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1.
Phytomedicine ; 133: 155885, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39096544

RESUMO

BACKGROUND: Endothelial dysfunction (ED), characterized by markedly reduced nitric oxide (NO) bioavailability, vasoconstriction, and a shift toward a proinflammatory and prothrombotic state, is an important contributor to hypertension, atherosclerosis, and other cardiovascular diseases. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is widely involved in cardiovascular development. Przewaquinone A (PA), a lipophilic diterpene quinone extracted from Salvia przewalskii Maxim, inhibits vascular contraction. PURPOSE: Herein, the goal was to explore the protective effect of PA on ED in vivo and in vitro, as well as the underlying mechanisms. METHODS: A human umbilical vein endothelial cell (HUVEC) model of ED induced by angiotensin II (AngII) was used for in vitro observations. Levels of AMPK, endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO), and endothelin-1 (ET-1) were detected by western blotting and ELISA. A mouse model of hypertension was established by continuous infusion of AngII (1000 ng/kg/min) for 4 weeks using osmotic pumps. Following PA and/or valsartan administration, NO and ET-1 levels were measured. The levels of AMPK signaling-related proteins in the thoracic aorta were evaluated by immunohistochemistry. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured using the tail cuff method. Isolated aortic vascular tone measurements were used to evaluate the vasodilatory function in mice. Molecular docking, molecular dynamics, and surface plasmon resonance imaging (SPRi) were used to confirm AMPK and PA interactions. RESULTS: PA inhibited AngII-induced vasoconstriction and vascular adhesion as well as activated AMPK signaling in a dose-dependent manner. Moreover, PA markedly suppressed blood pressure, activated vasodilation in mice following AngII stimulation, and promoted the activation of AMPK signaling. Furthermore, molecular simulations and SPRi revealed that PA directly targeted AMPK. AMPK inhibition partly abolished the protective effects of PA against endothelial dysfunction. CONCLUSION: PA activates AMPK and ameliorates endothelial dysfunction during hypertension.

2.
Poult Sci ; 103(10): 104064, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-39106704

RESUMO

Coccidiosis, caused by a protozoan parasite of the genus Eimeria, is one of the most severe contagious parasite diseases affecting the poultry industry worldwide. Using phytogenics to prevent chicken coccidiosis is a strategy aimed at combating the increasing issue of drug-resistant strains of Eimeria spp. This study demonstrates the anticoccidial activities of a medicinal herb, Trifolium pratense (TP) powder, and its ethanolic extract (designated TPE) against Eimeria spp. TPE exhibited significant suppressive activity against E. maxima oocyst sporulation and E. tenella sporozoite invasion and reproduction in Madin-Darby bovine kidney cells. Furthermore, administration of basal chicken diets containing TP powder or TPE to Eimeria-infected chickens significantly reduced the output of oocysts and severity of intestinal lesions. Dietary supplementation with TP significantly improved relative weight gain in E. tenella- and E. acervulina-infected chickens, while there was no significant improvement in E. maxima-infected chickens. The anticoccidial activities of TP and TPE on E. acervulina, E. tenella and E. maxima were further supported by anticoccidial index scores, which showed greater efficacy than those of amprolium, a commercial coccidiostat used in poultry. TP supplementation positively impacted the primary metabolism of chickens challenged with E. tenella or E. acervulina. The chemical fingerprints of TPE were established using liquid column chromatography; TPE contained 4 major compounds: ononin, sissotrin, formononetin, and biochanin A. In addition, various spectrometric methods were used to ensure the batch-to-batch consistency of TP/TPE. In conclusion, T. pratense is demonstrated to be a novel phytogenic supplement that can be used to control Eimeria-induced coccidiosis in chickens.

3.
J Neurovirol ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39158759

RESUMO

Herpes simplex virus-2 encephalitis (HSV2E) in immunocompetent adults is exceptionally rare, and the subsequent onset of autoimmune encephalitis after HSV2E is even less common. This report presents the inaugural Chinese case of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) induced by HSV2E, confirmed via metagenomic next-generation sequencing (mNGS). The patient demonstrated a favorable response to intravenous immunoglobulin (IVIG) monotherapy. This case emphasizes the importance of considering autoimmune encephalitis in patients exhibiting new or recurrent neurological symptoms after HSV2E recovery. Comprehensive mNGS and neuronal antibody testing are essential for timely diagnosis. Moreover, IVIG monotherapy can serve as an effective treatment for NMDARE induced by HSV2, providing a viable alternative, particularly when steroid therapy is contraindicated.

4.
Heliyon ; 10(15): e35165, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39161821

RESUMO

While resource bootstrapping is widely employed by novice entrepreneurs,and social identities and decision logic are studied as important antecedents of entrepreneurs' adoption of resource bootstrapping behaviors, both scholars and practitioners have but a hazy understanding on the configuration effect of entrepreneur's social identities and decision logic on resource bootstrapping behaviors. In this paper, we combined the necessary condition analysis (NCA) and fuzzy set qualitative comparative analysis (fsQCA) to explore the configuration effects of entrepreneur's social identity and decision logic on resource bootstrapping behaviors. Analysis of 411 questionnaire date acquired from novice entrepreneurs, we found that none of single antecedent condition of both the entrepreneur's social identity and decision logic constitute the necessary condition of novice entrepreneurs' high resource bootstrapping behaviors. We also found a substitutive relationship between Darwinian social identity and communitary social identity that will lead the novice entrepreneurs with high dual effectual-causal decision logic to choose high joint utilization bootstrapping, and a complementary relationship between the three social identities of novice entrepreneurs such that those with high dual effectual-causal decision logic prefer different resource bootstrapping behaviors because of different social identities.Furthermore, we found that the core and edge conditions in the decision logic play different roles in the resource bootstrapping behaviors of novice entrepreneurs, with the core decision logic conditions having a greater impact on the resource bootstrapping behaviors. These findings deepen our understanding of the causal complexity among entrepreneur's social identity, decision logic and resource bootstrapping behaviors. It also provides theoretical guidance for effective resource integration for novice entrepreneurs facing resource constraints.

5.
J Nanobiotechnology ; 22(1): 485, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138462

RESUMO

Nanozymes are promising antimicrobials, as they produce reactive oxygen species (ROS). However, the intrinsic lack of selectivity of ROS in distinguishing normal flora from pathogenic bacteria deprives nanozymes of the necessary selectivities of ideal antimicrobials. Herein, we exploit the physiological conditions of bacteria (high alkaline phosphatase (ALP) expression) using a novel CuO nanoparticle (NP) nanoenzyme system to initiate an ALP-activated ROS prodrug system for use in the on-demand precision killing of bacteria. The prodrug strategy involves using 2-phospho-L-ascorbic acid trisodium salt (AAP) that catalyzes the ALP in pathogenic bacteria to generate ascorbic acid (AA), which is converted by the CuO NPs, with intrinsic ascorbate oxidase- and peroxidase-like activities, to produce ROS. Notably, the prodrug system selectively kills Escherichia coli (pathogenic bacteria), with minimal influence on Staphylococcus hominis (non-pathogenic bacteria) due to their different levels of ALP expression. Compared to the CuO NPs/AA system, which generally depletes ROS during storage, CuO NPs/AAP exhibits a significantly higher stability without affecting its antibacterial activity. Furthermore, a rat model is used to indicate the applicability of the CuO NPs/AAP fibrin gel in wound disinfection in vivo with negligible side effects. This study reveals the therapeutic precision of this bifunctional tandem nanozyme platform against pathogenic bacteria in ALP-activated conditions.


Assuntos
Fosfatase Alcalina , Antibacterianos , Cobre , Desinfecção , Escherichia coli , Pró-Fármacos , Espécies Reativas de Oxigênio , Cobre/química , Cobre/farmacologia , Animais , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Fosfatase Alcalina/metabolismo , Ratos , Antibacterianos/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Desinfecção/métodos , Ácido Ascórbico/farmacologia , Ácido Ascórbico/química , Ácido Ascórbico/análogos & derivados , Nanopartículas Metálicas/química , Ratos Sprague-Dawley , Masculino
6.
Free Radic Biol Med ; 223: 357-368, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39127141

RESUMO

Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aß) transgenic nematodes by lowering endogenous FA levels and reducing Aß aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aß toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.

7.
BMC Public Health ; 24(1): 2259, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164696

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is a risk factor for cardiovascular disease (CVD), and CVD is a major challenge for cancer patients. This study aimed to investigate the prevalence and association of MetS and CVD among adult cancer patients. METHODS: This cross-sectional study included cancer patients aged > 18 years from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. The prevalence of MetS and CVD was calculated using weighted analysis. Multivariable logistic regression was used to assess the association between MetS and CVD. RESULTS: The study included 2658 adult cancer patients, of whom 1260 exhibited MetS and 636 had CVD. The weighted prevalence of MetS and CVD in cancer patients was 45.44%, and 19.23%, respectively. Multivariable logistic regression showed a 79% increased risk in higher CVD prevalence in cancer patients with MetS, with the OR (95% CI) of 1.79 (1.31, 2.44). Notably, obesity, elevated blood pressure (BP), high glucose, and low high density lipoprotein cholesterol (HDL-C) in the MetS components were significantly associated with higher CVD prevalence after adjusting for covariates. Moreover, the risk of CVD prevalence in cancer patients increased with more MetS components. Notably, MetS was more strongly linked to CVD in patients aged < 65 and women. CONCLUSIONS: Among adult cancer patients, over two-fifths (45.44%) were estimated to have MetS, while about one-fifth (19.23%) were considered to have CVD. Notably, obesity, elevated BP, high glucose, low HDL-C, and higher number of MetS components were found to be significantly associated with higher CVD prevalence among cancer adults. Cancer patients under 65 and women with MetS may be at increased risk of CVD.


Assuntos
Doenças Cardiovasculares , Síndrome Metabólica , Neoplasias , Inquéritos Nutricionais , Humanos , Feminino , Masculino , Síndrome Metabólica/epidemiologia , Neoplasias/epidemiologia , Neoplasias/complicações , Estudos Transversais , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Adulto , Prevalência , Idoso , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
8.
BMC Pediatr ; 24(1): 546, 2024 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-39182037

RESUMO

BACKGROUND: Fetal inflammatory response syndrome (FIRS) is a systemic inflammatory response caused by the activation of the fetal immune system. The serological diagnostic criterion for fetal inflammatory response syndrome is a cord blood interleukin-6 concentration that exceeds 11 pg/mL, while pathologic evidence indicates the presence of funisitis or chorionic vasculitis. It can affect all systems of the fetus. Alterations in patients' hematopoietic system are primarily reflected by changes in peripheral blood leukocyte and neutrophil counts. CASE PRESENTATION: We performed placental pathology to identify FIRS and showed two cases of neonatal leukemoid reaction caused by FIRS. These two babies' alterations in hematopoietic system resolves spontaneously with the inflammation relief, without specific interventions. During the 16­month and14- month follow­up period, their motor and intellectual development was normal. CONCLUSIONS: . Neonatal leukemoid reaction is a reactive disease characterized by abnormal blood parameters similar to those of leukemia, but not leukemia. It is an aberrant hematopoietic response that typically resolves spontaneously with cause relief without requiring specific interventions.


Assuntos
Reação Leucemoide , Síndrome de Resposta Inflamatória Sistêmica , Humanos , Reação Leucemoide/diagnóstico , Reação Leucemoide/sangue , Reação Leucemoide/etiologia , Feminino , Recém-Nascido , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/sangue , Gravidez , Recém-Nascido Prematuro , Masculino , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/sangue
9.
J Formos Med Assoc ; 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39147685

RESUMO

BACKGROUND/PURPOSE: Post-stroke dysphagia (PSD) is a common functional deficit after stroke. Temporal muscle thickness (TMT) had been proven to be an independent factor for PSD. However, the relationship between TMT and PSD based on quantitative swallowing kinematic analysis remains unexplored. We aimed to investigate the association between TMT and PSD using videofluoroscopic swallow study (VFSS). METHOD: We retrospectively recruited stroke patients from May 2015 to March 2020 in the tertiary referral hospital. A total of 83 patients with dysphagia met all the enrollment criteria and were included in the study. TMT was measured by non-contrast brain computed tomography (CT) images. Parameters of VFSS were obtained, including penetration-aspiration scale (PAS), oral transit time (OTT), pharyngeal transit time (PTT) and swallowing trigger time (STT) in four standardized barium formulas respectively. The association between TMT and variables of VFSS were analyzed by adjusted linear and logistic multivariate regression models. Subgroup analysis based on age, sex, and premorbid modified Rankin Scale (mRS) stratification was conducted. RESULTS: TMT was significantly correlated with gender and premorbid mRS as the confounders. Univariate regression showed smaller TMT (p = 0.010) and poorer premorbid mRS (p = 0.018) was associated with prolonged PTT of the thick formula; lesser TMT was associated with prolonged PTT of the paste formula (p = 0.037). Multivariate analyses after confounder-adjustment demonstrated TMT was an independent indicator for PTT in the thick formula (p = 0.028). CONCLUSIONS: TMT was associated with swallowing kinematic changes in patients diagnosed with PSD. TMT is an independent indicator for delayed pharyngeal stage in the thick standardized formula during deglutition in PSD patients.

10.
Dysphagia ; 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39066832

RESUMO

Spontaneous intracerebral hemorrhage (ICH) constitutes a significant portion of acute stroke incidents worldwide, often leading to post-stroke dysphagia (PSD), affecting 50-77% of survivors and worsening patient morbidity. This study aimed to identify predictive variables for PSD among patients with spontaneous ICH. A retrospective cohort study was conducted on adult patients with acute spontaneous ICH, confirmed by brain computed tomography, from June 2019 to June 2023. We analyzed demographic, neuroimaging, and stroke-specific characteristics and rehabilitation indicators. PSD was evaluated using nasogastric (NG) tube retention and the Functional Oral Intake Scale (FOIS) levels at 4 and 12 weeks post-ICH. Statistical analyses involved univariate and multivariate logistic regression to identify PSD predictors. A total of 310 ICH patients were included in the study. At 4 weeks, significant predictors for NG tube retention included 24-hour National Institute of Health Stroke Scale (NIHSS) scores, estimated glomerular filtration rate and sitting balance. At 12 weeks, hospital stay duration and ICH score were significant predictors for NG tube retention. Regarding the FOIS, significant predictors at 4 weeks included higher 24-hour NIHSS scores, compromised sitting balance, immobility-related complications, initial hematoma volume and intraventricular hemorrhages. At 12 weeks, older age and higher 24-hour NIHSS scores significantly predicted lower FOIS levels. Our findings demonstrate that PSD in ICH patients is influenced by a complex interplay of factors, including stroke severity, renal function, and physical impairment. The study highlights the importance of early neurological assessment, physical function, and comprehensive management in improving swallowing outcomes, emphasizing a multifaceted approach to enhancing outcomes for ICH survivors.

11.
BMC Plant Biol ; 24(1): 684, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39020284

RESUMO

Malus sieversii, commonly known as wild apples, represents a Tertiary relict plant species and serves as the progenitor of globally cultivated apple varieties. Unfortunately, wild apple populations are facing significant degradation in localized areas due to a myriad of factors. To gain a comprehensive understanding of the nutrient status and spatiotemporal variations of M. sieversii, green leaves were collected in May and July, and the fallen leaves were collected in October. The concentrations of leaf nitrogen (N), phosphorus (P), and potassium (K) were measured, and the stoichiometric ratios as well as nutrient resorption efficiencies were calculated. The study also explored the relative contributions of soil, topographic, and biotic factors to the variation in nutrient traits. The results indicate that as the growing period progressed, the concentrations of N and P in the leaves significantly decreased (P < 0.05), and the concentration of K in October was significantly lower than in May and July. Throughout plant growth, leaf N-P and N-K exhibited hyperallometric relationships, while P-K showed an isometric relationship. Resorption efficiency followed the order of N < P < K (P < 0.05), with all three ratios being less than 1; this indicates that the order of nutrient limitation is K > P > N. The resorption efficiencies were mainly regulated by nutrient concentrations in fallen leaves. A robust spatial dependence was observed in leaf nutrient concentrations during all periods (70.1-97.9% for structural variation), highlighting that structural variation, rather than random factors, dominated the spatial variation. Nutrient resorption efficiencies (NRE, PRE, and KRE) displayed moderate structural variation (30.2-66.8%). The spatial patterns of nutrient traits varied across growth periods, indicating they are influenced by multifactorial elements (in which, soil property showed the highest influence). In conclusion, wild apples manifested differentiated spatiotemporal variability and influencing factors across various leaf nutrient traits. These results provide crucial insights into the spatiotemporal patterns and influencing factors of leaf nutrient traits of M. sieversii at the permanent plot scale for the first time. This work is of great significance for the ecosystem restoration and sustainable management of degrading wild fruit forests.


Assuntos
Malus , Nitrogênio , Fósforo , Folhas de Planta , Potássio , Folhas de Planta/metabolismo , Malus/metabolismo , Malus/crescimento & desenvolvimento , Malus/fisiologia , China , Fósforo/metabolismo , Fósforo/análise , Nitrogênio/metabolismo , Potássio/metabolismo , Potássio/análise , Florestas , Nutrientes/metabolismo , Nutrientes/análise , Solo/química , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Análise Espaço-Temporal
12.
Metallomics ; 16(7)2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38955388

RESUMO

Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate was 63.0% (P < 0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays.


Assuntos
Antineoplásicos , Irídio , Mitocôndrias , Humanos , Irídio/química , Irídio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Animais , Células Hep G2 , Camundongos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Apoptose/efeitos dos fármacos , Oxiquinolina/farmacologia , Oxiquinolina/química , Oxiquinolina/análogos & derivados , Camundongos Endogâmicos BALB C , Mitofagia/efeitos dos fármacos , Camundongos Nus
14.
ERJ Open Res ; 10(4)2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38978550

RESUMO

The present study found that using viral filters at the proximal end of a spirometry and CPET test circuit did not significantly alter the test results, with the exception of a marginal decrease noted in peak work rate https://bit.ly/3Vkew95.

15.
Zhongguo Zhong Yao Za Zhi ; 49(11): 2906-2919, 2024 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-39041150

RESUMO

Rheumatoid arthritis(RA) is a condition in which the joints are in a weakly acidic environment. In RA, RA fibroblastlike synoviocytes( RAFLS) in the joints become abnormally activated and secrete a large amount of matrix metalloproteinases(MMPs), and the receptor protein CD44 on the cell membrane is specifically upregulated. Xuetongsu(XTS), an active ingredient in the Tujia ethnomedicine Xuetong, is known to inhibit the proliferation of RAFLS. However, its development and utilization have been limited due to poor targeting ability. A biomimetic XTS-Prussian blue nanoparticles(PB NPs) drug delivery system called THMPX NPs which can target CD44 was constructed in this study. The surface of THMPX NPs was modified with hyaluronic acid(HA) and a long chain of triglycerol monostearate(TGMS) and 3-aminobenzeneboronic acid(PBA)(PBA-TGMS). The overexpressed MMPs and H+ in inflammatory RAFLS can synergistically cleave the PBA-TGMS on the surface of the nanoparticles, exposing HA to interact with CD44. This allows THMPX NPs to accumulate highly in RAFLS, and upon near-infrared light irradiation, generate heat and release XTS, thereby inhibiting the proliferation and migration of RAFLS. Characterization revealed that THMPX NPs were uniform cubes with a diameter of(190. 3±4. 7) nm and an average potential of(-15. 3± 2. 3) m V. Upon near-infrared light irradiation for 5 min, the temperature of THMPX NPs reached 41. 5 ℃, indicating MMPs and H+-triggered drug release. Safety assessments showed that THMPX NPs had a hemolysis rate of less than 4% and exhibited no cytotoxicity against normal RAW264. 7 and human fibroblast-like synoviocytes(HFLS). In vitro uptake experiments demonstrated the significant targeting ability of THMPX NPs to RAFLS. Free radical scavenging experiments revealed excellent free radical clearance capacity of THMPX NPs, capable of removing reactive oxygen species in RAFLS. Cell counting kit-8 and scratch assays demonstrated that THMPX NPs significantly suppressed the viability and migratory ability of RAFLS. This study provides insights into the development of innovative nanoscale targeted drugs from traditional ethnic medicines for RA treatment.


Assuntos
Movimento Celular , Proliferação de Células , Metaloproteinases da Matriz , Nanopartículas , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Nanopartículas/química , Humanos , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Metaloproteinases da Matriz/metabolismo , Metaloproteinases da Matriz/genética , Ferrocianetos/química , Concentração de Íons de Hidrogênio , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/efeitos da radiação , Sinoviócitos/metabolismo , Lasers , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo
16.
J Med Chem ; 67(15): 13363-13382, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-38987863

RESUMO

Human telomerase reverse transcriptase (hTERT) may have noncanonical functions in transcriptional regulation and metabolic reprogramming in cancer cells, but it is a challenging target. We thus developed small-molecule ligands targeting hTERT promoter G-quadruplex DNA structures (hTERT G4) to downregulate hTERT expression. Ligand 5 showed high affinity toward hTERT G4 (Kd = 1.1 µM) and potent activity against triple-negative breast cancer cells (MDA-MB-231, IC50 = 1 µM). In cell-based assays, 5 not only exerts markedly inhibitory activity on classical telomere functions including decreased telomerase activity, shortened telomere length, and cellular senescence but also induces DNA damage, acute cellular senescence, and apoptosis. This study reveals that hTERT G4-targeting ligand may cause mitochondrial dysfunction, disrupt iron metabolism and activate ferroptosis in cancer cells. The in vivo antitumor efficacy of 5 was also evaluated in an MDA-MB-231 xenograft mouse model and approximately 78.7% tumor weight reduction was achieved. No observable toxicity against the major organs was observed.


Assuntos
Antineoplásicos , Regulação para Baixo , Quadruplex G , Regiões Promotoras Genéticas , Telomerase , Neoplasias de Mama Triplo Negativas , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Humanos , Quadruplex G/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Animais , Ligantes , Feminino , Regulação para Baixo/efeitos dos fármacos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Senescência Celular/efeitos dos fármacos , Camundongos Endogâmicos BALB C
17.
Natl Sci Rev ; 11(7): nwae195, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39045468

RESUMO

Endogenous opioid antinociception is a self-regulatory mechanism that reduces chronic pain, but its underlying circuit mechanism remains largely unknown. Here, we showed that endogenous opioid antinociception required the activation of mu-opioid receptors (MORs) in GABAergic neurons of the central amygdala nucleus (CEA) in a persistent-hyperalgesia mouse model. Pharmacogenetic suppression of these CEAMOR neurons, which mimics the effect of MOR activation, alleviated the persistent hyperalgesia. Furthermore, single-neuron projection analysis revealed multiple projectome-based subtypes of CEAMOR neurons, each innervating distinct target brain regions. We found that the suppression of axon branches projecting to the parabrachial nucleus (PB) of one subtype of CEAMOR neurons alleviated persistent hyperalgesia, indicating a subtype- and axonal-branch-specific mechanism of action. Further electrophysiological analysis revealed that suppression of a distinct CEA-PB disinhibitory circuit controlled endogenous opioid antinociception. Thus, this study identified the central neural circuit that underlies endogenous opioid antinociception, providing new insight into the endogenous pain modulatory mechanisms.

18.
J Magn Reson Imaging ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38855837

RESUMO

BACKGROUND: The impact of functional mitral regurgitation and type 2 mellitus diabetes (T2DM) on left ventricular (LV) strain in nonischemic dilated cardiomyopathy (NIDCM) patients remains unclear. PURPOSE: To evaluate the impact of mitral regurgitation severity on LV strain, and explore additive effect of T2DM on LV function across varying mitral regurgitation severity levels in NIDCM patients. STUDY TYPE: Retrospective. POPULATION: 352 NIDCM (T2DM-) patients (49.1 ± 14.6 years, 67% male) (207, 85, and 60 no/mild, moderate, and severe mitral regurgitation) and 96 NIDCM (T2DM+) patients (55.2 ± 12.4 years, 77% male) (47, 30, and 19 no/mild, moderate, and severe mitral regurgitation). FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession sequence. ASSESSMENT: LV geometric parameters and strain were measured and compared among groups. Determinants of LV strain were investigated. STATISTICAL TEST: Student's t-test, Mann-Whitney U test, one-way ANOVA, Kruskal-Wallis test, univariable and multivariable linear regression. P < 0.05 was considered statistically significant. RESULTS: LV GLPS and longitudinal PDSR decreased gradually with increasing mitral regurgitation severity in NIDCM patients with T2DM(GLPS: -5.7% ± 2.1% vs. -4.3% ± 1.6% vs. -2.6% ± 1.3%; longitudinal PDSR:0.5 ± 0.2 sec-1 vs. 0.4 ± 0.2 sec-1 vs. 0.3 ± 0.1 sec-1). NIDCM (T2DM+) demonstrated decreased GCPS and GLPS in the no/mild subgroup, reduced LV GCPS, GLPS, and longitudinal PDSR in the moderate subgroup, and reduced GRPS, GCPS, GLPS, and longitudinal PDSR in the severe subgroup compared with NIDCM (T2DM-) patients. Multivariable regression analysis identified that mitral regurgitation severity (ß = -0.13, 0.15, and 0.25 for GRPS, GCPS, and GLPS) and the presence of T2DM (ß = 0.14 and 0.13 for GCPS and GLPS) were independent determinants of LV strains in NIDCM patients. DATA CONCLUSION: Increased mitral regurgitation severity is associated with reduced LV strains in NIDCM patients with T2DM. The presence of T2DM exacerbated the decline of LV function across various mitral regurgitation levels in NIDCM patients, resulting in reduced LV strains. TECHNICAL EFFICACY: Stage 3.

19.
J Infect Public Health ; 17(7): 102464, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38865773

RESUMO

BACKGROUND: Long COVID, an emerging public health issue, is characterized by persistent symptoms following SARS-CoV-2 infection. This study aims to explore the relationship between post-COVID-19 symptomatology and patient distress employing Latent Class Analysis to uncover symptom co-occurrence patterns and their association with distress. METHODS: A cross-sectional study was conducted using an online survey among 240 participants from a university and affiliated hospital of southern Taiwan. The survey quantified distress due to persistent symptoms and assessed the prevalence of Long COVID, symptom co-occurrence, and latent symptom classes. Latent Class Analysis (LCA) identified distinct symptom patterns, and multiple regression models evaluated associations between symptom patterns, distress, and demographic factors. RESULTS: The study found that 80 % of participants experienced Long COVID, with symptoms persisting for over three months. Individuals with multiple COVID-19 infections showed a significant increase in general (ß = 1.79), cardiovascular (ß = 0.61), and neuropsychological symptoms (ß = 2.18), and higher total distress scores (ß = 6.35). Three distinct symptomatology classes were identified: "Diverse", "Mild", and "Severe" symptomatology. The "Mild Symptomatology" class was associated with lower distress (-10.61), while the "Severe Symptomatology" class showed a significantly higher distress due to symptoms (13.32). CONCLUSION: The study highlights the significant impact of Long COVID on individuals, with distinct patterns of symptomatology and associated distress. It emphasizes the cumulative effect of multiple COVID-19 infections on symptom severity and the importance of tailored care strategies.


Assuntos
COVID-19 , Síndrome de COVID-19 Pós-Aguda , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , COVID-19/psicologia , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Taiwan/epidemiologia , Inquéritos e Questionários , Idoso , Análise de Classes Latentes , Prevalência , Angústia Psicológica , Estresse Psicológico/epidemiologia , Adulto Jovem
20.
Ecotoxicol Environ Saf ; 280: 116581, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38875820

RESUMO

Screening and prioritizing research on frequently detected mixture systems in the environment is of great significance, as conducting toxicity testing on all mixtures is impractical. Therefore, the frequent itemset mining (FIM) was introduced and applied in this paper to identify variables that commonly co-occur in a dataset. Based on the dataset of the quaternary ammonium compounds (QACs) in the water environment, the four frequent QAC mixture systems with detection rate ≥ 35 % were found, including [BDMM]+Cl--[BTMM]+Cl- (M1), [BDMM]+Cl--[BHMM]+Cl- (M2), [BTMM]+Cl- -[BHMM]+Cl- (M3), and [BDMM]+Cl--[BTMM]+Cl--[BHMM]+Cl- (M4). [BDMM]+Cl-, [BTMM]+Cl-, and [BHMM]+Cl- are benzyl dodecyl dimethyl ammonium chloride, benzyl tetradecyl dimethyl ammonium chloride, and benzyl hexadecyl dimethyl ammonium chloride, respectively. Then, the toxicity of the representative mixture rays and components for the four frequently detected mixture systems was tested using Vibrio qinghaiensis sp.-Q67 (Q67) as a luminescent indicator organism at 0.25 and 12 h. The toxicity of the mixtures was predicted using concentration addition (CA) and independent action (IA) models. It was shown that both the components and the representative mixture rays for the four frequently detected mixture systems exhibited obvious acute and chronic toxicity to Q67, and their median effective concentrations (EC50) were below 7 mg/L. Both CA and IA models predicted the toxicity of the four mixture systems well. However, the CA model had a better predictive ability for the toxicity of the M3 and M4 mixtures than IA at 12 h.


Assuntos
Compostos de Amônio Quaternário , Poluentes Químicos da Água , Compostos de Amônio Quaternário/toxicidade , Poluentes Químicos da Água/toxicidade , Monitoramento Ambiental/métodos , Testes de Toxicidade/métodos , Mineração de Dados
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