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1.
Phytother Res ; 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839050

RESUMO

Pediatric intestinal development is immature, vulnerable to external influences and produce a variety of intestinal diseases. At present, breakthroughs have been made in the treatment of pediatric intestinal diseases, but there are still many challenges, such as toxic side effects, drug resistance, and the lack of more effective treatments and specific drugs. In recent years, dietary polyphenols derived from plants have become a research hotspot in the treatment of pediatric intestinal diseases due to their outstanding pharmacological activities such, as anti-inflammatory, antibacterial, antioxidant and regulation of intestinal flora. This article reviewed the mechanism of action and clinical evidence of dietary polyphenols in the treatment of pediatric intestinal diseases, and discussed the influence of physiological characteristics of children on the efficacy of polyphenols, and finally prospected the new dosage forms of polyphenols in pediatrics.

2.
Angew Chem Int Ed Engl ; : e202407752, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844430

RESUMO

Inherently chiral calix[4]arenes are an excellent structural scaffold for asymmetric synthesis, chiral recognition, sensing, and circularly polarized luminescence. However, their catalytic asymmetric synthesis remains challenging. Herein, we report an efficient synthesis of inherently chiral calix[4]arene derivatives via cascade asymmetric cyclization and oxidation reactions. The three-component reaction features a broad substrate scope (33 examples), high efficiency (up to 90% yield), and excellent enantioselectivity (>95% ee on average). The potential applications of calix[4]arene derivatives are highlighted by their synthetic transformation and a detailed investigation of their photophysical and chiroptical properties.

3.
Front Cardiovasc Med ; 11: 1372519, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38836061

RESUMO

Background: The effect of type 2 diabetes mellitus (T2DM) on coronary atherosclerosis detected on coronary computed tomography angiography (CCTA) in hypertensive patients has attracted increasing attention. This study investigated the relationships of T2DM with coronary artery plaque characteristics and semiquantitative CCTA scores in hypertensive patients. Materials and methods: In this single-center study, 1,700 hypertensive patients, including 850 T2DM [HT(T2DM+)] and 850 non-T2DM [HT(T2DM-)] individuals, were retrospectively analyzed after propensity matching. Plaque type, extent, coronary stenosis, segment involvement score (SIS), segment stenosis score (SSS), and CT-based Leaman score (CT-LeSc) based on CCTA were assessed and compared between the two groups. Results: HT(T2DM+) patients had more coronary segments with calcified plaque (2.08 ± 2.20 vs. 1.40 ± 1.91), mixed plaque (2.90 ± 2.87 vs. 2.50 ± 2.66), nonobstructive stenosis (4.23 ± 2.44 vs. 3.62 ± 2.42), and obstructive stenosis (1.22 ± 2.18 vs. 0.78 ± 1.51), a lower proportion of 1-vessel disease (15.3% vs. 25.5%), a higher proportion of 3-vessel disease (59.6% vs. 46.7%), and higher SIS (5.5 ± 3.1 vs. 4.4 ± 3.0), SSS (10.3 ± 8.5 vs. 7.7 ± 7.1), and CT-LeSc (9.4 ± 5.6 vs. 7.9 ± 5.2) than HT(T2DM-) patients (all P-values <0.05). Multivariable analysis revealed that T2DM was an independent risk factor for calcified plaque [odds ratio (OR) = 2.213], obstructive coronary artery disease (CAD) (OR = 1.271), multivessel disease (OR = 1.838), SIS > 4 (OR = 1.910), SSS > 6 (OR = 1.718), and CT-LeSc > 5 (OR = 1.584) in hypertension population (all P-values <0.05). Conclusion: T2DM was independently associated with the presence of calcified coronary artery plaque and increased the risk of obstructive CAD, multivessel disease, and CT-LeSc > 5 in hypertensive patients. More attention should be given to the assessment and management for coronary atherosclerosis in hypertensive patients with T2DM, as this population may have a higher risk of cardiovascular events.

4.
Front Nutr ; 11: 1378969, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38840695

RESUMO

Purpose: Specific nutrients found in food, such as minerals, antioxidants, and macronutrients, have a significant impact on immune function and human health. However, there is currently limited research exploring the relationship between specific nutrients, immune system function, and thyroid dysfunction commonly observed in autoimmune thyroid diseases, which manifest predominantly as hyperthyroidism or hypothyroidism. Therefore, the objective of this study was to investigate the connections between dietary traits and thyroid dysfunction, as well as the potential mediating role of immune cells, using Mendelian randomization (MR) analysis. Methods: The two-step MR analysis used single-nucleotide polymorphisms as instruments, with a threshold of p < 5e-08 for nutrients and thyroid dysfunction, and p < 5e-06 for immune cells. Data from different GWAS databases and UK Biobank were combined to analyze 8 antioxidants and 7 minerals, while the data for 4 macronutrients came from a cohort of 235,000 individuals of European. The outcome data (hypothyroidism, N = 3340; hyperthyroidism, N = 1840; free thyroxin [FT4], N = 49,269; thyroid-stimulating hormone [TSH], N = 54,288) were source from the ThyroidOmics consortium. Immune trait data, including 731 immune phenotypes, were collected from the GWAS catalog. Results: The results revealed that nutrient changes, such as lycopene, toenail and blood selenium, and α-tocopherol, impacted the immune system. Immune cells also affected thyroid function, with cDC cells promoting hypothyroidism and median fluorescence intensity (MFI) phenotypes correlating strongly with FT4 levels. Toenail and blood selenium reduce the relative cell counts (RCC) phenotypes of immune cells (CD62L- plasmacytoid DC %DC and transitional B cells %Lymphocyte), thereby diminishing its promoting effect on hypothyroidis. Furthermore, toenail and blood selenium mainly impacted phenotypes in three types of T cells (CD25 + ⁣ + CD8br, CD3 on CD45RA- CD4+, and CD45RA on Terminally Differentiated CD8br), reinforcing the negative regulation of FT4 levels. Conclusion: The role of immune cells as mediators in the relationship between nutrients and thyroid dysfunction highlights their potential as diagnostic or therapeutic markers. Toenail and blood selenium levels can indirectly impact hypothyroidism by influencing the RCC levels of two types of immune cells, and can indirectly affect FT4 levels by influencing three types of T cells.

5.
Bioconjug Chem ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38857526

RESUMO

Bacterial keratitis, an ocular emergency, is the predominant cause of infectious keratitis. However, diagnostic procedures for it are invasive, time-consuming, and expeditious, thereby limiting effective treatment for the disease in the clinic. It is imperative to develop a timely and convenient method for the noninvasive diagnosis of bacterial keratitis. Fluorescence imaging is a convenient and noninvasive diagnostic method with high sensitivity. In this study, a type of nitroreductase-responsive probe (NTRP), which responds to nitroreductase to generate fluorescence signals, was developed as an activatable fluorescent probe for the imaging diagnosis of bacterial keratitis. Imaging experiments both in vitro and in vivo demonstrated that the probe exhibited "turn-on" fluorescence signals in response to nitroreductase-secreting bacteria within 10 min. Furthermore, the fluorescence intensity reached its highest at 4 or 6 h in vitro and at 30 min in vivo when the excitation wavelength was set at 520 nm. Therefore, the NTRP has the potential to serve as a feasible agent for the rapid and noninvasive in situ fluorescence diagnosis of bacterial keratitis.

6.
Cell Death Differ ; 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862581

RESUMO

The oncogenic potential of chromosome 8q22 copy number gain in liver cancer remains to be depicted. Here, we report that ZNF706, encoded by a gene mapped to chromosome 8q22, is a C2H2-type zinc finger protein. However, the biological function and mechanism of ZNF706 have been poorly investigated. Clinically, ZNF706 expression was elevated in hepatocellular carcinoma (HCC), and high ZNF706 expression was associated with unfavorable survival in HCC patients. Functional experiments revealed that ZNF706 knockdown inhibited HCC progression both in vitro and in vivo. RNA sequencing (RNA-seq) and chromatin immunoprecipitation-based deep sequencing (ChIP-seq) revealed that mechanistically, ZNF706 is a crucial ferroptosis regulator and that SLC7A11 is a critical target of ZNF706. In addition, ZNF706 knockdown inhibited SLC7A11 expression, increased lipid peroxidation, and promoted ferroptosis. Further analysis revealed that ZNF706 is a novel direct target transcriptionally activated by MYC in HCC cells. Importantly, MYC depletion reduced SLC7A11-mediated redox homeostasis, and this effect was reversed by ZNF706 reexpression. Collectively, our data demonstrate that ZNF706 is a potential oncogene in liver cancer and functions as a ferroptosis regulator by modulating SLC7A11 expression, constituting a potential therapeutic target for HCC.

7.
Adv Mater ; : e2405458, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839062

RESUMO

Manganese (Mn)-based Prussian blue analogs (PBAs) are of great interest as a prospective cathode material for sodium-ion batteries (SIBs) due to their high redox potential, easy synthesis, and low cost. However, the Jahn-Teller effect and low electrical conductivity of Mn-based PBA cause poor structure stability and unsatisfactory performance during the cycling. Herein, a novel nickel- and copper-codoped K2Mn[Fe(CN)6] cathode is developed via a simple coprecipitation strategy. The doping elements improve the electrical conductivity of Mn-based PBA by reducing the bandgap, as well as suppress the Jahn-Teller effect by stabilizing the framework, as verified by the density functional theory calculations. Simultaneously, the substitution of sodium with potassium in the lattice is beneficial for filling vacancies in the PBA framework, leading to higher average operating voltages and superior structural stability. As a result, the as-prepared Mn-based cathode exhibits excellent reversible capacity (116.0 mAh g-1 at 0.01 A g-1) and superior cycling stability (81.8% capacity retention over 500 cycles at 0.1 A g-1). This work provides a profitable doping strategy to inhibit the Jahn-Teller structural deformation for designing stable cathode material of SIBs.

8.
Am J Cancer Res ; 14(5): 2390-2407, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38859844

RESUMO

Colorectal cancer is one of the most common malignancies with a high incidence, metastatic tendency and low 5-year survival rate. Resveratrol, a polyphenolic compound has been shown to inhibit colorectal cancer metastasis in recent studies. Its underlying molecular mechanism remains to be elucidated. Our findings demonstrated that miR-125b-5p, acting as a tumor suppressor, was conspicuously down-regulated in both colorectal cancer tissues and cell lines. The expression of miR-125b-5p negatively correlated with the expression of its direct target TNF receptor associated factor 6 (TRAF6). Both miR-125b-5p overexpression and TRAF6 knockdown inhibited metastasis of colorectal cancer cells. In addition, we uncovered that resveratrol up-regulated miR-125b-5p by increasing its stability and suppressed TRAF6-induced signal pathway in a dose/time-dependent manner. Resveratrol could significantly curtail the migration and invasion of colorectal cancer cells, which was counteracted by miR-125b-5p knockdown or TRAF6 overexpression. These results indicated that resveratrol could restrain colorectal cancer metastasis by promoting miR-125b-5p/TRAF6 signaling axis. Furthermore, lung metastasis models of colorectal cancer were constructed by tail vein injection. Down-regulation of miR-125b-5p could facilitate colorectal cancer metastasis in vivo, which could be impeded by resveratrol. In conclusion, our findings delineated the miR-125b-5p/TRAF6 signaling axis as a novel molecular mechanism underlying the metastatic process in colorectal cancer, as well as a prospective therapeutic target. Resveratrol disrupts colorectal cancer metastasis by activating miR-125b-5p/TRAF6 signal pathway and might improve the clinical outcome of colorectal cancer patients with low expression of miR-125b-5p.

9.
J Transl Med ; 22(1): 528, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824544

RESUMO

Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 µmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.


Assuntos
Aminoácidos , Proliferação de Células , Fluoretos , Músculo Liso Vascular , Ratos Sprague-Dawley , Animais , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Fluoretos/farmacologia , Linhagem Celular , Aminoácidos/metabolismo , Proliferação de Células/efeitos dos fármacos , Ratos , Movimento Celular/efeitos dos fármacos , Masculino , Aorta/patologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Metabolômica , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Redes Reguladoras de Genes/efeitos dos fármacos
10.
Can Geriatr J ; 27(2): 116-125, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38827428

RESUMO

Background: Community support programs can improve quality of life for people living with dementia and their care partners. Important to the successful implementation of such programs is close engagement with end-users to gain a better understanding of their needs. This study describes the perspectives of people living with dementia, care partners, and health-care providers on the First Link® dementia support program provided by the Alzheimer Society of British Columbia (ASBC). Methods: Following a large-scale survey (N=1,164), semi-structured interviews were conducted with participants to explore in greater detail the different needs and themes that emerged from the first phase of the study. The interviews explored: 1) experiences with the program; 2) future planning; 3) meaning of independence; and 4) impact of the program on emotional and physical well-being. Results: A total of 48 participants were interviewed in this study. Knowledge and education were key factors that helped participants manage the impact of dementia. Learning about dementia, the experiences of others, strategies on how to manage symptoms, what to plan for in the future, and how to access different services in the community, was tied to increased feelings of confidence and comfort, and decreased stress. Participants also provided suggestions for improvement of the First Link® dementia program such as further embedding the program into the patient journey, providing more services in remote areas, providing education for health-care providers, and increasing awareness of the program. Conclusion: By emphasizing the lived experiences and needs of those living with dementia and their caregivers, this work will inform future research-based program evaluations globally and, in turn, improve the existing services to support people living with-and impacted by-dementia.

11.
Nanotechnology ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834038

RESUMO

Give the emergence of drug resistance in bacteria resulting from antibiotic misuse, there is an urgent need for research and application of novel antibacterial approaches. In recent years, nanoparticles have garnered significant attention due to their potential to disrupt bacteria cellular structure through loading drugs and special mechanisms, thus rendering them inactive. In this study, the surface of hollow polydopamine nanoparticles was utilized for the growth of Prussian blue (PB), resulting in the formation of HPDA-PB NPs. Incorporation of Co element during the preparation process led to partial doping of PB with Co2+ ions. The performance test results demonstrated that the HPDA-PB NPs exhibited superior photothermal conversion efficiency and POD-like activity compared to PB NPs. HPDA-PB nanoparticles have the ability to catalyze the formation of hydroxyl radicals from H2O2 in a weakly acidic environment. Due to the small PB particles on the surface and the presence of Co2+ doping, they have strong broad-spectrum antibacterial properties. Both in vitro and in vivo evaluations confirm their efficacy against various bacterial strains, particularly S. aureus, and their potential to promote wound healing, making them a promising candidate for advanced wound care and antimicrobial applications. .

13.
Cancer Med ; 13(11): e7330, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38845478

RESUMO

OBJECTIVES: Patients with advanced colorectal cancer (CRC) have multiple concurrent physical and psychological symptoms. This study aimed to explore the relationship between anxiety, depression, and symptom burden in advanced CRC. METHODS: A multicenter cross-sectional study was conducted in 10 cancer centers from geographically and economically diverse sites in China. A total of 454 patients with advanced CRC completed the Hospital Anxiety and Depression Scale and the MD Anderson Symptom Inventory. Multiple regression analysis was applied to explore the relationship between anxiety, depression and symptom burden. RESULTS: About one-third of the patients showed symptoms of anxiety or depression. Patients with anxiety or depression reported significantly higher symptom burden than those without (p < 0.001). Patients with anxiety or depression reported a higher proportion of moderate-to-severe (MS) symptom number than those without (p < 0.001). About 52% of the patients with anxiety or depression reported at least three MS symptoms. The prevalence of MS symptoms was ranging from 7.3% (shortness of breath) to 22% (disturbed sleep), and in patients with anxiety or depression was 2-10 times higher than in those without (p < 0.001). Disease stage (ß = -2.55, p = 0.003), anxiety (ß = 15.33, p < 0.001), and depression (ß = 13.63, p < 0.001) were associated with higher symptom burden. CONCLUSIONS: Anxiety and depression in patients with advanced cancer correlated with higher symptom burden. Findings may lead oncology professionals to pay more attention to unrecognized and untreated psychological symptoms in symptom management for advanced cancer patients.


Assuntos
Ansiedade , Neoplasias Colorretais , Depressão , Humanos , Neoplasias Colorretais/psicologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/complicações , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Depressão/epidemiologia , Depressão/etiologia , Depressão/psicologia , Ansiedade/epidemiologia , Ansiedade/psicologia , Idoso , China/epidemiologia , Prevalência , Adulto , Idoso de 80 Anos ou mais , Qualidade de Vida , Carga de Sintomas
14.
BMC Genomics ; 25(1): 559, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840048

RESUMO

BACKGROUND: The crossbreeding of specialized beef cattle breeds with Chinese indigenous cattle is a common method of genetic improvement. Xia'nan cattle, a crossbreed of Charolais and Nanyang cattle, is China's first specialized beef cattle breed with independent intellectual property rights. After more than two decades of selective breeding, Xia'nan cattle exhibit a robust physique, good environmental adaptability, good tolerance to coarse feed, and high meat production rates. This study analyzed the population genetic structure, genetic diversity, and genomic variations of Xia'nan cattle using whole-genome sequencing data from 30 Xia'nan cattle and 178 published cattle genomic data. RESULT: The ancestry estimating composition analysis showed that the ancestry proportions for Xia'nan cattle were mainly Charolais with a small amount of Nanyang cattle. Through the genetic diversity studies (nucleotide diversity and linkage disequilibrium decay), we found that the genomic diversity of Xia'nan cattle is higher than that of specialized beef cattle breeds in Europe but lower than that of Chinese native cattle. Then, we used four methods to detect genome candidate regions influencing the excellent traits of Xia'nan cattle. Among the detected results, 42 genes (θπ and CLR) and 131 genes (FST and XP-EHH) were detected by two different detection strategies. In addition, we found a region in BTA8 with strong selection signals. Finally, we conducted functional annotation on the detected genes and found that these genes may influence body development (NR6A1), meat quality traits (MCCC1), growth traits (WSCD1, TMEM68, MFN1, NCKAP5), and immunity (IL11RA, CNTFR, CCL27, SLAMF1, SLAMF7, NAA35, and GOLM1). CONCLUSION: We elucidated the genomic features and population structure of Xia'nan cattle and detected some selection signals in genomic regions potentially associated with crucial economic traits in Xia'nan cattle. This research provided a basis for further breeding improvements in Xia'nan cattle and served as a reference for genetic enhancements in other crossbreed cattle.


Assuntos
Variação Genética , Seleção Genética , Sequenciamento Completo do Genoma , Bovinos/genética , Animais , Sequenciamento Completo do Genoma/métodos , Desequilíbrio de Ligação , Genômica/métodos , Polimorfismo de Nucleotídeo Único , Genoma , Genética Populacional , Cruzamento , Locos de Características Quantitativas , Fenótipo
15.
Arch Sex Behav ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849704

RESUMO

Cabotegravir (CAB-LA), the first long-acting injectable pre-exposure prophylaxis (PrEP), has been approved for use in the USA and is not currently on the market in China. However, willingness to use CAB-LA and associated factors among men who have sex with men (MSM) have not yet been evaluated in China. A cross-sectional study was conducted in Guangxi, China, in 2022 recruiting 1,006 MSM. Their mean age was 30.2 years, 74.2% had college or above education, and 48.6% had a monthly income between 3,000 and 5,999 Chinese yuan (CNY). Most (73.4%) had previously heard of PrEP while few (8.3%) had ever used this type of preventative medication. Willingness to use CAB-LA was 79.8% and was positively associated with eight variables: younger age, being married to a woman, having a low monthly income, having six or more male partners in the past six months, having only regular male partners in the past month, having a high perceived risk of HIV infection, and history of using PrEP. Ten other variables were not significantly associated with willingness to use CAB-LA. Among 894 participants who were willing to use or did not definitely reject using CAB-LA, the main concerns about CAB-LA were its side effects (90.2%), efficacy (63.6%), and high cost (58.2%). Only 14.7% were willing to pay more than 1,200 CNY (~US$180) every two months to use CAB-LA. The preferred injection places were centers for disease control facilities, hospitals, and social organizations. Many (89.0%) said that they would recommend CAB-LA to their male sexual partners. We conclude that willingness to use CAB-LA was high among MSM in Guangxi. However, implementation of CAB-LA faces tough challenges due to its high cost and the low use of PrEP. Peer education may play a large role in the implementation of CAB-LA in China.

16.
J Infect ; 89(2): 106190, 2024 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-38834107

RESUMO

OBJECTIVES: This study aimed to determine the association of early use of oral antiviral drugs (including nirmatrelvir-ritonavir and molnupiravir) with the risk of post COVID-19 condition (PCC) and compare the possible efficacy of nirmatrelvir-ritonavir and molnupiravir. METHODS: PubMed, Web of Science, Embase, Cochrane, MedRxiv, and Psycinfo were searched from inception until November 1, 2023. We included studies that assessed the effect of oral antiviral drugs on the incidence of PCC. Pairwise and network meta-analyses were conducted using a random-effects model. Risk ratios (RRs) for oral antiviral drugs were calculated with a confidence interval (CI). RESULTS: Nine observational studies containing 866,066 patients were included. Nirmatrelvir-ritonavir and molnupiravir were evaluated in eight and two studies respectively, with both drugs evaluated in one study. Pair-wise meta-analysis showed that early oral antiviral drugs reduced PCC risk (RR 0.77, 95% CI 0.68-0.88). Network meta-analysis showed that nirmatrelvir-ritonavir may perform better than molnupiravir (surface under the cumulative ranking curve: 95.5% vs. 31.6%) at reducing PCC risk. CONCLUSIONS: Early use of oral antiviral drugs may potentially protect against developing PCC in non-hospitalized patients with COVID-19. These findings support the standardized administration of oral antiviral drugs in patients during the acute phase of COVID-19 according to the guidelines.

17.
Cancer Biol Ther ; 25(1): 2366451, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38857055

RESUMO

BACKGROUND: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood. METHODS: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or ß-adrenergic receptor (ß-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-ß (TGF-ß) receptor Type I kinase (Ly2157299) in vitro. TGF-ß1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested. RESULTS: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-ß1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion. CONCLUSIONS: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-ß1 signaling during this process. In addition, ß-AR/TGF-ß1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.


Assuntos
Bevacizumab , Neoplasias Colorretais , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neovascularização Patológica , Transdução de Sinais , Fator de Crescimento Transformador beta1 , Animais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Humanos , Neovascularização Patológica/metabolismo , Camundongos , Fator de Crescimento Transformador beta1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Propranolol/farmacologia , Linhagem Celular Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Masculino , Movimento Celular , Norepinefrina/farmacologia , Norepinefrina/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Angiogênese , Pirazóis , Quinolinas
18.
Cereb Cortex ; 34(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38836287

RESUMO

Somatic mutations have been identified in 10% to 63% of focal cortical dysplasia type II samples, primarily linked to the mTOR pathway. When the causative genetic mutations are not identified, this opens the possibility of discovering new pathogenic genes or pathways that could be contributing to the condition. In our previous study, we identified a novel candidate pathogenic somatic variant of IRS-1 c.1791dupG in the brain tissue of a child with focal cortical dysplasia type II. This study further explored the variant's role in causing type II focal cortical dysplasia through in vitro overexpression in 293T and SH-SY5Y cells and in vivo evaluation via in utero electroporation in fetal brains, assessing effects on neuronal migration, morphology, and network integrity. It was found that the mutant IRS-1 variant led to hyperactivity of p-ERK, increased cell volume, and was predominantly associated with the MAPK signaling pathway. In vivo, the IRS-1 c.1791dupG variant induced abnormal neuron migration, cytomegaly, and network hyperexcitability. Notably, the ERK inhibitor GDC-0994, rather than the mTOR inhibitor rapamycin, effectively rescued the neuronal defects. This study directly highlighted the ERK signaling pathway's role in the pathogenesis of focal cortical dysplasia II and provided a new therapeutic target for cases of focal cortical dysplasia II that are not treatable by rapamycin analogs.


Assuntos
Proteínas Substratos do Receptor de Insulina , Sistema de Sinalização das MAP Quinases , Mutação , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Animais , Malformações do Desenvolvimento Cortical do Grupo I/genética , Malformações do Desenvolvimento Cortical do Grupo I/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neurônios/metabolismo , Neurônios/patologia , Movimento Celular/genética , Células HEK293 , Feminino , Displasia Cortical Focal , Epilepsia
19.
Pestic Biochem Physiol ; 202: 105958, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38879340

RESUMO

The wheat aphid Sitobion miscanthi is a dominant and destructive pest in agricultural production. Insecticides are the main substances used for effective control of wheat aphids. However, their extensive application has caused severe resistance of wheat aphids to some insecticides; therefore, exploring resistance mechanisms is essential for wheat aphid management. In the present study, CYP6CY2, a new P450 gene, was isolated and overexpressed in the imidacloprid-resistant strain (SM-R) compared to the imidacloprid-susceptible strain (SM-S). The increased sensitivity of S. miscanthi to imidacloprid after knockdown of CYP6CY2 indicates that it could be associated with imidacloprid resistance. Subsequently, the posttranscriptional regulation of CYP6CY2 in the 3' UTR by miR-3037 was confirmed, and CYP6CY2 participated in imidacloprid resistance. This finding is critical for determining the role of P450 in relation to the resistance of S. miscanthi to imidacloprid. It is of great significance to understand this regulatory mechanism of P450 expression in the resistance of S. miscanthi to neonicotinoids.


Assuntos
Afídeos , Sistema Enzimático do Citocromo P-450 , Resistência a Inseticidas , Inseticidas , MicroRNAs , Neonicotinoides , Nitrocompostos , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Inseticidas/farmacologia , Resistência a Inseticidas/genética , Afídeos/genética , Afídeos/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Imidazóis/farmacologia
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