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1.
Front Immunol ; 15: 1406409, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994358

RESUMO

Objective: There have been reports of neuromyelitis optica spectrum disorder (NMOSD) coexisting with connective tissue disorders. The objective of this study was to describe the characteristics of NMOSD coexisting with autoimmune diseases (AID). Methods: This retrospective study evaluated NMOSD patients with and without AID. The enrolled patients had at least one attack, with duration of more than 1 year. Data on the demographics, clinical features, and laboratory findings were assessed. The Poisson model was used to investigate the risk factors associated with the annualized relapse rate (ARR), whereas the Cox model was used to evaluate the risk factors for the first relapse. Results: A total of 180 patients (154 women and 26 men) with NMOSD were identified: 45 had AID and 135 did not. Female patients had a higher prevalence of concomitant AID (p = 0.006) and a greater relapse rate within the first year. There were no statistically significant differences in the characteristics of patients. Kaplan-Meier analysis revealed that NMOSD patients with seropositive aquaporin 4 antibodies (AQP4-Ab; log-rank: p = 0.044), had a shorter time to relapse. Patients seropositive for AQP4-Ab (HR = 2.402, 95%CI = 1.092-5.283, p = 0.029) had a higher risk of suffering a first relapse, according to the Cox model. Patients with and without AID showed a similar declining tendency in terms of change in ARR throughout the first 5 years of the disease. The ARR was greater in the first year [incidence rate ratio (IRR) = 1.534, 95%CI = 1.111-2.118] and the first 2 years (IRR = 1.474, 95%CI = 1.056-2.058) in patients with coexisting AID diagnosis prior to the NMOSD onset. Conclusions: Patients with NMOSD with coexisting AID had similar characteristics when compared with those without AID. NMOSD patients with AID diagnosed before onset had a higher risk of relapse in the early stage of the disease.


Assuntos
Aquaporina 4 , Doenças Autoimunes , Neuromielite Óptica , Recidiva , Humanos , Neuromielite Óptica/epidemiologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/diagnóstico , Feminino , Masculino , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/complicações , Aquaporina 4/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Fatores de Risco , Idoso , Adulto Jovem
2.
PeerJ ; 12: e17706, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006021

RESUMO

Objectives: To evaluate the efficacy of peri-trigger female reproductive hormones (FRHs) in the prediction of oocyte maturation in normal ovarian reserve patients during the in vitro fertilization-embryo transfer (IVF-ET) procedure. Materials and Methods: A hospital database was used to extract data on IVF-ET cases from January 2020 to September 2021. The levels of female reproductive hormones, including estradiol (E2), luteinizing hormone (LH), progesterone (P), and follicle-stimulating hormone (FSH), were initially evaluated at baseline, the day of the trigger, the day after the trigger, and the day of oocyte retrieval. The relative change in E2, LH, P, FSH between time point 1 (the day of trigger and baseline) and time point 2 (the day after the trigger and day on the trigger) was defined as E2_RoV1/2, LH_RoV1/2, P_RoV1/2, and FSH_RoV1/2, respectively. Univariable and multivariable regression were performed to screen the peri-trigger FRHs for the prediction of oocyte maturation. Results: A total of 118 patients were enrolled in our study. Univariable analysis revealed significant associations between E2_RoV1 and the rate of MII oocytes in the GnRH-agonist protocol group (p < 0.05), but not in the GnRH-antagonist protocol group. Conversely, P_RoV2 emerged as a potential predictor for the rate of MII oocytes in both protocol groups (p < 0.05). Multivariable analysis confirmed the significance of P_RoV2 in predicting oocyte maturation rate in both groups (p < 0.05), while the association of E2_RoV1 was not significant in either group. However, within the subgroup of high P_RoV2 in the GnRH-agonist protocol group, association was not observed to be significant. The C-index was 0.83 (95% CI [0.73-0.92]) for the GnRH-agonist protocol group and 0.77 (95% CI [0.63-0.90]) for the GnRH-antagonist protocol group. The ROC curve analysis further supported the satisfactory performance of the models, with area under the curve (AUC) values of 0.79 for the GnRH-agonist protocol group and 0.81 for the GnRH-antagonist protocol group. Conclusions: P_RoV2 showed significant predictive value for oocyte maturation in both GnRH-agonist and GnRH-antagonist protocol groups, which enhances the understanding of evaluating oocyte maturation and inform individualized treatment protocols in controlled ovarian hyperstimulation during IVF-ET for normal ovarian reserve patients.


Assuntos
Transferência Embrionária , Estradiol , Fertilização in vitro , Hormônio Foliculoestimulante , Hormônio Luteinizante , Reserva Ovariana , Indução da Ovulação , Progesterona , Humanos , Feminino , Adulto , Estudos Retrospectivos , Fertilização in vitro/métodos , Reserva Ovariana/efeitos dos fármacos , Reserva Ovariana/fisiologia , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Transferência Embrionária/métodos , Progesterona/sangue , Indução da Ovulação/métodos , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Gravidez , Oogênese/efeitos dos fármacos , Oogênese/fisiologia , Recuperação de Oócitos/métodos
3.
Lancet Planet Health ; 8(7): e463-e475, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38969474

RESUMO

BACKGROUND: Nipah virus is a zoonotic paramyxovirus responsible for disease outbreaks with high fatality rates in south and southeast Asia. However, knowledge of the potential geographical extent and risk patterns of the virus is poor. We aimed to establish an integrated spatiotemporal and phylogenetic database of Nipah virus infections in humans and animals across south and southeast Asia. METHODS: In this geospatial modelling analysis, we developed an integrated database containing information on the distribution of Nipah virus infections in humans and animals from 1998 to 2021. We conducted phylodynamic analysis to examine the evolution and migration pathways of the virus and meta-analyses to estimate the adjusted case-fatality rate. We used two boosted regression tree models to identify the potential ecological drivers of Nipah virus occurrences in spillover events and endemic areas, and mapped potential risk areas for Nipah virus endemicity. FINDINGS: 749 people and eight bat species across nine countries were documented as being infected with Nipah virus. On the basis of 66 complete genomes of the virus, we identified two clades-the Bangladesh clade and the Malaysia clade-with the time of the most recent common ancestor estimated to be 1863. Adjusted case-fatality rates varied widely between countries and were higher for the Bangladesh clade than for the Malaysia clade. Multivariable meta-regression analysis revealed significant relationships between case-fatality rate estimates and viral clade (p=0·0021), source country (p=0·016), proportion of male patients (p=0·036), and travel time to health-care facilities (p=0·036). Temperature-related bioclimate variables and the probability of occurrence of Pteropus medius were important contributors to both the spillover and the endemic infection models. INTERPRETATION: The suitable niches for Nipah virus are more extensive than previously reported. Future surveillance efforts should focus on high-risk areas informed by updated projections. Specifically, intensifying zoonotic surveillance efforts, enhancing laboratory testing capacity, and implementing public health education in projected high-risk areas where no human cases have been reported to date will be crucial. Additionally, strengthening wildlife surveillance and investigating potential modes of transmission in regions with documented human cases is needed. FUNDING: The Key Research and Development Program of China.


Assuntos
Infecções por Henipavirus , Vírus Nipah , Vírus Nipah/fisiologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/transmissão , Humanos , Animais , Quirópteros/virologia , Sudeste Asiático/epidemiologia , Filogenia , Zoonoses/epidemiologia , Zoonoses/virologia
4.
iScience ; 27(7): 110025, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38974972

RESUMO

Drug repurposing is a promising approach to find new therapeutic indications for approved drugs. Many computational approaches have been proposed to prioritize candidate anticancer drugs by gene or pathway level. However, these methods neglect the changes in gene interactions at the edge level. To address the limitation, we develop a computational drug repurposing method (iEdgePathDDA) based on edge information and pathway topology. First, we identify drug-induced and disease-related edges (the changes in gene interactions) within pathways by using the Pearson correlation coefficient. Next, we calculate the inhibition score between drug-induced edges and disease-related edges. Finally, we prioritize drug candidates according to the inhibition score on all disease-related edges. Case studies show that our approach successfully identifies new drug-disease pairs based on CTD database. Compared to the state-of-the-art approaches, the results demonstrate our method has the superior performance in terms of five metrics across colorectal, breast, and lung cancer datasets.

5.
World J Gastrointest Surg ; 16(6): 1691-1699, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38983312

RESUMO

BACKGROUND: Given the current organ shortage crisis, split liver transplantation (SLT) has emerged as a promising alternative for select end-stage liver disease patients. AIM: To introduce an ex-vivo liver graft splitting approach and evaluate its safety and feasibility in SLT. METHODS: A retrospective analysis was conducted on the liver transplantation data from cases performed at our center between April 1, 2022, and May 31, 2023. The study included 25 SLT cases and 81 whole liver transplantation (WLT) cases. Total ex-vivo liver splitting was employed for SLT graft procurement in three steps. Patient outcomes were determined, including liver function parameters, postoperative complications, and perioperative mortality. Group comparisons for categorical variables were performed using the χ²-test. RESULTS: In the study, postoperative complications in the 25 SLT cases included hepatic artery thrombosis (n = 1) and pulmonary infections (n = 3), with no perioperative mortality. In contrast, among the 81 patients who underwent WLT, complications included perioperative mortality (n = 1), postoperative pulmonary infections (n = 8), abdominal infection (n = 1), hepatic artery thromboses (n = 3), portal vein thrombosis (n = 1), and intra-abdominal bleeding (n = 5). Comparative analysis demonstrated significant differences in alanine aminotransferase (176.0 vs 73.5, P = 0.000) and aspartate aminotransferase (AST) (42.0 vs 29.0, P = 0.004) at 1 wk postoperatively, and in total bilirubin (11.8 vs 20.8, P = 0.003) and AST (41.5 vs 26.0, P = 0.014) at 2 wk postoperatively. However, the overall incidence of complications was comparable between the two groups (P > 0.05). CONCLUSION: Our findings suggest that the total ex-vivo liver graft splitting technique is a safe and feasible approach, especially under the expertise of an experienced transplant center. The approach developed by our center can serve as a valuable reference for other transplantation centers.

6.
Zhongguo Zhong Yao Za Zhi ; 49(13): 3441-3451, 2024 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-39041116

RESUMO

Type 2 diabetes(T2DM) is a metabolic disorder marked by glucose toxicity, lipotoxicity, insulin resistance, and other pathological manifestations, representing a pressing global health concern. Obesity stands out as a pivotal risk factor for T2DM development. When combined with T2DM, obesity exacerbates insulin resistance and metabolic abnormalities. The disturbance in the inflammatory microenvironmental balance between adipose and pancreatic islet tissue emerges as a significant contributor to obese with T2DM development. Macrophages play a crucial role in maintaining immune homeostasis and responding to inflammation in adipose and pancreatic islet tissue. Individuals with obese with T2DM exhibit an imbalanced M1/M2 macrophage polarization, contributing to the progression of glycolipid metabolism abnormalities. Hence, restoring the equilibrium of macrophage polarization becomes imperative for obese with T2DM treatment. Scientific researchers have demonstrated that traditional Chinese medicine(TCM) therapies can effectively modulate macrophage polarization, offering a viable approach for treating obese with T2DM. In light of the existing evidence, this study systematically reviewed the research progress of TCM targeting the balance of M1/M2 macrophage polarization to ameliorate obese with T2DM, so as to furnish evidence supporting the clinical diagnosis and treatment of obese with T2DM with TCM while also contributing to the exploration of the biological basis of obese with T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Medicamentos de Ervas Chinesas , Macrófagos , Obesidade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/complicações , Obesidade/tratamento farmacológico , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/complicações , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Animais , Medicina Tradicional Chinesa
7.
Artigo em Inglês | MEDLINE | ID: mdl-39034205

RESUMO

BACKGROUND: Access to health care is an important factor affecting survival of patients with multiple myeloma (MM) in the U.S. general population. The U.S. Military Health System (MHS) provides universal health care to beneficiaries and has been associated with improved survival across multiple malignancies. In this study, we compared survival of MHS beneficiaries with MM with MM patients from the U.S. general population. MATERIALS AND METHODS: The Department of Defense's Automated Central Tumor Registry (ACTUR) and the Surveillance, Epidemiology and End Results (SEER) databases were used to extract data for MM patients from MHS and the U.S. general population, respectively. Patients had histologically confirmed MM between 1987 and 2013 and were followed through 2015 for overall survival. Two SEER patients were matched to each ACTUR patient by age group, sex, race, and diagnosis year group. Five and 10-year survival was compared between ACTUR and SEER patients to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) with adjustment for potential confounders. RESULTS: Median survival of the ACTUR patients was 47.1 months (95% CI: 43.9-50.4) compared to 33.0 months (95% CI, 32.0-35.0) of the SEER patients. Five and 10-year death rates were significantly lower for ACTUR patients than the SEER patients with an adjusted HR of 0.74 (95% CI, 0.68-0.81) and 0.79 (95% CI, 0.74-0.85), respectively. The survival advantage of ACTUR patients was preserved when stratified by age, sex, race, and diagnosis year. CONCLUSION: MHS beneficiaries with MM had improved overall survival compared to MM patients from the U.S. general population.

9.
Front Immunol ; 15: 1375013, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39040110

RESUMO

Introduction: Immunotherapy is critical for treating many cancers, and its therapeutic success is linked to the tumor microenvironment. Although anti-angiogenic drugs are used to treat gastric cancer (GC), their efficacy remains limited. Cancer-associated fibroblast (CAF)-targeted therapies complement immunotherapy; however, the lack of CAF-specific markers poses a challenge. Therefore, we developed a CAF angiogenesis prognostic score (CAPS) system to evaluate prognosis and immunotherapy response in patients with GC, aiming to improve patient stratification and treatment efficacy. Methods: We assessed patient-derived GC CAFs for promoting angiogenesis using EdU, cell cycle, apoptosis, wound healing, and angiogenesis analysis. Results: We then identified CAF-angiogenesis-associated differentially-expressed genes, leading to the development of CAPS, which included THBS1, SPARC, EDNRA, and VCAN. We used RT-qPCR to conduct gene-level validation, and eight GEO datasets and the HPA database to validate the CAPS system at the gene and protein levels. Six independent GEO datasets were utilized for validation. Overall survival time was shorter in the high- than the low-CAPS group. Immune microenvironment and immunotherapy response analysis showed that the high-CAPS group had a greater tendency toward immune escape and reduced immunotherapy efficacy than the low-CAPS group. Discussion: CAPS is closely associated with GC prognosis and immunotherapy outcomes. It is therefore an independent predictor of GC prognosis and immunotherapy efficacy.


Assuntos
Fibroblastos Associados a Câncer , Imunoterapia , Neovascularização Patológica , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Neoplasias Gástricas/terapia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/imunologia , Microambiente Tumoral/imunologia , Prognóstico , Imunoterapia/métodos , Neovascularização Patológica/imunologia , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Biomarcadores Tumorais
10.
Diabetes Obes Metab ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38962934

RESUMO

AIM: To investigate the associations of body mass index (BMI), waist circumference (WC) and the weight-adjusted waist index (WWI) with the impairment of activities of daily living (ADL) in older Chinese people. METHODS: A total of 13 260 participants aged 65 years and older from the 2018 Chinese Longitudinal Healthy Longevity Survey were included in this cross-sectional study. BMI, WC and the WWI were calculated from measurements of height, weight and WC. Binary logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Non-linear correlations were investigated using restricted cubic spline curves. RESULTS: In multivariate logistic regression fully adjusted for confounding variables, our analyses revealed significant associations between WC and WWI and ADL impairment, with adjusted ORs (95% CI) of 1.01 (1.00, 1.01) and 1.08 (1.03, 1.12), respectively. Meanwhile, participants with a high WWI had a higher risk of ADL impairment compared with those with a low WWI, with an adjusted OR (95% CI) of 1.12 (1.02, 1.23). Subgroup analyses showed that only the association between WWI and ADL impairment did not differ in any of the different populations. In addition, we found that BMI, WC and WWI were non-linearly associated with ADL impairment. CONCLUSIONS: There are significant associations between WC and WWI and ADL impairment in older Chinese people. The findings show the ability of the WWI to serve as a comprehensive and effective indicator of obesity in older Chinese people and emphasize the importance of assessing WWI in screening and preventing ADL impairment in older people.

11.
Front Pharmacol ; 15: 1355269, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38962317

RESUMO

Gastric cancer, the fifth most prevalent cancer worldwide, is often diagnosed in advanced stages with limited treatment options. Examining the tumor microenvironment (TME) and its metabolic reprogramming can provide insights for better diagnosis and treatment. This study investigates the link between TME factors and metabolic activity in gastric cancer using bulk and single-cell RNA-sequencing data. We identified two molecular subtypes in gastric cancer by analyzing the distinct expression patterns of 81 prognostic genes related to the TME and metabolism, which exhibited significant protein-level interactions. The high-risk subtype had increased stromal content, fibroblast and M2 macrophage infiltration, elevated glycosaminoglycans/glycosphingolipids biosynthesis, and fat metabolism, along with advanced clinicopathological features. It also exhibited low mutation rates and microsatellite instability, associating it with the mesenchymal phenotype. In contrast, the low-risk group showed higher tumor content and upregulated protein and sugar metabolism. We identified a 15-gene prognostic signature representing these characteristics, including CPVL, KYNU, CD36, and GPX3, strongly correlated with M2 macrophages, validated through single-cell analysis and an internal cohort. Despite resistance to immunotherapy, the high-risk group showed sensitivity to molecular targeted agents directed at IGF-1R (BMS-754807) and the PI3K-mTOR pathways (AZD8186, AZD8055). We experimentally validated these promising drugs for their inhibitory effects on MKN45 and MKN28 gastric cells. This study unveils the intricate interplay between TME and metabolic pathways in gastric cancer, offering potential for enhanced diagnosis, patient stratification, and personalized treatment. Understanding molecular features in each subtype enriches our comprehension of gastric cancer heterogeneity and potential therapeutic targets.

12.
Spectrochim Acta A Mol Biomol Spectrosc ; 321: 124686, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38950479

RESUMO

Neomycin sulfate (NEO) is a kind of aminoglycoside antibiotics. Because of its strong ototoxicity, nephrotoxicity and other side effects, its content in the body should be strictly monitored during use. In this paper, a rapid colorimetric detection method for NEO based on ultrasmall polyvinylpyrrolidone modified gold nanoparticles (PVP/Au NPs) with peroxidase-like activity was developed. Firstly, ultra small PVP/Au NPs with weak peroxidase-like activity were synthetized. When they were mixed with NEO, strong hydrogen bonds were formed between NEO and PVP, resulting in the aggregation of PVP/Au NPs, and the aggregated PVP/Au NPs showed stronger peroxidase-like activity. Therefore, rapid colorimetric detection of NEO was achieved by utilizing the enhanced peroxidase-like activity mechanism caused by the aggregation of ultra small PVP/Au NPs. The naked eye detection limit of this method is 50 nM. Within the range of 1 nM-300 nM, there was a good linear relationship between NEO concentration and the change in absorbance intensity of PVP/Au NPs-H2O2-TMB solution at 652 nm, with the regression curve of y = 0.0045x + 0.0525 (R2 = 0.998), and the detection limit is 1 nM. In addition, this method was successfully applied to the detection of NEO in mouse serum. The recoveries were 104.4 % -107.6 % compared with HPLC assay results, indicating that this method for NEO detection based on PVP/Au NPs has great potential in actual detection of NEO in serum.

13.
Nanoscale ; 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39037336

RESUMO

Solid-state lithium batteries have advantages of high energy density and usage safety and are considered as promising next-generation power sources. Among them, the garnet-type oxide electrolyte has become a widely studied inorganic electrolyte due to its high ionic conductivity and chemical stability. In this paper, nanoscale Y2O3 (NYO) particles are introduced as sintering aids for fabricating Ta-doped Li7La3Zr2O12 (LLZTO) ceramics, and the sintering effects of various NYO ratios on the properties of LLZTO are investigated. Among the samples, the LLZTO-5%NYO sample exhibits the highest ionic conductivity (7.39 × 10-4 S cm-1) and the lowest activation energy (0.17 eV). At various current densities, the polarization voltage of LLZTO-5%NYO is also the lowest without a short circuit. The full cells of LFP|LLZTO-5%NYO|Li exhibit a high capacity of 163.9 mA h g-1 with a high initial coulombic efficiency of 97.4%, and the capacity retention rate is up to 98.1% after 50 cycles. This work may inspire the development of analogous solid-state electrolytes and lithium batteries.

14.
Inorg Chem ; 63(28): 13117-13126, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38946108

RESUMO

Constructing the plasmonic metal/semiconductor heterostructure with a suitable Schottky barrier height (SBH) and the sufficiently reliable active sites is of importance to achieve highly efficient and selective photocatalytic CO2 reduction into hydrocarbon fuels. Herein, we report Au/sulfur vacancy-rich ZnIn2S4 (Au/VSR-ZIS) hierarchical photocatalysts, fabricated via in situ photodepositing Au nanoparticles (NPs) onto the nanosheet self-assembled ZnIn2S4 (ZIS) micrometer flowers (MFs) with rich sulfur vacancies (VS). Density functional theory (DFT) calculations confirm that for the Au/VSR-ZIS system, the Au NPs serve as the reaction sites for H2O oxidation, and the VSR-ZIS MFs serve as those for CO2 reduction. The rich VS in the Au/VSR-ZIS hybrid can reduce its SBH so as to boost more hot electrons in the Au NPs across its Schottky barrier and then inject into the conduction band (CB) of the VSR-ZIS MFs. In addition, VS can also act as the electron sink to trap the photogenerated electrons, retarding the recombination of photogenerated carriers. The two merits effectively enhance the photogenerated electron density in the surface of VSR-ZIS MFs, availing CO2 photoreduction. In addition, the introduction of rich VS in the Au/VSR-ZIS hybrid can offer more active sites, benefiting the CO2 adsorption and accelerating the desorption of CO* from the surface of the photocatalyst. Therefore, under visible light illumination with no sacrificial reagent, the optimum photocatalyst (Au/VSR-ZIS-0.4) presents the enhanced and selective CO2 photoreduction into CO (8.15 µmol g-1h-1 and near 100%), which are superior to those of most of ZIS-based and plasmon-based photocatalysts. The photocatalytic activity is about 40.0-fold as high as that of the Vs-poor-ZIS (VSP-ZIS) MFs. This work contributes a viable strategy for designing highly efficient plasmonic photocatalysts by using the synergism of the anion vacancies and the optimized SBH induced by them.

15.
Bioorg Chem ; 150: 107584, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38964146

RESUMO

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Cinamatos , Triazóis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Cinamatos/química , Cinamatos/farmacologia , Cinamatos/síntese química , Humanos , Camundongos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Relação Estrutura-Atividade , Estrutura Molecular , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Relação Dose-Resposta a Droga , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Descoberta de Drogas , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Masculino
16.
Artigo em Inglês | MEDLINE | ID: mdl-39011845

RESUMO

OBJECTIVES: To establish the epidemiology cut-off (ECOFF) values of eravacycline against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus, from a multi-centre study in China. METHODS: We collected 2500 clinical isolates from five hospitals in China from 2017 to 2020. The MICs of eravacycline were determined using broth microdilution. The ECOFF values of eravacycline against the five species commonly causing cIAIs were calculated using visual estimation and ECOFFinder following the EUCAST guideline. RESULTS: The MICs of eravacycline against all the strains were in the range of 0.004-16 mg/L. The ECOFF values of eravacycline were 0.5 mg/L for E. coli, 2 mg/L for K. pneumonia and E. cloacae, and 0.25 mg/L for A. baumannii and S. aureus, consistent with the newest EUCAST publication of eravacycline ECOFF values for the populations. No discrepancy was found between the visually estimated and 99.00% ECOFF values calculated using ECOFFinder. CONCLUSIONS: The determined ECOFF values of eravacycline against the five species can assist in distinguishing wild-type from non-wild-type strains. Given its promising activity, eravacycline may represent a member of the tetracycline class in treating cIAIs caused by commonly encountered Gram-negative and Gram-positive pathogens.

17.
Tissue Eng Regen Med ; 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38842768

RESUMO

BACKGROUND: The therapeutic potential of exosomes from human umbilical cord mesenchymal stem cells (HUMSCs-Exo) for delivering specific circular RNAs (circRNAs) in treating premature ovarian failure (POF) is not well understood. This study aimed to explore the efficacy of HUMSCs-Exo in delivering hsa_circ_0002021 for POF treatment, focusing on its effects on granulosa cell (GC) senescence and ovarian function. METHODS: Bioinformatic analysis was conducted on circRNA profiles using the GSE97193 dataset from GEO, targeting granulosa cells from varied age groups. To simulate granulosa cell senescence, KGN cells were treated with cyclophosphamide (CTX). HUMSCs were transfected with pcDNA 3.1 vectors to overexpress hsa_circ_0002021, and the HUMSCs-Exo secreted were isolated. These exosomes were characterized by transmission electron microscopy (TEM) and Western blotting to confirm exosomal markers CD9 and CD63. Co-culture of these exosomes with CTX-treated KGN cells was performed to assess ß-galactosidase activity, oxidative stress markers, ROS levels, and apoptosis via flow cytometry. Interaction between hsa_circ_0002021, microRNA-125a-5p (miR-125a-5p), and cyclin-dependent kinase 6 (CDK6) was investigated using dual-luciferase assays and RNA immunoprecipitation (RIP). A POF mouse model was induced with CTX, treated with HUMSCs-Exo, and analyzed histologically and via immunofluorescence staining. Gene expression was quantified using RT-qPCR and Western blot. RESULTS: hsa_circ_0002021 was under expressed in both in vivo and in vitro POF models and was effectively delivered by HUMSCs-Exo to KGN cells, showing a capability to reduce GC senescence. Overexpression of hsa_circ_0002021 in HUMSCs-Exo significantly enhanced these anti-senescence effects. This circRNA acts as a competitive adsorbent of miR-125a-5p, regulating CDK6 expression, which is crucial in modulating cell cycle and apoptosis. Enhanced expression of hsa_circ_0002021 in HUMSCs-Exo ameliorated GC senescence in vitro and improved ovarian function in POF models by modulating oxidative stress and cellular senescence markers. CONCLUSION: This study confirms that hsa_circ_0002021, when delivered through HUMSCs-Exo, can significantly mitigate GC senescence and restore ovarian function in POF models. These findings provide new insights into the molecular mechanisms of POF and highlight the therapeutic potential of circRNA-enriched exosomes in treating ovarian aging and dysfunction.

18.
Mil Med ; 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38836854

RESUMO

INTRODUCTION: It has been demonstrated that there was an increase in later-stage prostate cancer (PCa) at diagnosis after the U.S. Preventive Services Task Force recommended against prostate-specific antigen screening for prostate cancer. However, the cancer characteristics at diagnosis within the equal-access Military Health System (MHS) during the period have not been described. In this study, we compared PCa stage at diagnosis and its trends between the military health care system and the general public and further compared the trends in tumor stage by race. MATERIALS AND METHODS: This study was based on nonidentifiable data from the U.S. Department of Defense's Central Cancer Registry (CCR) and the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Patients diagnosed between 2004 and 2014 were included. The distributions of PCa stage at diagnosis over time were compared between the 2 populations. Comparisons were further conducted for White and Black patients, respectively. RESULTS: Among the 11,895 patients in the CCR and 544,142 patients in SEER, the majority of patients were diagnosed with stage I or II prostate cancer. However, the CCR had a larger proportion of early-stage tumors (stages I and II combined) with 84.3% vs. 80.0% of SEER patients. The proportion of late-stage tumors (stages III and IV combined) increased over time from 2008 for both populations and the proportion of early-stage tumors decreased for the general population. In terms of temporal distributions by race, the trends were the same between White and Black groups in the general population. In the MHS, the trends in the White patients were similar to those in the general population, but in the Black patients, the percentages of stages I and II at diagnosis continued to increase and those of stages III and IV decreased, differing from those in the general population. CONCLUSIONS: The MHS consistently diagnosed PCa at an earlier stage than the U.S. general population across all time periods evaluated in this study. Although similar trends were observed for White patients between both populations, the proportion of stages I and II at diagnosis increased from 2012 among Black patients in the MHS, which stands in sharp contrast to trends in the U.S. general population. Although the differences between the two populations may be associated with various factors, differences in accessibility to care and thus the use of prostate-specific antigen testing might play an important role.

19.
Hepatol Commun ; 8(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38934719

RESUMO

BACKGROUND: MASH is a common clinical disease that can lead to advanced liver conditions, but no approved pharmacotherapies are available due to an incomplete understanding of its pathogenesis. Damaged DNA binding protein 1 (DDB1) participates in lipid metabolism. Nevertheless, the function of DDB1 in MASH is unclear. METHODS: Clinical liver samples were obtained from patients with MASH and control individuals by liver biopsy. Hepatocyte-specific Ddb1-knockout mice and liver Hmgb1 knockdown mice were fed with a methionine-and choline-deficient diet to induce MASH. RESULTS: We found that the expression of DDB1 in the liver was significantly decreased in MASH models. Hepatocyte-specific ablation of DDB1 markedly alleviated methionine-and choline-deficient diet-induced liver steatosis but unexpectedly exacerbated inflammation and fibrosis. Mechanistically, DDB1 deficiency attenuated hepatic steatosis by downregulating the expression of lipid synthesis and uptake genes. We identified high-mobility group box 1 as a key candidate target for DDB1-mediated liver injury. DDB1 deficiency upregulated the expression and extracellular release of high-mobility group box 1, which further increased macrophage infiltration and activated HSCs, ultimately leading to the exacerbation of liver inflammation and fibrosis. CONCLUSIONS: These data demonstrate the independent regulation of hepatic steatosis and injury in MASH. These findings have considerable clinical implications for the development of therapeutic strategies for MASH.


Assuntos
Proteínas de Ligação a DNA , Fígado Gorduroso , Proteína HMGB1 , Hepatócitos , Cirrose Hepática , Camundongos Knockout , Animais , Camundongos , Hepatócitos/metabolismo , Hepatócitos/patologia , Cirrose Hepática/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Proteínas de Ligação a DNA/genética , Humanos , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Fígado Gorduroso/patologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/genética , Masculino , Deficiência de Colina/complicações , Modelos Animais de Doenças , Metionina/deficiência , Fígado/patologia , Fígado/metabolismo , Metabolismo dos Lipídeos
20.
Mater Today Bio ; 26: 101106, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38883421

RESUMO

Breaking the poor permeability of immune checkpoint inhibitors (ICIs) caused by the stromal barrier and reversing the immunosuppressive microenvironment are significant challenges in pancreatic cancer immunotherapy. In this study, we synthesized core-shell Fe3O4@TiO2 nanoparticles to act as carriers for loading VISTA monoclonal antibodies to form Fe3O4@TiO2@VISTAmAb (FTV). The nanoparticles are designed to target the overexpressed ICIs VISTA in pancreatic cancer, aiming to improve magnetic resonance imaging-guided sonodynamic therapy (SDT)-facilitated immunotherapy. Laser confocal microscopy and flow cytometry results demonstrate that FTV nanoparticles are specifically recognized and phagocytosed by Panc-2 cells. In vivo experiments reveal that ultrasound-triggered TiO2 SDT can induce tumor immunogenic cell death (ICD) and recruit T-cell infiltration within the tumor microenvironment by releasing damage-associated molecular patterns (DAMPs). Furthermore, ultrasound loosens the dense fibrous stroma surrounding the pancreatic tumor and increases vascular density, facilitating immune therapeutic efficiency. In summary, our study demonstrates that FTV nanoparticles hold great promise for synergistic SDT and immunotherapy in pancreatic cancer.

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