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1.
PeerJ ; 12: e17661, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38978758

RESUMO

Leaf mustard (Brassica juncea L. Czern & Coss), an important vegetable crop, experiences pronounced adversity due to seasonal drought stress, particularly at the seed germination stage. Although there is partial comprehension of drought-responsive genes, the role of long non-coding RNAs (lncRNAs) in adjusting mustard's drought stress response is largely unexplored. In this study, we showed that the drought-tolerant cultivar 'Weiliang' manifested a markedly lower base water potential (-1.073 MPa vs -0.437 MPa) and higher germination percentage (41.2% vs 0%) than the drought-susceptible cultivar 'Shuidong' under drought conditions. High throughput RNA sequencing techniques revealed a significant repertoire of lncRNAs from both cultivars during germination under drought stress, resulting in the identification of 2,087 differentially expressed lncRNAs (DELs) and their correspondingly linked 12,433 target genes. It was noted that 84 genes targeted by DEL exhibited enrichment in the photosynthesis pathway. Gene network construction showed that MSTRG.150397, a regulatory lncRNA, was inferred to potentially modulate key photosynthetic genes (Psb27, PetC, PetH, and PsbW), whilst MSTRG.107159 was indicated as an inhibitory regulator of six drought-responsive PIP genes. Further, weighted gene co-expression network analysis (WGCNA) corroborated the involvement of light intensity and stress response genes targeted by the identified DELs. The precision and regulatory impact of lncRNA were verified through qPCR. This study extends our knowledge of the regulatory mechanisms governing drought stress responses in mustard, which will help strategies to augment drought tolerance in this crop.


Assuntos
Secas , Regulação da Expressão Gênica de Plantas , Germinação , Mostardeira , RNA Longo não Codificante , Mostardeira/genética , Germinação/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Estresse Fisiológico/genética , Sementes/genética , Sementes/crescimento & desenvolvimento , RNA de Plantas/genética , RNA de Plantas/metabolismo , Redes Reguladoras de Genes
2.
Nano Lett ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953881

RESUMO

Acute methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a common and serious lung infection with high morbidity and mortality rates. Due to the increasing antibiotic resistance, toxicity, and pathogenicity of MRSA, there is an urgent need to explore effective antibacterial strategies. In this study, we developed a dry powder inhalable formulation which is composed of porous microspheres prepared from poly(lactic-co-glycolic acid) (PLGA), internally loaded with indocyanine green (ICG)-modified, heat-resistant phages that we screened for their high efficacy against MRSA. This formulation can deliver therapeutic doses of ICG-modified active phages to the deep lung tissue infection sites, avoiding rapid clearance by alveolar macrophages. Combined with the synergistic treatment of phage therapy and photothermal therapy, the formulation demonstrates potent bactericidal effects in acute MRSA pneumonia. With its long-term stability at room temperature and inhalable characteristics, this formulation has the potential to be a promising drug for the clinical treatment of MRSA pneumonia.

3.
Eur Clin Respir J ; 11(1): 2372901, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38946716

RESUMO

Background: Bronchiectasis is a disease with predominantly neutrophilic inflammation. As a readily available biomarker, there is little evidence to support the use of blood neutrophil-to-lymphocyte ratio (NLR) to predict bronchiectasis exacerbation severe enough to warrant hospitalization. Methods: A registry-based retrospective cohort study was conducted at a in Hong Kong. Chinese patients with non-cystic fibrosis (CF) bronchiectasis were retrospectively reviewed and subsequently followed up to investigate the association of NLR and the need for hospitalization for bronchiectasis exacerbation. Data on the NLR for patients in a clinically stable state in 2018 were collected and patients followed up from 1 January 2019 to 31 December 2022. The primary outcome was the need for hospitalization due to bronchiectasis exacerbation over the next 4 years. Results: We reviewed 473 Chinese patients with non-CF bronchiectasis, of whom 94 required hospitalization for bronchiectasis exacerbation during the 4-year follow-up period. Multi-variable logistic regression adjusted for E-FACED score (Exacerbation, Forced expiratory volume in 1 s (FEV1), Age, Chronic colonization, Extension, and Dyspnea score), gender, age, smoking status, and presence of co-existing chronic obstructive pulmonary disease (COPD) was conducted to compare patients with highest and lowest quartile NLR. Results revealed that those with NLR at the highest quartile were at increased risk of hospitalization for bronchiectasis exacerbation with an adjusted odds ratio (aOR) of 2.02 (95% confidence interval = 1.00-4.12, p = 0.05). Conclusion: Blood NLR may serve as a marker to predict the need for hospitalization due to bronchiectasis exacerbation.

4.
Chem Sci ; 15(26): 10135-10145, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38966363

RESUMO

The dual catalysis strategy is an efficient and powerful tool to fulfill the stereodivergent synthesis of stereoisomeric products from the same set of starting materials. Great attention has been given to the construction of chiral compounds with two contiguous stereocenters. However, the synthesis of two remote noncontiguous stereocenters is more challenging and is less developed, despite the high demand for synthetic tactics. We herein developed an unprecedented example of the stereodivergent preparation of synthetically useful and biologically important chiral ζ-hydroxy amino ester derivatives containing remote 1,6-noncontiguous stereocenters and a unique ß,γ-unsaturation moiety. This cascade dehydrogenation/1,6-Michael addition/hydrogenation protocol between readily-available ketoimine esters and racemic branched dienyl carbinols was rationally realized with bimetallic copper/ruthenium relay catalysis. The key features of the process were atom economy, step economy, and redox-neutrality. All four stereoisomers of chiral ζ-hydroxy amino ester derivatives were easily achieved by the orthogonal permutations of a chiral copper catalyst and chiral ruthenium catalyst. Importantly, a much more challenging stereodivergent synthesis of all eight stereoisomers of chiral peptide products containing three remote stereocenters was accomplished with excellent results through the cooperation of two chiral catalyst pairs and substrate enantiomers.

5.
Cancer Lett ; : 217104, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38969163

RESUMO

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95% Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

6.
J Hazard Mater ; 476: 135062, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38959831

RESUMO

Microplastics (MPs) are emerging pollutants, causing potential threats to aquatic ecosystems and serious concern in aggregating with microalgae (critical primary producers). When entering water bodies, MPs are expected to sink below the water surface and disperse into varying water compartments with different light intensities. However, how light influences the aggregation processes of algal cells onto MPs and the associated molecular coupling mechanisms and derivative risks remain poorly understood. Herein, we investigated the aggregation behavior between polystyrene microplastics (mPS, 10 µm) and Chlorella pyrenoidosa under low (LL, 15 µmol·m-2·s-1), normal (NL, 55 µmol·m-2·s-1), and high light (HL, 150 µmol·m-2·s-1) conditions from integrated in vivo and in silico assays. The results indicated that under LL, the mPS particles primarily existed independently, whereas under NL and HL, C. pyrenoidosa tightly bounded to mPS by secreting more protein-rich extracellular polymeric substances. Infrared spectroscopy analysis and density functional theory calculation revealed that the aggregation formation was driven by non-covalent interaction involving van der Waals force and hydrogen bond. These processes subsequently enhanced the deposition and adherence capacity of mPS and relieved its phytotoxicity. Overall, our findings advance the practical and theoretical understanding of the ecological impacts of MPs in complex aquatic environments.

7.
Europace ; 26(7)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38938169

RESUMO

AIMS: Subclinical atrial fibrillation (AF) is associated with increased risk of progression to clinical AF, stroke, and cardiovascular death. We hypothesized that in pacemaker patients requiring dual-chamber rate-adaptive (DDDR) pacing, closed loop stimulation (CLS) integrated into the circulatory control system through intra-cardiac impedance monitoring would reduce the occurrence of atrial high-rate episodes (AHREs) compared with conventional DDDR pacing. METHODS AND RESULTS: Patients with sinus node dysfunctions (SNDs) and an implanted pacemaker or defibrillator were randomly allocated to dual-chamber CLS (n = 612) or accelerometer-based DDDR pacing (n = 598) and followed for 3 years. The primary endpoint was time to the composite endpoint of the first AHRE lasting ≥6 min, stroke, or transient ischaemic attack (TIA). All AHREs were independently adjudicated using intra-cardiac electrograms. The incidence of the primary endpoint was lower in the CLS arm (50.6%) than in the DDDR arm (55.7%), primarily due to the reduction in AHREs lasting between 6 h and 7 days. Unadjusted site-stratified hazard ratio (HR) for CLS vs. DDDR was 0.84 [95% confidence interval (CI), 0.72-0.99; P = 0.035]. After adjusting for CHA2DS2-VASc score, the HR remained 0.84 (95% CI, 0.71-0.99; P = 0.033). In subgroup analyses of AHRE incidence, the incremental benefit of CLS was greatest in patients without atrioventricular block (HR, 0.77; P = 0.008) and in patients without AF history (HR, 0.73; P = 0.009). The contribution of stroke/TIA to the primary endpoint (1.3%) was low and not statistically different between study arms. CONCLUSION: Dual-chamber CLS in patients with SND is associated with a significantly lower AHRE incidence than conventional DDDR pacing.


Assuntos
Fibrilação Atrial , Estimulação Cardíaca Artificial , Frequência Cardíaca , Ataque Isquêmico Transitório , Marca-Passo Artificial , Síndrome do Nó Sinusal , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/terapia , Fibrilação Atrial/epidemiologia , Idoso , Síndrome do Nó Sinusal/terapia , Síndrome do Nó Sinusal/fisiopatologia , Estimulação Cardíaca Artificial/métodos , Ataque Isquêmico Transitório/prevenção & controle , Ataque Isquêmico Transitório/epidemiologia , Pessoa de Meia-Idade , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/epidemiologia , Incidência , Resultado do Tratamento , Fatores de Tempo , Fatores de Risco , Desfibriladores Implantáveis , Técnicas Eletrofisiológicas Cardíacas , Acelerometria , Idoso de 80 Anos ou mais
8.
Nat Commun ; 15(1): 4990, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862530

RESUMO

Laser-based light detection and ranging (LIDAR) offers a powerful tool to real-timely map spatial information with exceptional accuracy and owns various applications ranging from industrial manufacturing, and remote sensing, to airborne and in-vehicle missions. Over the past two decades, the rapid advancements of optical frequency combs have ushered in a new era for LIDAR, promoting measurement precision to quantum noise limited level. For comb LIDAR systems, to further improve the comprehensive performances and reconcile inherent conflicts between speed, accuracy, and ambiguity range, innovative demodulation strategies become crucial. Here we report a dispersive Fourier transform (DFT) based LIDAR method utilizing phase-locked Vernier dual soliton laser combs. We demonstrate that after in-line pulse stretching, the delay of the flying pulses can be identified via the DFT-based spectral interferometry instead of temporal interferometry or pulse reconstruction. This enables absolute distance measurements with precision starting from 262 nm in single shot, to 2.8 nm after averaging 1.5 ms, in a non-ambiguity range over 1.7 km. Furthermore, our DFT-based LIDAR method distinctly demonstrates an ability to completely eliminate dead zones. Such an integration of frequency-resolved ultrafast analysis and dual-comb ranging technology may pave a way for the design of future LIDAR systems.

9.
Adv Sci (Weinh) ; : e2309471, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38889269

RESUMO

Patients with glycogen storage disease type Ib (GSD-Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD-Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo-polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single-cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper-activation of the CCL4L2-VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD-Ib. Collectively, the microbiota-driven pathomechanism of IBD is demonstrated in GSD-Ib and revealed the active role of the CCL4L2-VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2-VISR axis may represent a potential therapy for GSD-associated IBD.

10.
Chin Med J (Engl) ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38879805

RESUMO

BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (Tregs), an increase in the cluster of differentiation 8 positive (CD8+) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8+ T cells, and induced the proportion of Tregs. Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION: Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cell in RA.

11.
J Thorac Dis ; 16(5): 2767-2775, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38883640

RESUMO

Background: Bronchiectasis is a common respiratory disease with neutrophilic inflammation being the predominant pathophysiology. Systemic immune-inflammation index (SII) is a simple and readily available biomarker being studied in various conditions including asthma, chronic obstructive pulmonary disease, and interstitial lung disease, but not in bronchiectasis. We aim to investigate the prognostic role of SII in bronchiectasis with this study. Methods: A retrospective cohort study in Chinese patients with non-cystic fibrosis (CF) bronchiectasis was conducted in Hong Kong, to investigate the association between baseline SII and of hospitalized bronchiectasis exacerbation risk over 4.5 years of follow-up, as well as correlating with disease severity in bronchiectasis. The baseline SII in 2018 was calculated based on stable-state complete blood count. Results: Among 473 Chinese patients with non-CF bronchiectasis were recruited, 94 of the patients had hospitalized bronchiectasis exacerbation during the follow-up period. Higher SII was associated with increased hospitalized bronchiectasis exacerbation risks with adjusted odds ratio (aOR) of 1.001 [95% confidence interval (CI): 1.000-1.001, P=0.003] for 1 unit (cells/µL) increase in SII count and aOR of 1.403 (95% CI: 1.126-1.748, P=0.003) for 1 standard deviation (SD) increase in SII. SII was found to have significant negative association with baseline forced expiratory volume in the first second (FEV1) (in litre and percentage predicted), forced vital capacity (FVC) in percentage; and significant positive correlation with the extent of bronchiectasis and baseline neutrophil to lymphocyte ratio (NLR). Conclusions: SII could serve as biomarker to predict the risks of hospitalized exacerbation in bronchiectasis patients, as well as correlating with the disease severity.

13.
Animals (Basel) ; 14(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38891682

RESUMO

Crytosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi are important diarrheal pathogens with a global distribution that threatens the health of humans and animals. Despite cattle being potential transmission hosts of these protozoans, the associated risks to public health have been neglected. In the present study, a total of 1155 cattle fecal samples were collected from 13 administrative regions of Heilongjiang Province. The prevalence of Cryptosporidium spp., G. duodenalis, and E. bieneusi were 5.5% (64/1155; 95% CI: 4.2-6.9), 3.8% (44/1155; 95% CI: 2.7-4.9), and 6.5% (75/1155; 95% CI: 5.1-7.9), respectively. Among these positive fecal samples, five Cryptosporidium species (C. andersoni, C. bovis, C. ryanae, C. parvum, and C. occultus), two G. duodenalis assemblages (E and A), and eight E. bieneusi genotypes (BEB4, BEB6, BEB8, J, I, CHS7, CHS8, and COS-I) were identified. Phylogenetic analysis showed that all eight genotypes of E. bieneusi identified in the present study belonged to group 2. It is worth noting that some species/genotypes of these intestinal protozoans are zoonotic, suggesting a risk of zoonotic disease transmission in endemic areas. The findings expanded our understanding of the genetic composition and zoonotic potential of Cryptosporidium spp., G. duodenalis, and E. bieneusi in cattle in Heilongjiang Province.

14.
Sci Rep ; 14(1): 13881, 2024 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-38880813

RESUMO

While studies have suggested increased risks of severe COVID-19 infection in chronic obstructive pulmonary disease (COPD), the persistent and delayed consequences of COVID-19 infection on patients with COPD upon recovery remain unknown. A prospective clinical study was conducted in Hong Kong to investigate the persistent and delayed outcomes of patients with COPD who had COVID-19 infection of different severity (mild-moderate COVID-19 and severe COVID-19), compared with those who did not. Chinese patients with COPD ≥ 40 years old were recruited from March to September 2021. They were prospectively followed up for 24.9 ± 5.0 months until 31st August 2023. The primary outcome was the deterioration in COPD control defined as the change in mMRC dyspnea scale. The secondary outcomes included the change in exacerbation frequency and non-COVID-19 respiratory mortality (including death from COPD exacerbation or bacterial pneumonia). 328 patients were included in the analysis. Patients with mild-moderate and severe COVID-19 infection had statistically significant increased risks of worsening of mMRC dyspnoea scale by increase in 1 score from baseline to follow-up with adjusted odds ratios of 4.44 (95% CI = 1.95-10.15, p < 0.001) and 6.77 (95% CI = 2.08-22.00, p = 0.001) respectively. Patients with severe COVID-19 infection had significantly increased risks of increase in severe COPD exacerbation frequency with adjusted odds ratios of 4.73 (95% CI = 1.55-14.41, p = 0.006) non-COVID-19 respiratory mortality from COPD exacerbation or pneumonia with adjusted hazard ratio of 11.25 (95% CI = 2.98-42.45, p < 0.001). After recovery from COVID-19, worsening of COPD control from worsening of dyspnea, increase in severe exacerbation frequency to non-COVID-19 respiratory mortality (COPD exacerbation and pneumonia) was observed among patients with severe COVID-19. Mild to moderate COVID-19 was also associated with symptomatic deterioration.


Assuntos
COVID-19 , Doença Pulmonar Obstrutiva Crônica , Índice de Gravidade de Doença , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/mortalidade , COVID-19/mortalidade , COVID-19/complicações , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos Prospectivos , Hong Kong/epidemiologia , SARS-CoV-2/isolamento & purificação , Dispneia , Progressão da Doença
15.
Ying Yong Sheng Tai Xue Bao ; 35(4): 1092-1100, 2024 Apr 18.
Artigo em Chinês | MEDLINE | ID: mdl-38884244

RESUMO

To explore the influence of climate change and human activities on grassland phenology in Anhui Pro-vince, and quantify the contribution rate of climate change and human activities to phenology, we extracted the phenology of grassland, including the start of growing season (SOS) and the end of growing season (EOS), based on the normalized difference vegetation index (NDVI) dataset of Anhui Province from 2003 to 2020. The temporal and spatial characteristics and future evolution trends of phenological changes were analyzed using slope trend ana-lysis, Mann-Kendall non-parametric test, and Hurst index. We further conducted correlation analysis and residual analysis based on the datasets of mean annual temperature and mean annual precipitation to explore the responses of phenology to climate change and human activities, and quantify their contribution rate. The results showed that SOS and EOS showed an advancing trend with a rate of 0.8 and 0.7 days per year from 2003 to 2020. SOS in the sou-thern part of the study area was significantly earlier than in the central and northern regions, while EOS gradually advanced from south to north. Both SOS and EOS in the future showed an advancing trend. SOS was negatively correlated with annual average temperature, while positively correlated with annual precipitation. EOS was negatively correlated with both annual average temperature and annual precipitation. The proportion of the area where SOS was advanced driven by both climate change and human activities was 56.9%, and the value was 48.3% for EOS. Human activities were the main driving factor for phenology, and climate change was the secondary driving factor. The relative contributions of human activities and climate change to SOS were 66.4% and 33.6%, and to EOS were 61.2% and 38.8%, respectively. Human activities had stronger impact on SOS and EOS than climate change, resulting in earlier phenology.


Assuntos
Mudança Climática , Pradaria , Atividades Humanas , China , Estações do Ano , Humanos , Ecossistema , Poaceae/crescimento & desenvolvimento
16.
Mitochondrion ; 78: 101918, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38871013

RESUMO

Alzheimer's disease (AD) is currently one of the most serious public health concerns in the world. However, the best approach to treat AD has yet to be discovered, implying that we must continue to work hard to find new AD target genes. In this study, we further analysed Gene Expression Omnibus (GEO) data and discovered that the expression of the Mitochondria glutamate carrier SLC25A18 is associated with AD by screening the differentially expressed genes in different regions of the brains of Alzheimer's disease patients. To verify the expression of SLC25A18 during Alzheimer's disease development, we analysed animal models (5×FAD transgenic AD animal model, chemically induced AD animal model, natural ageing animal model), and the results showed that the expression of SLC25A18 was increased in animal models of AD. Further investigation of the different regions found that SLC25A18 expression was elevated in the EC, TeA, and CA3, and expressed in neurons. Next, We found that Aß42 treatment elevated SLC25A18 expression in Neuro 2A cells. Reducing SLC25A18 expression attenuated mitochondrial dysfunction and neuronal apoptosis caused by Aß42. Overexpression of SLC25A18 increased ATP and intracellular superoxide anions but decreased mitochondrial membrane potential. The results indicate that SLC25A18 affects mitochondrial function and neuronal apoptosis, and is related to AD, which makes it a potential target for treating brain dysfunction.

17.
Chem Pharm Bull (Tokyo) ; 72(6): 584-595, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38945947

RESUMO

In order to introduce a cost-effective strategy method for commercial scale dry granulation at the early clinical stage of drug product development, we developed dry granulation process using formulation without API, fitted and optimized the process parameters adopted Design of Experiment (DOE). Then, the process parameters were confirmed using one formulation containing active pharmaceutical ingredient (API). The results showed that the roller pressure had significant effect on particle ratio (retained up to #60 mesh screen), bulk density and tapped density. The roller gap had significant influence on particle ratio and specific energy. The particle ratio was significantly affected by the mill speed (second level). The tabletability of the powder decreased after dry granulation. The effect of magnesium stearate on the tabletability was significant. In the process validation study, the properties of the prepared granules met the requirements for each response studied in the DOE. The prepared tablets showed higher tensile strength, good content uniformity of filled capsules, and the dissolution profiles of which were consistent with that of clinical products. This drug product process development and research strategies could be used as a preliminary experiment for the dry granulation process in the early clinical stage.


Assuntos
Comprimidos , Comprimidos/química , Tamanho da Partícula , Composição de Medicamentos , Pós/química , Ácidos Esteáricos/química , Resistência à Tração , Excipientes/química , Solubilidade
18.
Front Biosci (Landmark Ed) ; 29(6): 233, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38940043

RESUMO

BACKGROUND: This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated by TIG1 in melanoma cells and its impact on cell growth. METHODS: The effects of TIG1 expression on cell viability and death were assessed using water-soluble tetrazolium 1 (WST-1) mitochondrial staining and lactate dehydrogenase release assays. RNA sequencing and Western blot analysis were employed to investigate the genes regulated by TIG1 in melanoma cells. Additionally, the correlation between TIG1 expression and its downstream genes was analyzed in a melanoma tissue array. RESULTS: TIG1 expression in melanoma cells was associated with decreased cell viability and increased cell death. RNA-sequencing (RNA-seq), quantitative reverse transcription PCR (reverse RT-QPCR), and immunoblots revealed that TIG1 expression induced the expression of Endoplasmic Reticulum (ER) stress response-related genes such as Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (HERPUD1), Binding immunoglobulin protein (BIP), and DNA damage-inducible transcript 3 (DDIT3). Furthermore, analysis of the melanoma tissue array revealed a positive correlation between TIG1 expression and the expression of HERPUD1, BIP, and DDIT3. Additionally, attenuation of the ER stress response in melanoma cells weakened the impact of TIG1 on cell growth. CONCLUSIONS: TIG1 expression effectively hinders the growth of melanoma cells. TIG1 induces the upregulation of ER stress response-related genes, leading to an increase in caspase-3 activity and subsequent cell death. These findings suggest that the ability of retinoic acid to prevent melanoma formation may be associated with the anticancer effect of TIG1.


Assuntos
Sobrevivência Celular , Estresse do Retículo Endoplasmático , Regulação Neoplásica da Expressão Gênica , Melanoma , Humanos , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Morte Celular/genética , Apoptose/genética , Apoptose/efeitos dos fármacos , Proliferação de Células/genética , Proliferação de Células/efeitos dos fármacos , Proteínas de Membrana
19.
Prog Brain Res ; 286: 235-258, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38876577

RESUMO

Physical activity is known for its positive effects on cognition and affect, with existing literature suggesting that these mental health benefits may be optimally experienced by incorporating cognitive and motor demands during physical activity (PA). However, the existing body of literature lacks a comprehensive guideline for designing the qualitative characteristics of a PA program. Accordingly, this narrative review aimed to (1) provide a working two-dimension model that operationally defines the cognitive and motor demands involved in PA and the rationale for systematically studying these qualitative aspects of PA, (2) identify methods to assess the cognitive and motor demands of PA and address associated methodological issues, and (3) offer potential future directions for research on the cognitive and motor aspects of PA in support of the development of PA programs designed to maximize PA-induced cognitive and affective benefits. We anticipate this article to inform the need for future research and development on this topic, aiming to create clear, evidence-based guidelines for designing innovative and effective PA interventions.


Assuntos
Cognição , Exercício Físico , Saúde Mental , Humanos , Cognição/fisiologia , Exercício Físico/fisiologia , Atividade Motora/fisiologia
20.
World J Clin Cases ; 12(16): 2789-2795, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38899280

RESUMO

BACKGROUND: Vitamin deficiencies are linked to various eye diseases, and the influence of vitamin D on cataract formation has been noted in prior research. However, detailed investigations into the causal relationship between 25-(OH)D status and cataract development remain scarce. AIM: To explore a possible causal link between cataracts and vitamin D. METHODS: In this study, we explored the causal link between 25-(OH)D levels and cataract development using Mendelian randomization. Our analytical approach included inverse-variance weighting (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. The primary analyses utilized IVW with random effects, supplemented by sensitivity and heterogeneity tests using both IVW and MR-Egger. MR-Egger was also applied for pleiotropy testing. Additionally, a leave-one-out analysis helped identify potentially impactful single-nucleotide polymorphisms. RESULTS: The analysis revealed a positive association between 25-(OH)D levels and the risk of developing cataracts (OR = 1.11, 95%CI: 1.00-1.22; P = 0.032). The heterogeneity test revealed that our IVW analysis exhibited minimal heterogeneity (P > 0.05), and the pleiotropy test findings confirmed the absence of pleiotropy within our IVW analysis (P > 0.05). Furthermore, a search of the human genotype-phenotype association database failed to identify any potentially relevant risk-factor single nucleotide polymorphisms. CONCLUSION: There is a potential causal link between 25-(OH)D levels and the development of cataracts, suggesting that greater 25-(OH)D levels may be a contributing risk factor for cataract formation. Further experimental research is required to confirm these findings.

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