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1.
Nat Commun ; 15(1): 7164, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223156

RESUMO

High-throughput sequencing technologies have increasingly led to discovery of disease-causing genetic variants, primarily in postnatal multi-cell DNA samples. However, applying these technologies to preimplantation genetic testing (PGT) in nuclear or mitochondrial DNA from single or few-cells biopsied from in vitro fertilised (IVF) embryos is challenging. PGT aims to select IVF embryos without genetic abnormalities. Although genotyping-by-sequencing (GBS)-based haplotyping methods enabled PGT for monogenic disorders (PGT-M), structural rearrangements (PGT-SR), and aneuploidies (PGT-A), they are labour intensive, only partially cover the genome and are troublesome for difficult loci and consanguineous couples. Here, we devise a simple, scalable and universal whole genome sequencing haplarithmisis-based approach enabling all forms of PGT in a single assay. In a comparison to state-of-the-art GBS-based PGT for nuclear DNA, shallow sequencing-based PGT, and PCR-based PGT for mitochondrial DNA, our approach alleviates technical limitations by decreasing whole genome amplification artifacts by 68.4%, increasing breadth of coverage by at least 4-fold, and reducing wet-lab turn-around-time by ~2.5-fold. Importantly, this method enables trio-based PGT-A for aneuploidy origin, an approach we coin PGT-AO, detects translocation breakpoints, and nuclear and mitochondrial single nucleotide variants and indels in base-resolution.


Assuntos
Diagnóstico Pré-Implantação , Sequenciamento Completo do Genoma , Humanos , Diagnóstico Pré-Implantação/métodos , Sequenciamento Completo do Genoma/métodos , Feminino , Fertilização in vitro/métodos , Testes Genéticos/métodos , Aneuploidia , Gravidez , DNA Mitocondrial/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Genoma Humano/genética
2.
Heliyon ; 10(17): e37415, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39296136

RESUMO

Background: High circulatory lipoprotein(a) [Lp(a)] concentration promotes atherosclerosis; however, its efficacy in predicting the extent of atherosclerotic coronary heart disease (CHD) with coronary artery obstruction and major adverse cardiovascular events (MACEs) in diabetic patients remains questionable. This study aimed to examine whether elevated circulating Lp(a) levels exacerbate CHD and to assess their utility in predicting MACEs in individuals diagnosed with type 2 diabetes mellitus (T2DM). Methods: In total, 4332 patients diagnosed with T2DM who underwent coronary angiography (CAG) were included and categorized into two groups (CHD and non-CHD) based on the CAG results. We used a correlation analysis to explore the potential links between the levels of circulating Lp(a) and CHD severity. Cox regression analysis was performed to evaluate MACEs. Results: The concentrations of circulating Lp(a) were markedly elevated in the CHD group and positively correlated with disease severity. Our results indicate that elevated circulating Lp(a) is a crucial risk factor that significantly contributes to both the progression and severity of CHD. The differences between the two groups are evident in the risk of CHD occurrence [odds ratio (OR) = 1.597, 95 % confidence interval (CI): 1.354-1.893, p < 0.001], the different levels of vessel involvement (OR = 1.908 for triple-vessel vs. single-vessel disease, 95 % CI: 1.401-2.711, p < 0.001), and their relation to the Gensini Score (OR = 2.002 for high vs. low GS, 95 % CI: 1.514-2.881, p < 0.001). Over the course of the 7-year follow-up period, the multivariate Cox regression analysis indicated that increased levels Lp(a) levels are independently associated with the occurrence of MACEs [hazard ratio (HR) = 1.915, 95 % CI: 1.571-2.493, p < 0.001]. Conclusion: We confirmed a positive correlation among circulating Lp(a) levels, CHD lesions count, and Gensini scores. Moreover, Lp(a) levels have predictive significance for the occurrence of MACEs in T2DM patients.

3.
Artigo em Inglês | MEDLINE | ID: mdl-39297025

RESUMO

Purpose: Exploring the effects of acupuncture at the "Yizhi Tiaoshen" acupoint on blood oxygen metabolism and neurological function changes in the brain regions of AD model rats. Methods: The AD model was replicated by intraperitoneal injection of D-galactose combined with bilateral hippocampal CA1 injection of Okadaic acid (OA). Thirty rats with successfully replicated model were selected through Morris water maze experiment and randomly divided into model group, donepezil hydrochloride group, and acupuncture group, with 10 rats in each group. After treatment, fNIRs were used to detect changes in Oxy Hb, Deoxy Hb, and Total Hb in the cerebral cortex of rats in each group, in order to evaluate the neurological function changes in key brain areas. Results: The escape latency of the donepezil hydrochloride group and the acupuncture group was shortened, the number of crossings through the original platform increased, and the duration of stay in the quadrant where the original platform was located was prolonged. Based on fNIRs detection, the main differential channels of blood oxygen metabolism in AD rats were identified as 2-2 and 8-7, corresponding to the prefrontal and parietal lobes, respectively. The concentrations of Oxy Hb and Total Hb were significantly increased in both treatment groups, while the concentration of Deoxy Hb was significantly decreased. Conclusion: Acupuncture with the "Yizhi Tiaoshen" acupoint formula and donepezil hydrochloride can improve the learning and memory function of AD rats, and its mechanism may be related to improving blood oxygen metabolism in the prefrontal and parietal regions and protecting neuronal function.

4.
Cytokine ; 183: 156755, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39276536

RESUMO

UFMylation, a novel ubiquitin-like protein modification system, has been recently found to be activated in inflammation. However, the effects of UFMylation activation on inflammation in vivo remains unclear. In the present study, we generated a UFMylation activated mice using transgenic (TG) techniques. Lipopolysaccharide (LPS) was used to induce systemic inflammation in both TG and non-transgenic (NTG) mice. Serum cytokines were detected using a Mouse Cytokine Array, and the proportions of splenic NK, B and T cells were determined by using flow cytometry. We found that TG mice showed increased serum G-CSF, TNF RII and decreased serum TCA-3, CD30L, bFGF, IL-15 and MIG compared with NTG mice at baseline. Furthermore, serum cytokines in TG mice exhibited different responses to LPS compared to NTG mice. LPS up-regulated serum TNF RII, G-CSF, MCP-5, RANTES, KC, BLC, MIG and down-regulated IL-1b, IL-2, IL-3, IL-4, IL-5, IL-7, IL-10, IL-12p40, IL-15, IL-17, IFN-γ, TCA-3, Eotaxin-2, LIX, MCP-1, TNFα, GM-CSF in NTG mice, whereas LPS up-regulated G-CSF, MCP-5, RANTES, KC, BLC, MIG, ICAM-1, PF4, Eotaxin, CD30L, MIP-1a, TNFRI and down-regulated IL-1b, IL-3, LIX, MCP-1, TNFα, GM-CSF in TG mice. Data from flow cytometry indicated that LPS significantly reduced the percentages of NK and NKT cells in NTG mice, whereas UFMylation activation inhibited LPS-induced NKT cell decrease. The proportions of B cells, total CD4+ and total CD8+ T cells were comparable between TG and NTG mice in response to LPS treatment, whereas the percentages of CD4+CD69+ and CD8+CD69+T cells were lower in TG mice. These findings suggest that UFMylation may alter LPS-induced serum cytokine profile and participate in splenic T cell activation in vivo.


Assuntos
Citocinas , Lipopolissacarídeos , Ativação Linfocitária , Baço , Animais , Camundongos , Linfócitos B/metabolismo , Linfócitos B/imunologia , Citocinas/metabolismo , Citocinas/sangue , Inflamação/metabolismo , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/imunologia , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Baço/metabolismo , Baço/imunologia , Linfócitos T/metabolismo , Linfócitos T/imunologia
5.
J Int Med Res ; 52(9): 3000605241277689, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39301791

RESUMO

OBJECTIVE: This study evaluated the 50% effective dose (ED50) and 95% effective dose (ED95) of butorphanol tartrate in patients undergoing painless gastroscopy. METHODS: Patients who underwent painless gastroscopy at Binzhou Medical University Hospital were divided into the youth, middle-aged, and older groups. The ED50 and ED95 required for successful sedation using butorphanol tartrate were measured using the Dixon up-and-down method in patients in the different age groups. Patients in each group were administered intravenous butorphanol 5 minutes before gastroscopy. Each patient was administered 2 mg/kg propofol. The ED50 and ED95 of butorphanol were calculated using probit analysis. RESULTS: In total, 95 patients were included. The ED50s of butorphanol in the youth, middle-aged, and older groups were 7.384, 6.657, and 6.364 µg/kg, respectively. The ED95s of butorphanol doses in these groups were 9.108, 8.419, and 7.348 µg/kg, respectively. CONCLUSIONS: The ED50 and ED95 varied among the age groups, indicating that the effective dose decreases with age.


Assuntos
Butorfanol , Gastroscopia , Humanos , Butorfanol/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Gastroscopia/métodos , Idoso , Fatores Etários , Relação Dose-Resposta a Droga , Adulto Jovem , Adolescente , Propofol/administração & dosagem
6.
Int J Biochem Cell Biol ; 176: 106662, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39293559

RESUMO

Dysregulated protein homeostasis, characterized by abnormal protein accumulation and aggregation, is a key contributor to the progression of neurodegenerative disorders such as Huntington's disease and spinocerebellar ataxia type 3 (SCA3). Previous studies have identified PIAS1 gene variants in patients with late-onset SCA3 and Huntington's disease. This study aims to elucidate the role of PIAS1 and its S510G variant in modulating the pathogenic mechanisms of SCA3. Through in vitro biochemical analyses and in vivo assays, we demonstrate that PIAS1 stabilizes both wild-type and mutant ataxin-3 (ATXN3). The PIAS1 S510G variant, however, selectively reduces the stability and SUMOylation of mutant ATXN3, thereby decreasing its aggregation and toxicity while maintaining the stability of wild-type ATXN3. This effect is mediated by a weakened interaction with the SUMO-conjugating enzyme UBC9 in the presence of mutant ATXN3. In Drosophila models, downregulation of dPIAS1 resulted in reduced levels of mutant ATXN3 and alleviated associated phenotypes, including retinal degeneration and motor dysfunction. Our findings suggest that the PIAS1 S510G variant acts as a genetic modifier of SCA3, highlighting the potential of targeting SUMOylation as a therapeutic strategy for this disease.

7.
Ecotoxicol Environ Saf ; 285: 117061, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39303633

RESUMO

Bisphenol H (BPH) has emerged as a potential alternative to bisphenol A (BPA), which has been curtailed for use due to concerns over its reproductive and endocrine toxicity. This study investigates whether BPH exerts antiandrogenic effects by impairing Leydig cell function, a critical component in testosterone production. We administered orally BPH to adult male rats at doses of 0, 1, 10, and 100 mg/kg/day for 7 days. Notably, BPH treatment resulted in a dose-dependent reduction in testicular testosterone levels, with significant decreases observed at ≥ 1 mg/kg/day. Additionally, BPH affected the expression of key genes involved in steroidogenesis and cholesterol metabolism, including Nr5a1, Nr3c4, Lhcgr, Scarb1, and Star, at higher doses (10 and/or 100 mg/kg/day). The study also revealed alterations in antioxidant gene expression (Sod2 and Cat) and modulation of m6A-related genes (Ythdf1-3 and Foxo3) and their proteins. Through MeRIP-qPCR analysis, we identified increased m6A modifications in Scarb1 and Star genes following BPH exposure. In vitro experiments with primary Leydig cells confirmed that BPH enhanced oxidative stress and diminished testosterone production, which were partially mitigated by antioxidant vitamin E supplementation and Ythdf3 knockdown. Meanwhile, simultaneous administration of BPH and vitamin E to primary Leydig cells partially counteracted BPH-induced alterations in the Ythdf3 expression. Our findings underscore a novel mechanism by which BPH disrupts Leydig cell function through the oxidative stress-m6A modification-autophagy pathway, raising concerns about its potential reproductive toxicity.

8.
Zhen Ci Yan Jiu ; 49(8): 858-866, 2024 Aug 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-39318316

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease with high incidence in the elderly population, and the synaptic changes in central neurons are the key pathological feature. The clinical effect of acupuncture and moxibustion in the treatment of AD is positive, and the research on the mechanism of acupuncture intervention of AD from the perspective of central synaptic plasticity regulation has been conducted uninterruptedly. In the present paper, we made a summation about the relevant experimental studies in recent years, and analyzed its mechanisms underlying improvement of AD by regulating synaptic plasticity from 1) repairing synaptic structure (synaptic contact area ï¼»total number of synapses, synaptic surface density, synaptic number densityï¼½, postsynaptic dense zone thickness, synaptic gap width, and interface curvature), 2) improving synaptic transmission efficiency (regulating long-term potentiation and long-term depression), 3) promoting the expression of synapse related proteins (synaptophysin, postsynaptic density protein 95, growth associated protein 43), 4) regulating the expression of neurotransmitters (acetylcholine, monoamines, amino acids, etc.) and receptors (α7 nicotinic acetylcholine receptor, glutaminergic receptor, etc.), and 5) improving the level of neurotrophic factors (brain derived neurotrophic factor, BDNF) and BDNF/SYN/microtubule-associated protein 2 signaling, etc., hoping to provide a reference for future studies.


Assuntos
Terapia por Acupuntura , Doença de Alzheimer , Plasticidade Neuronal , Doença de Alzheimer/terapia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Humanos , Animais , Sinapses/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética
9.
Chemistry ; : e202402688, 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39325539

RESUMO

In the Morita-Baylis-Hillman (MBH) reaction, a nucleophile undergoes ß-addition to activated alkenes or alkynes, forming reactive intermediates for subsequent carbon-carbon or carbon-hetero bond formation. By using a π-conjugated acceptor, however, an unprecedented reactivity of 1,3-enynoates and indane-1,3-diones was uncovered in the presence of phosphines. When indan-1,3-diones were used, Î³-addition of phosphines to 1,3-enynoates was observed for the first time; moderate to good yields were obtained for 14 substances containing the prominent spirocyclopropane scaffold with 100% retention of (Z)-alkene. When 2-methyl-indan-1,3-diones were used, di(tri)-substituted furans were produced through the δ-addition pathway, with 20 substances and a yield of up to 88% being achieved. Control experiments and density functional theory calculations were conducted to obtain insights into the unconventional γ-addition reaction pathway.

10.
Chem Biol Interact ; 403: 111251, 2024 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-39313105

RESUMO

Bisphenol A (BPA) and its analogues are widely used industrial chemicals. Placental 3ß-hydroxysteroid dehydrogenases (3ß-HSDs) catalyse the conversion of pregnenolone to progesterone. However, the potency of BPA analogues in inhibiting 3ß-HSDs activity remains unclear. We investigated the inhibitory effect of 10 BPA analogues on 3ß-HSDs activity using an in vitro assay and performed the structure-activity relationship and in silico docking analysis. BPH was the most potent inhibitor of human 3ß-HSD1, with an IC50 value of 0.95 µM. BPFL, BPG, DABPA, BPAP, BPZ, DMBPA, and BPB also inhibited human 3ß-HSD1 activity, albeit with lower potency. BPG was the most potent inhibitor of rat 3ß-HSD4, with an IC50 value of 1.14 µM. BPAP, BPFL, BPG, BPH, BPZ, DABPA, and DMBPA are mixed inhibitors of human 3ß-HSD1 and they significantly inhibited human JAr cells to secrete progesterone. The LogP values were inversely correlated with the inhibitory effects. Docking analysis showed that most BPA analogues bind to steroid-binding site of both 3ß-HSDs. A pharmacophore containing hydrogen bond donor and hydrophobic region was generated for predicting the inhibitory strength of BPA analogues. In conclusion, this study demonstrates that some BPA analogues are potent inhibitors of 3ß-HSDs and lipophilicity determines the inhibitory potency.

11.
Microorganisms ; 12(9)2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39338575

RESUMO

Nitrogen-cycling processes in the deep sea remain understudied. This study investigates the distribution of nitrogen-cycling microbial communities in the deep-sea surface sediments of the western South China Sea, using metagenomic sequencing and real-time fluorescent quantitative PCR techniques to analyze their composition and abundance, and the effects of 11 environmental parameters, including NH4+-N, NO3--N, NO2--N, PO43--P, total nitrogen (TN), total organic carbon (TOC), C/N ratio, pH, electrical conductivity (EC), SO42-, and Cl-. The phylum- and species-level microbial community compositions show that five sites can be grouped as a major cluster, with sites S1 and S9 forming a sub-cluster, and sites S13, S19, and S26 forming the other; whereas sites S3 and S5 constitute a separate cluster. This is also evident for nitrogen-cycling functional genes, where their abundance is influenced by distinct environmental conditions, including water depths (shallower at sites S1 and S9 against deeper at sites S13, S19, and S26) and unique geological features (sites S3 and S5), whereas the vertical distribution of nitrogen-cycling gene abundance generally shows a decreasing trend against sediment depth. Redundancy analysis (RDA) exploring the correlation between the 11 environmental parameters and microbial communities revealed that the NO2--N, C/N ratio, and TN significantly affect microbial community composition (p < 0.05). This study assesses the survival strategies of microorganisms within deep-sea surface sediments and their role in the marine nitrogen cycle.

12.
Anal Chem ; 96(36): 14471-14479, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39185581

RESUMO

The spatial constraints imposed by the DNA structure have significant implications for the walking efficiency of three-dimensional DNA walkers. However, accurately quantifying and manipulating steric hindrance remains a challenging task. This study presents a steric hindrance-controlled DNA walker utilizing an enzymatic strand displacement amplification (ESDA) strategy for detecting microRNA-21 (miR-21) with tunable dynamic range and sensitivity. The steric hindrance of the DNA walker was precisely manipulated by varying the length of empty bases from 6.5 Što 27.4 Šat the end of the track strand and adjusting the volumetric dimensions of the hairpin structure from 9.13 nm3 to 26.2 nm3 at the terminus of the single-foot DNA walking strand. This method demonstrated a tunable limit of detection for miR-21 ranging from 3.6 aM to 35.6 nM, along with a dynamic range from ∼100-fold to ∼166 000-fold. Impressively, it exhibited successful identification of cancer cells and clinical serum samples with high miR-21 expression. The proposed novel strategy not only enables tunable detection of miRNA through the regulation of steric hindrance but also achieves accurate and quantitative analysis of the steric hindrance effect, promising broader applications in personalized medicine, early disease detection, and drug development.


Assuntos
DNA , MicroRNAs , Técnicas de Amplificação de Ácido Nucleico , MicroRNAs/análise , MicroRNAs/sangue , Humanos , DNA/química , Limite de Detecção , Técnicas Biossensoriais
13.
Dalton Trans ; 53(35): 14866-14874, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39189107

RESUMO

In this study, we present a series of theoretically designed B2G14G14' molecules, featuring four-membered-ring heterocycles containing boron and heavy group 14 elements (G14 and G14' = Si, Ge, Sn, and Pb). Through the use of density functional theory (DFT), natural bond orbital (NBO) analysis, quantum theory of atoms in molecules (QTAIM), and electron localization function (ELF), our studies demonstrate a strong π single bond between the bridgehead G14 and G14' atoms, with minimal participation from a very weak G14-G14' σ bond. Additionally, the nucleus independent chemical shift (NICS), anisotropy of current-induced density (ACID), and adaptive natural density partitioning (AdNDP) analyses definitively establish the presence of both σ-aromaticity and π-aromaticity in these inorganic four-membered heterocyclic neutral molecules.

14.
Int J Mol Sci ; 25(16)2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39201744

RESUMO

Idiopathic granulomatous mastitis (IGM) is a rare condition characterised by chronic inflammation and granuloma formation in the breast. The aetiology of IGM is unclear. By focusing on the protein-coding regions of the genome, where most disease-related mutations often occur, whole-exome sequencing (WES) is a powerful approach for investigating rare and complex conditions, like IGM. We report WES results on paired blood and tissue samples from eight IGM patients. Samples were processed using standard genomic protocols. Somatic variants were called with two analytical pipelines: nf-core/sarek with Strelka2 and GATK4 with Mutect2. Our WES study of eight patients did not find evidence supporting a clear genetic component. The discrepancies between variant calling algorithms, along with the considerable genetic heterogeneity observed amongst the eight IGM cases, indicate that common genetic drivers are not readily identifiable. With only three genes, CHIT1, CEP170, and CTR9, recurrently altering in multiple cases, the genetic basis of IGM remains uncertain. The absence of validation for somatic variants by Sanger sequencing raises further questions about the role of genetic mutations in the disease. Other potential contributors to the disease should be explored.


Assuntos
Sequenciamento do Exoma , Mastite Granulomatosa , Humanos , Feminino , Mastite Granulomatosa/genética , Mastite Granulomatosa/patologia , Mastite Granulomatosa/diagnóstico , Adulto , Mutação , Genômica/métodos , Pessoa de Meia-Idade , Predisposição Genética para Doença
15.
Fish Shellfish Immunol ; 153: 109836, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39147177

RESUMO

Pseudomonas plecoglossicida is one of most important pathogenic bacterial species in large yellow croaker and several other commercially valuable fish species. In our previous study, a GacS deficient mutant (ΔgacS) was constructed and its virulence showed substantially attenuated. In present study, the safety, immunogenicity and protective effect of the ΔgacS were evaluated in large yellow croaker as a live-attenuated vaccine candidate. It was shown that the ΔgacS strain exhibited good safety to large yellow croaker and there was no mortality or clinical symptoms observed in all fish that infected by ΔgacS strain with the doses range from 2 × 105~107 CFU per fish via intraperitoneal injection (IP) or immersion (IM), and almost all bacteria were cleaned up in the spleen of the fish at 14-day post infection. Specific antibodies could be detected at 7-day and 14-day post infection by direct agglutination method, and the valences of antibodies and bactericidal activities of the serum were significant increased with vaccination doses and vaccination time. Moreover, the expressions of some molecules and cytokines involved in specific immune responses were detected in the ΔgacS strain immunization group and control group. After challenged by the wild-type (WT) strain XSDHY-P, the relative percentage survival (RPS) showed highly correlated with the immunized dosage regardless of vaccination methods. It showed that the RPS of the IP groups were 39.47 %, 57.89 %, 71.05 % with the immune dosage in a descending order, respectively, and the RPS of the IM groups were 26.31 %, 36.84 %, 76.31 % with the immune dosage in a descending order, respectively. In summary, the ΔgacS strain exhibited safety and good protective effect to large yellow croaker and was a potential live vaccine candidate.


Assuntos
Doenças dos Peixes , Perciformes , Infecções por Pseudomonas , Pseudomonas , Vacinas Atenuadas , Animais , Doenças dos Peixes/imunologia , Doenças dos Peixes/prevenção & controle , Perciformes/imunologia , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Infecções por Pseudomonas/veterinária , Infecções por Pseudomonas/prevenção & controle , Infecções por Pseudomonas/imunologia , Pseudomonas/imunologia , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/administração & dosagem , Vacinas contra Pseudomonas/imunologia , Vacinas contra Pseudomonas/genética , Imunogenicidade da Vacina
16.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1869(8): 159559, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39179098

RESUMO

Trimethylamine N-oxide (TMAO), a metabolite produced by intestinal flora, is recognized as an independent risk factor for atherosclerosis and atherosclerotic cardiovascular diseases. However, the underlying mechanism remains poorly understood. Here, we showed that dietary TMAO supplementation accelerates atherosclerosis in ApoE-/- mice. Pyroptosis and the expression of phospholipid-modifying enzyme MBOAT2 were increased in endothelial cells within atherosclerotic lesions. Genetic upregulation of MBOAT2 via adeno-associated virus with endothelium-specific promoter results in increased atherosclerotic lesions in ApoE-/- mice. Mechanistically, the overexpression of MBOAT2 disrupted glycerophospholipid metabolism and induced endothelial cell pyroptosis in an Endoplasmic reticulum stress-dependent manner. These data reveal that TMAO promotes endothelial cell pyroptosis and the progression of atherosclerotic lesions through the upregulation of MBOAT2, indicating that MBOAT2 is a promising therapeutic target for atherosclerosis.


Assuntos
Aterosclerose , Células Endoteliais , Metilaminas , Piroptose , Animais , Humanos , Masculino , Camundongos , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Estresse do Retículo Endoplasmático , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/efeitos dos fármacos , Metilaminas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigenases
17.
Dig Dis Sci ; 69(9): 3382-3391, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39090445

RESUMO

BACKGROUND/AIMS: Crohn's Disease (CD) can affect the entire gastrointestinal tract, including the upper sections (UGI), which is often overlooked, especially in Asian populations. There's a notable gap in research regarding the impact of UGI involvement on the intricate landscape of ensuing complications. This study aims to address this gap. METHODS: Conducting a retrospective study at Chang Gung Memorial Hospital from January 2001 to September 2023, we compared CD patients with UGI (Montreal L4) involvement against non-L4 counterparts, focusing on baseline characteristics, post-diagnosis complications, and overall outcomes. Routine UGI endoscopy was performed around the time of diagnosis in all patients followed in our inflammatory bowel disease (IBD) center, and all CD patients with adequate follow-up were included in this study. RESULTS: The study included 212 CD patients, 111 in the L4 group and 101 in the non-L4 group, with an average follow-up of 40.8 ± 15.1 months. At baseline, individuals in the L4 category demonstrated elevated smoking rates, increased Crohn's Disease Activity Index scores, a higher prevalence of strictures, and a more prevalent usage of biologics and proton pump inhibitors. Moreover, this group was characterized by reduced albumin levels. Upon concluding the follow-up, those with L4 involvement continued to show escalated CDAI scores and hospitalization frequencies, alongside heightened C-reactive protein levels and diminished albumin concentrations. Additionally, the occurrence of UGI involvement, stricturing disease at the time of diagnosis, and a younger age at the onset of CD were pinpointed as independent predictors for the development of new-onset strictures. CONCLUSIONS: CD patients with UGI involvement exhibit elevated disease activity and serve as independent predictors for the development of intestinal strictures. Thorough UGI evaluations at the time of diagnosis, coupled with assertive treatment strategies, are essential for managing these patients effectively.


Assuntos
Doença de Crohn , Humanos , Doença de Crohn/complicações , Doença de Crohn/epidemiologia , Doença de Crohn/diagnóstico , Estudos Retrospectivos , Masculino , Feminino , Adulto , Constrição Patológica , Pessoa de Meia-Idade , Trato Gastrointestinal Superior/patologia , Endoscopia Gastrointestinal , Adulto Jovem , Fatores de Risco
18.
Anal Chim Acta ; 1319: 342980, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39122289

RESUMO

The traditional preparation method of ratiometric probes faces challenges such as cumbersome preparation and low sensitivity. Thus, there is an urgent need to provide a simple method of preparing a highly sensitive ratiometric probe. Here, Eu3+-doped zinc-based organic framework (Eu/Zn-MOF) was prepared through hydrothermal method for the detection of tetracycline analogs (TCs). Under the same excitation conditions, the probe can simultaneously display valuable fluorescence and second-order scattering signals. The developed probe enabled specific identification and fast detection (1 min) of TCs, including tetracycline, oxytetracycline, doxycycline, and chlortetracycline. The linear detection ranges of tetracycline, oxytetracycline, doxycycline and chlortetracycline were respectively 100 nM - 200 µM, 100 nM - 200 µM, 98 nM - 195 µM, and 97 nM - 291 µM, and the corresponding detection limits were respectively 15.79 nM, 20.83 nM, 15.31 nM, and 28.30 nM. The developed sensor was successfully applied to detect TCs in real samples, and the recovery rate was from 92.54 % to 109.69 % and the relative standard deviation was from 0.04 % to 2.97 %. Moreover, the heterometallic Eu/Zn-MOF was designed as a ratiometric neuron for Boolean logic computing and information encryption based on the specific identification of TCs. As a proof of concept, molecular steganography was successfully employed to encode, store, and conceal information by transforming the specific identification patterns of Eu/Zn-MOF into binary strings. This study is anticipated to advance the application of metal-organic frameworks in logic detection and information security, and bridging the gap between molecular sensors and the realm of information.


Assuntos
Európio , Estruturas Metalorgânicas , Espectrometria de Fluorescência , Zinco , Estruturas Metalorgânicas/química , Európio/química , Zinco/química , Zinco/análise , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Tetraciclinas/análise , Limite de Detecção , Antibacterianos/análise , Tetraciclina/análise , Fluorescência
19.
J Colloid Interface Sci ; 677(Pt B): 40-48, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39133997

RESUMO

CoFe-based catalysts are efficient electrocatalysts for the oxygen evolution reaction (OER) in alkaline media. Here, we present a simple one-pot hydrothermal method for synthesizing a series of CoFe glycerates with controllable surface morphologies and investigate their potential as highly efficient catalysts for the OER in alkaline media. These CoFe glycerates exhibit a unique yolk-shell microsphere structure assembled from ultrathin nanosheets. The adjustment of the surface nanosheet size is achieved by varying the CoFe ratio, ensuring a more efficient electrocatalytic system for the OER process. Due to the abundant active sites provided by the yolk-shell structure and interleaved ultrathin nanosheets, Co3Fe1 glycerate (Co3Fe1 gly) demonstrates a low overpotential (283 mV) and a small Tafel slope (44.61 mV dec-1) at 10 mA cm-2. Additionally, Co3Fe1 gly exhibits excellent durability in alkaline electrolytes. Moreover, a series of characterizations demonstrate that the active sites of Co3Fe1 gly are the high-valence Co species generated during the OER process. This study opens a promising avenue for utilizing efficient and low-cost electrocatalysts to enhance OER performance.

20.
ACS Omega ; 9(30): 33270-33278, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39100323

RESUMO

The effect of chemical element on the reactivity for carbazolation reaction of phenylacetylene utilizing G13(C6F5)3 (Lewis acid) and G15-carbazole (Lewis base) was theoretically investigated using density functional theory (M06-2X-D3/def2-TZVP), where G13 represents Group 13 elements and G15 represents Group 15 elements. Through activation strain model (ASM) analysis, it is apparent that the reactivity of the entire carbazolation reaction is chiefly governed by the structural strain energy of the alkyne fragment. In other words, if G13(C6F5)3 or G15-carbazole features an atomic radius that is either too small (e.g., B atom) or too large (e.g., Tl or Bi atom), it results in inadequate orbital overlap between the reactants due to the impact of steric effects. This, in turn, results in an elevation of the activation energy for such reactions, thereby impeding the alkyne from undergoing the carbazole catalytic reaction. In light of the above analyses, our theoretical findings suggest that, except for Tl(C6F5)3, the other four Lewis acid catalysts (B(C6F5)3, Al(C6F5)3, Ga((C6F5)3, and In((C6F5)3) demonstrate effectiveness in catalyzing the carbazolation reaction of alkyne alongside with N-carbazole. Additionally, it is anticipated that, among the five categories of G15-carbazole molecules studied, only N-carbazole can participate in the carbazolation reaction with alkyne catalyzed by B(C6F5)3, considering both kinetic and thermodynamic factors at room temperature. Our theoretical investigations, as outlined in this study, indicate that the carbazolation reaction of the alkyne, catalyzed by G13(C6F5)3 and G15-carbazole, follows Hammond's postulate. To put it more plainly, when the transition state of the chemical reaction occurs earlier, it results in a decrease in activation energy.

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