risco , Fatores de Tempo , Incidência , Causas de Morte , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/epidemiologia , Japão/epidemiologia
9.
Br J Cancer ; 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266624

RESUMO

BACKGROUND: Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ. METHODS: Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors. RESULTS: TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma. CONCLUSION: Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.

10.
J Ethnopharmacol ; 335: 118646, 2024 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-39097210

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ligustrum lucidum W.T. Aiton is a traditional Chinese medicine that has long been used with high hepatoprotective therapeutic and condition value. Specnuezhenide (SP), the standard prominent secoiridoid compound of Fructus Ligustri Lucidi may ameliorate hepatic inflammation in chronic liver diseases. AIM OF THE STUDY: Regulating inflammation through SIRT6-P2X7R axis has caused the emergence of novel molecular mechanism strategies for reversing hepatic fibrosis. This study focused on the mechanism of SP in modulating the liver inflammatory microenvironment in hepatic fibrosis. MATERIALS AND METHODS: C57BL/6 mice with hepatic fibrosis were stimulated with thioacetamide (TAA) prior to administration of SP. Hepatic stellate cells (HSCs) or normal mouse primary hepatocytes were exposed to transforming growth factor-ß (TGF-ß) treatment. Meanwhile, normal mouse bone marrow-derived macrophages (BMDMs) were treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP), aiming to obtain the conditioned medium. HSCs and hepatocytes were transfected with SIRT6 knockdown vector (siRNA-SIRT6) to estimate the impact of SP on the SIRT6-P2X7R/NLRP3 signaling pathway. RESULTS: SP suppressed the HSCs extracellular matrix (ECM) deposition as well as pro-inflammatory cytokine levels induced by the medium of BMDMs or TGF-ß. In addition, SP also significantly up-regulated SIRT6, inhibited P2X7R-NLRP3 inflammasome in HSCs and hepatocytes, and functioned as MDL-800 (a SIRT6 agonist). SP reduced the hepatocytes pyroptosis and further prevented the occurrence of inflammatory response in the liver. SP could inhibit the activation of BMDMs and impede IL-1ß and IL-18 from entering extracellular regions. Moreover, deficiency of SIRT6 in HSCs or hepatocytes reduced SP's regulation of P2X7R suppression. For TAA-treated mice, SP mitigated histopathological changes, ECM accumulation, EMT process, and NETs formation in hepatic fibrosis. CONCLUSIONS: Therefore, SP decreased inflammatory response via SIRT6-P2X7R/NLRP3 pathway and suppressed fibrillogenesis. These findings supported SP as the novel candidate to treat hepatic fibrosis.


Assuntos
Cirrose Hepática , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais , Sirtuínas , Animais , Sirtuínas/metabolismo , Sirtuínas/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos , Masculino , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Tioacetamida/toxicidade , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Anti-Inflamatórios/farmacologia
11.
Br J Clin Pharmacol ; 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39112438

RESUMO

AIMS: Omalizumab is an anti-immunoglobulin E (IgE) monoclonal antibody that was first approved by the United States (US) Food and Drug Administration (FDA) for the treatment of allergic asthma in 2003. The pivotal trials supporting the initial approval of omalizumab used dosing determined by patient's baseline IgE and body weight, with the goal of reducing the mean free IgE level to approximately 25 ng/mL or less. While the underlying parameters supporting the dosing table remained the same, subsequent studies and analyses have resulted in approved alternative versions of the dosing table, including the European Union (EU) asthma dosing table, which differs in weight bands and maximum allowable baseline IgE and omalizumab dose. In this study, we leveraged modelling and simulation approaches to predict and compare the free IgE reduction and forced expiratory volume in 1 second (FEV1) improvement with omalizumab dosing based on the US and EU asthma dosing tables. METHODS: Previously established population pharmacokinetic-IgE and IgE-FEV1 models were used to predict and compare post-treatment free IgE and FEV1 based on the US and EU dosing tables. Clinical trial simulations (with virtual asthma populations) and Monte Carlo simulations were performed to provide both breadth and depth in the comparisons. RESULTS: The US and EU asthma dosing tables were predicted to result in generally comparable free IgE suppression and FEV1 improvement. CONCLUSIONS: Despite the similar free IgE and FEV1 outcomes from simulations, this has not been clinically validated with respect to the registrational endpoint of reduction in annualized asthma exacerbations.

12.
Nat Commun ; 15(1): 6677, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39107283

RESUMO

Clarification of the cytotoxic function of T cells is crucial for understanding human immune responses and immunotherapy procedures. Here, we report a high-throughput Bessel oblique plane microscopy (HBOPM) platform capable of 3D live imaging and phenotyping of chimeric antigen receptor (CAR)-modified T-cell cytotoxicity against cancer cells. The HBOPM platform has the following characteristics: an isotropic subcellular resolution of 320 nm, large-scale scouting over 400 interacting cell pairs, long-term observation across 5 hours, and quantitative analysis of the Terabyte-scale 3D, multichannel, time-lapse image datasets. Using this advanced microscopy platform, several key subcellular events in CAR-T cells are captured and comprehensively analyzed; these events include the instantaneous formation of immune synapses and the sustained changes in the microtubing morphology. Furthermore, we identify the actin retrograde flow speed, the actin depletion coefficient, the microtubule polarization and the contact area of the CAR-T/target cell conjugates as essential parameters strongly correlated with CAR-T-cell cytotoxic function. Our approach will be useful for establishing criteria for quantifying T-cell function in individual patients for all T-cell-based immunotherapies.


Assuntos
Imageamento Tridimensional , Imunoterapia Adotiva , Microtúbulos , Receptores de Antígenos Quiméricos , Linfócitos T , Humanos , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Imageamento Tridimensional/métodos , Imunoterapia Adotiva/métodos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microtúbulos/metabolismo , Linhagem Celular Tumoral , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo , Citotoxicidade Imunológica , Actinas/metabolismo , Microscopia/métodos , Fenótipo
13.
J Am Heart Assoc ; 13(16): e034920, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39158557

RESUMO

BACKGROUND: Little is known about the characteristics and long-term clinical outcomes of patients with heart failure with improved ejection fraction (HFimpEF) after acute myocardial infarction. METHODS AND RESULTS: From a multicenter, consecutive cohort of patients with acute myocardial infarction undergoing percutaneous coronary intervention, patients with an initial echocardiogram with left ventricular ejection fraction ≤40% and at least 1 follow-up echocardiogram after 14 days and within 2 years of the initial event were considered for analyses. HFimpEF was defined as an initial left ventricular ejection fraction ≤40% and serial left ventricular ejection fraction >40% with an increase of ≥10% from baseline at follow-up. Independent factors predicting HFimpEF were identified, and clinical outcomes of patients with HFimpEF were compared with those without improvement. From an initial cohort of 10 719 patients with acute myocardial infarction, 191 patients with HFimpEF and 256 patients with non-HFimpEF who had initial and follow-up echocardiographic data were analyzed. The median follow-up duration was 4.5 (interquartile range, 2.9-5.0) years. The factors predicting HFimpEF were lower peak creatine kinase myocardial band, smaller left ventricular dimensions, lower ratio between early mitral inflow velocity and mitral annular early diastolic velocity ', and the use of ß blockers or renin-angiotensin system blockers at discharge. HFimpEF was associated with a significantly decreased risk of all-cause death compared with non-HFimpEF (hazard ratio, 0.377 [95% CI, 0.234-0.609]; P<0.001). In 2-year landmark analysis, these findings were consistent not only before but also after the landmark point. Similar findings were true for cardiovascular death and admission for heart failure. CONCLUSIONS: Patients with HFimpEF after acute myocardial infarction showed distinct clinical and echocardiographic characteristics and were associated with better long-term clinical outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02806102.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Intervenção Coronária Percutânea , Volume Sistólico , Função Ventricular Esquerda , Humanos , Masculino , Feminino , Volume Sistólico/fisiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/mortalidade , Idoso , Pessoa de Meia-Idade , Função Ventricular Esquerda/fisiologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Fatores de Tempo , Ecocardiografia , Recuperação de Função Fisiológica , Prognóstico , Fatores de Risco , Resultado do Tratamento
14.
J Med Virol ; 96(8): e29873, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39165041

RESUMO

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants raises concerns regarding the effectiveness of immunity acquired from previous Omicron subvariants breakthrough infections (BTIs) or reinfections (RIs) against the current circulating Omicron subvariants. In this study, we prospectively investigate the dynamic changes of virus-specific antibody and T cell responses among 77 adolescents following Omicron BA.2.3 BTI with or without subsequent Omicron BA.5 RI. Notably, the neutralizing antibodies (NAbs) titers against various detected SARS-CoV-2 variants, especially the emerging Omicron CH.1.1, XBB.1.5, XBB.1.16, EG.5.1, and JN.1 subvariants, exhibited a significant decrease along the time. A lower level of IgG and NAbs titers post-BTI was found to be closely associated with subsequent RI. Elevated NAbs levels and shortened antigenic distances were observed following Omicron BA.5 RI. Robust T cell responses against both Omicron BA.2- and CH.1.1-spike peptides were observed at each point visited. The exposure to Omicron BA.5 promoted phenotypic differentiation of virus-specific memory T cells, even among the non-seroconversion adolescents. Therefore, updated vaccines are needed to provide effective protection against newly emerging SARS-CoV-2 variants among adolescents.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19 , Células T de Memória , Reinfecção , SARS-CoV-2 , Humanos , Adolescente , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Masculino , Reinfecção/imunologia , Reinfecção/virologia , Feminino , Células T de Memória/imunologia , Estudos Prospectivos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Formação de Anticorpos , Glicoproteína da Espícula de Coronavírus/imunologia , Memória Imunológica , Criança , Linfócitos T/imunologia
15.
Osteoporos Int ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093437

RESUMO

Vertebral tumors in patients with tumor-induced osteomalacia (TIO) have a low diagnostic rate and poor postoperative outcomes. The application of 68 Ga-DOTATATE-PET/CT significantly increased the detection rate. Compared with tumor curettage, segmental resection was recommended as the preferred surgical type due to its high recovery rate. PURPOSE: Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic osteomalacia, and surgery is the first-line therapy. Most TIO tumors are found in the bones of the appendicular skeleton, cranium, and paranasal sinuses but rarely in the vertebrae. Tumor curettage and segmental resection are the two main surgical options for vertebral TIO patients. However, research on the clinical characteristics and surgical prognosis of vertebral TIO patients is rare. In the present study, for the first time, we investigated the clinical characteristics of 16 vertebral TIO patients and compared the surgical outcomes of patients who underwent surgery via two different surgical methods. METHODS: This was a retrospective cohort study. In this study, we included 16 adult TIO patients with lesions in vertebrae from Peking Union Medical College Hospital (PUMCH), all of whom underwent surgery. Baseline laboratory data were collected through medical records review. Technetium-99 m octreotide scintigraphy (99Tcm-OCT) and 68gallium-DOTA-TATE-positron emission tomography/computed tomography (68 Ga-DOTATATE-PET/CT) were conducted at the Department of Nuclear Medicine of PUMCH. The tumor histopathology was confirmed by a senior pathologist at our center. RESULTS: Vertebral TIO patients had lower serum phosphorus and TmP/GFR and higher serum alkaline phosphatase (ALP), serum parathyroid hormone (PTH), and serum C-terminal cross-linked telopeptide of type I collagen (ß-CTX) levels than the normal range. The sensitivity of 68 Ga‒DOTATATE PET/CT was 100%, significantly greater than that of 99Tcm-OCT (40%). After comparing the outcomes between the two surgical methods, we found that the recovery rate after segmental resection (62.5%) was greater than that after tumor curettage (12.5%). In the thoracic and sacral vertebrae, segmental resection surgery had a good prognosis. CONCLUSION: 68 Ga-DOTATATE PET/CT could serve as the first diagnostic tool in patients with vertebral TIO, and segmental resection could be used as the preferred surgery. This study would raise awareness of the clinical features and management of these rare vertebral TIO patients.

16.
Am J Reprod Immunol ; 92(2): e13903, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39177075

RESUMO

INTRODUCTION: To explore the mechanisms of labor by investigating the autophagy of placental and fetal membranes tissue in normal pregnant women. METHODS: Placenta and fetal membranes were collected from women with singleton pregnancies without any medical complications and from women who delivered vaginally (labor-initiated group; L group) or by caesarean section (labor-noninitiated group; NL group). Autophagosomes were observed by transmission electron microscopy (TEM). Immunofluorescence and western blotting (WB) were used to detect protein levels of the autophagy markers LC3A and LC3B. TEM, immunohistochemistry (IHC), and WB were used to compare autophagy in different parts of the placenta and fetal membranes in the L and NL groups. The expression of LC3B/LC3A, ROCK1, and ROCK2 in the placenta of nonpregnant and pregnant rats was detected by WB and IHC. RESULTS: TEM and IHC results showed an increase in the number of autophagosomes and autophagic lysosomes in the L group, and WB results indicated an increase in the LC3B/A ratio between the placenta and fetal membranes in the L group. Autophagy was significantly increased on the maternal side of the placenta in the L group, and the level of autophagy became higher near rupture in the fetal membranes and near the point where the umbilical cord joins the placenta in the L group. The LC3B/A ratio increased and ROCK1 and ROCK2 levels decreased in postnatal rats. DISCUSSION: Autophagy can occur in the placenta and fetal membranes and its activity is higher at the onset of labor, suggesting a role in labor.


Assuntos
Autofagia , Proteínas Associadas aos Microtúbulos , Placenta , Quinases Associadas a rho , Feminino , Gravidez , Humanos , Autofagia/fisiologia , Placenta/metabolismo , Placenta/ultraestrutura , Quinases Associadas a rho/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Ratos , Adulto , Início do Trabalho de Parto , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Membranas Extraembrionárias/metabolismo , Trabalho de Parto/metabolismo , Ratos Sprague-Dawley
17.
Angew Chem Int Ed Engl ; : e202412796, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39126151

RESUMO

Photocatalytic overall splitting of pure water (H2O) without sacrificial reagent to hydrogen (H2) and oxygen (O2) holds a great potential for achieving carbon neutrality. Herein, by anchoring cobalt sulfide (Co9S8) as cocatalyst and cadmium sulfide (CdS) as light absorber to channel wall of a porous polymer microreactor (PP12), continuous violent H2 and O2 bubbling productions from photocatalytic overall splitting of pure H2O without sacrificial reagent is achieved, with H2 and O2 production rates as high as 4.41 and 2.20 mmol h-1 gcat.-1 respectively. These are significantly enhanced than those in the widely used stirred tank-type reactor in which no O2 is produced and H2 production rate is only 0.004 mmol h-1 gcat.-1. Besides improved charge separation and interaction of H2O with photocatalyst in PP12, bonding interaction of Co9S8 with PP12 creates abundant catalytic active sites for simultaneous productions of H2 and O2, thus leading to the significantly enhanced H2 and O2 bubbling productions in PP12. This offers a new strategy to enhance photocatalytic overall splitting of pure H2O without sacrificial reagent.

18.
Microorganisms ; 12(8)2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39203420

RESUMO

Cyanobacterial harmful algal blooms (CyanoHABs) cause health and environmental effects worldwide. Cyanophage is a virus that exclusively infects cyanobacteria. Using cyanophages to control blooms is the latest biological control method. However, little research on the genomics of cyanophages and the presence of numerous proteins with unidentified functions in cyanophage genomes pose challenges for their practical application and comprehensive investigation. We selected the broad-spectrum and efficient cyanophage YongM for our study. On the one hand, through rational analysis, we analyze essential genes, establish the minimal cyanophage genome and single essential gene modules, and examine the impact of essential modules on growth. Additionally, we conducted ultraviolet mutagenesis on YongM to generate more efficient cyanophages' critical modules through random mutagenesis. Then, we sequenced and analyzed the functionality of the mutational gene modules. These findings highlight several gene modules that contribute to a deeper understanding of the functional components within cyanophage genomes.

19.
Comput Biol Med ; 179: 108835, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38996550

RESUMO

Gene regulatory networks (GRNs) are crucial for understanding organismal molecular mechanisms and processes. Construction of GRN in the epithelioma papulosum cyprini (EPC) cells of cyprinid fish by spring viremia of carp virus (SVCV) infection helps understand the immune regulatory mechanisms that enhance the survival capabilities of cyprinid fish. Although many computational methods have been used to infer GRNs, specialized approaches for predicting the GRN of EPC cells following SVCV infection are lacking. In addition, most existing methods focus primarily on gene expression features, neglecting the valuable network structural information in known GRNs. In this study, we propose a novel supervised deep neural network, named MEFFGRN (Matrix Enhancement- and Feature Fusion-based method for Gene Regulatory Network inference), to accurately predict the GRN of EPC cells following SVCV infection. MEFFGRN considers both gene expression data and network structure information of known GRN and introduces a matrix enhancement method to address the sparsity issue of known GRN, extracting richer network structure information. To optimize the benefits of CNN (Convolutional Neural Network) in image processing, gene expression and enhanced GRN data were transformed into histogram images for each gene pair respectively. Subsequently, these histograms were separately fed into CNNs for training to obtain the corresponding gene expression and network structural features. Furthermore, a feature fusion mechanism was introduced to comprehensively integrate the gene expression and network structural features. This integration considers the specificity of each feature and their interactive information, resulting in a more comprehensive and precise feature representation during the fusion process. Experimental results from both real-world and benchmark datasets demonstrate that MEFFGRN achieves competitive performance compared with state-of-the-art computational methods. Furthermore, study findings from SVCV-infected EPC cells suggest that MEFFGRN can predict novel gene regulatory relationships.


Assuntos
Doenças dos Peixes , Redes Reguladoras de Genes , Infecções por Rhabdoviridae , Rhabdoviridae , Animais , Rhabdoviridae/genética , Doenças dos Peixes/genética , Doenças dos Peixes/virologia , Infecções por Rhabdoviridae/genética , Infecções por Rhabdoviridae/virologia , Carpas/genética , Carpas/virologia , Biologia Computacional/métodos , Redes Neurais de Computação , Cyprinidae/genética
20.
Mol Cancer ; 23(1): 152, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39085861

RESUMO

Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8+ T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Paclitaxel , Doenças do Sistema Nervoso Periférico , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Humanos , Animais , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Feminino , Camundongos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo
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