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1.
J Immunol ; 212(1): 130-142, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37975680

RESUMO

Pigs are the most suitable model to study various therapeutic strategies and drugs for human beings, although knowledge about cell type-specific transcriptomes and heterogeneity is poorly available. Through single-cell RNA sequencing and flow cytometry analysis of the types in the jejunum of pigs, we found that innate lymphoid cells (ILCs) existed in the lamina propria lymphocytes (LPLs) of the jejunum. Then, through flow sorting of live/dead-lineage (Lin)-CD45+ cells and single-cell RNA sequencing, we found that ILCs in the porcine jejunum were mainly ILC3s, with a small number of NK cells, ILC1s, and ILC2s. ILCs coexpressed IL-7Rα, ID2, and other genes and differentially expressed RORC, GATA3, and other genes but did not express the CD3 gene. ILC3s can be divided into four subgroups, and genes such as CXCL8, CXCL2, IL-22, IL-17, and NCR2 are differentially expressed. To further detect and identify ILC3s, we verified the classification of ILCs in the porcine jejunum subgroup and the expression of related hallmark genes at the protein level by flow cytometry. For systematically characterizing ILCs in the porcine intestines, we combined our pig ILC dataset with publicly available human and mice ILC data and identified that the human and pig ILCs shared more common features than did those mouse ILCs in gene signatures and cell states. Our results showed in detail for the first time (to our knowledge) the gene expression of porcine jejunal ILCs, the subtype classification of ILCs, and the markers of various ILCs, which provide a basis for an in-depth exploration of porcine intestinal mucosal immunity.


Assuntos
Imunidade Inata , Linfócitos , Humanos , Animais , Camundongos , Suínos , Jejuno , Células Matadoras Naturais , Mucosa
2.
Plant Cell Physiol ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38988198

RESUMO

As a model plant for bryophytes, Marchantia polymorpha offers insights into the role of RNA silencing in aiding early land plants navigate the challenges posed by high-temperature environments. Genomic analysis revealed unique ARGONAUTE1 ortholog gene (MpAGO1) in M. polymorpha that is regulated by two species-specific microRNAs (miRNAs), miR11707.1 and miR11707.2. Comparative studies of small RNA profiles from M. polymorpha cellular and MpAGO1 immunoprecipitation (MpAGO1-IP) profiles at various temperatures, along with analyses of Arabidopsis AGO1 (AtAGO1), revealed that MpAGO1 has a low-selectivity for a diverse range of small RNA species than AtAGO1. Protein structural comparisons revealed no discernible differences in the MID domains of MpAGO1 and AtAGO1, suggesting the complexity of miRNA species specificity and necessitating further exploration. Small RNA profiling and size exclusion chromatography have pinpointed a subset of M. polymorpha miRNAs, notably miR11707, that remain in free form within the cell at 22°C but are loaded into MpAGO1 at 28°C to engage in RNA silencing. Investigations into the mir11707 gene editing (mir11707ge) mutants provided evidence of the regulation of miR11707 in MpAGO1. Notably, while MpAGO1 mRNA expression decreases at 28°C, the stability of the MpAGO1 protein and its associated miRNAs is essential for enhancing the RISC activity, revealing the importance of RNA silencing in enabling M. polymorpha to survive thermal stress. This study advances our understanding of RNA silencing in bryophytes and provides groundbreaking insights into the evolutionary resilience of land plants to climatic adversities.

3.
Plant Cell Physiol ; 65(7): 1115-1134, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38545690

RESUMO

The miR390-derived TAS3 trans-acting short-interfering RNAs (tasiRNAs) module represents a conserved RNA silencing pathway in the plant kingdom; however, its characterization in the bryophyte Marchantia polymorpha is limited. This study elucidated that MpDCL4 processes MpTAS3 double-stranded RNA (dsRNA) to generate tasiRNAs, primarily from the 5'- and 3'-ends of dsRNA. Notably, we discovered a novel tasiRNA, tasi78A, which can negatively regulate a cytochrome P450 gene, MpCYP78A101. Additionally, tasi78A was abundant in MpAGO1, and transient expression assays underscored the role of tasi78A in repressing MpCYP78A101. A microRNA, miR11700, also regulates MpCYP78A101 expression. This coordinate regulation suggests a role in modulating auxin signaling at apical notches of gemma, influencing the growth and sexual organ development of M. polymorpha and emphasizing the significance of RNA silencing in MpCYP78A101 regulation. However, phylogenetic analysis identified another paralog of the CYP78 family, Mp1g14150, which may have a redundant role with MpCYP78A101, explaining the absence of noticeable morphological changes in loss-of-function plants. Taken together, our findings provide new insights into the combined regulatory roles of miR390/MpTAS3/miR11700 in controlling MpCYP78A101 and expand our knowledge about the biogenesis and regulation of tasiRNAs in M. polymorpha.


Assuntos
Sistema Enzimático do Citocromo P-450 , Regulação da Expressão Gênica de Plantas , Marchantia , MicroRNAs , RNA Interferente Pequeno , Marchantia/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Filogenia , RNA de Plantas/genética , RNA de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
4.
Biol Reprod ; 111(1): 135-147, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38401166

RESUMO

OBJECTIVE: This study aimed to explore the specific pathways by which HOX transcript antisense intergenic RNA contributes to the pathogenesis of unexplained recurrent spontaneous abortion. METHODS: Real-time quantitative PCR was employed to assess the differential expression levels of HOX transcript antisense intergenic RNA in chorionic villi tissues from unexplained recurrent spontaneous abortion patients and women with voluntarily terminated pregnancies. HTR-8/SVneo served as a cellular model. Knockdown and overexpression of HOX transcript antisense intergenic RNA in the cells were achieved through siRNA transfection and pcDNA3.1 transfection, respectively. Cell viability, migration, and invasion were evaluated using cell counting kit-8, scratch, and Transwell assays, respectively. The interaction among the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 axis was predicted through bioinformatics analysis and confirmed through in vitro experiments. Furthermore, the regulatory effects of the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 signaling axis on cellular behaviors were validated in HTR-8/SVneo cells. RESULTS: We found that HOX transcript antisense intergenic RNA was downregulated in chorionic villi tissues from unexplained recurrent spontaneous abortion patients. Overexpression of HOX transcript antisense intergenic RNA significantly enhanced the viability, migration, and invasion of HTR-8/SVneo cells, while knockdown of HOX transcript antisense intergenic RNA had the opposite effects. We further confirmed the regulatory effect of the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 signaling axis in unexplained recurrent spontaneous abortion. Specifically, HOX transcript antisense intergenic RNA and fibrillin 2 were found to reduce the risk of unexplained recurrent spontaneous abortion by enhancing cell viability, migration, and invasion, whereas miR-1277-5p exerted the opposite effects. CONCLUSION: HOX transcript antisense intergenic RNA promotes unexplained recurrent spontaneous abortion development by targeting inhibition of miR-1277-5p/fibrillin 2 axis.


Assuntos
Aborto Habitual , Movimento Celular , MicroRNAs , RNA Longo não Codificante , Transdução de Sinais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Feminino , Aborto Habitual/genética , Aborto Habitual/metabolismo , Aborto Habitual/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Gravidez , Fibrilina-2/genética , Fibrilina-2/metabolismo , Adulto , Proliferação de Células , Linhagem Celular , Trofoblastos/metabolismo , Trofoblastos/fisiologia , Vilosidades Coriônicas/metabolismo
5.
Am J Geriatr Psychiatry ; 32(5): 611-621, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38199936

RESUMO

OBJECTIVE: Eradication of hepatitis C virus (HCV) infection has been linked with improvement in neurocognitive function, but few studies have evaluated the effect of antiviral treatment/ response on risk of dementia. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we investigated how antiviral therapy impacts the risk of developing dementia among patients with HCV. METHODS: A total of 17,485 HCV patients were followed until incidence of dementia, death, or last follow-up. We used an extended landmark modeling approach, which included time-varying covariates and propensity score justification for treatment selection bias, as well as generalized estimating equations (GEE) with a link function as multinominal distribution for a discrete time-to-event data. Death was considered a competing risk. RESULTS: After 15 years of follow-up, 342 patients were diagnosed with incident dementia. Patients who achieved sustained virological response (SVR) had significantly decreased risk of dementia compared to untreated patients, with hazard ratios (HRs) of 0.32 (95% CI 0.22-0.46) among patients who received direct-acting antiviral (DAA) treatment and 0.41 (95% CI 0.26-0.60) for interferon-based (IFN) treatment. Risk reduction remained even when patients failed antiviral treatment (HR 0.38, 95% CI 0.38-0.51). Patients with cirrhosis, Black/African American patients, and those without private insurance were at significantly higher risk of dementia. CONCLUSION: Antiviral treatment independently reduced the risk of dementia among HCV patients, regardless of cirrhosis. Our findings support the importance of initiation antiviral therapy in chronic HCV-infected patients.


Assuntos
Demência , Hepatite C Crônica , Hepatite C , Humanos , Antivirais/efeitos adversos , Hepacivirus , Estudos de Coortes , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Demência/etiologia , Demência/induzido quimicamente
6.
Int J Med Sci ; 21(10): 1814-1823, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39113885

RESUMO

Background: BMS-1166, a PD-1/PD-L1 inhibitor, inhibits the binding of PD-L1 to PD-1, restores T cell function, and enhances tumor immune response. However, mutations in the tumor suppressor or impaired cellular signaling pathways may also lead to cellular transformation. In this study, the SW480 and SW480R cell lines were used as the model to elucidate the treatment with BMS-1166, BEZ235, and their combination. Methods: MTT and colony-formation assays were used to evaluate cell proliferation. Wound-healing assay was used to assess cell migration. Cell cycle and apoptosis were analyzed by flow cytometry. The phosphorylation level of the key kinases in the PI3K/Akt/mTOR and MAPK pathways, PD-L1, and the protein levels related to the proliferation, migration, and apoptosis were assessed using western blotting. Results: BEZ235 enhanced BMS-1166-mediated cell proliferation and migration inhibition in SW480 and SW480R cells and promoted apoptosis. Interestingly, the downregulation of the negative regulator PTEN raised the PD-L1 level, which was abolished by the inhibition of Akt. BMS-1166 promoted PI3K, Akt, mTOR, and Erk phosphorylation. However, the combination of BEZ235 with BMS-1166 suppressed the expression of PI3K, p-Akt, p-mTOR, and p-Erk in SW480 and SW480R cells compared to BMS-1166 or BEZ235 single treatment by inhibiting the binding of PD1 to PD-L1. Conclusions: PD-1 binds to PD-L1 and activates the PI3K/mTOR and MAPK pathways, which might be the molecular mechanism of acquired resistance of CRC to BMS-1166. The combination of the two drugs inhibited the phosphorylation of PI3K, Akt, and Erk in the PI3K/mTOR and MAPK pathway, i.e., BEZ235 enhanced the BMS-1166 treatment effect by blocking the PI3K/mTOR pathway and interfering with the crosstalk of the MAPK pathway. Therefore, these findings provide a theoretical basis for BMS-1166 combined with BEZ235 in the trial treatment of colorectal cancer.


Assuntos
Apoptose , Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Imidazóis , Inibidores de Fosfoinositídeo-3 Quinase , Quinolinas , Serina-Treonina Quinases TOR , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Sinergismo Farmacológico , Imidazóis/farmacologia , Inibidores de MTOR/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores
7.
Lipids Health Dis ; 23(1): 83, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509578

RESUMO

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.


Assuntos
Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Fitosteróis/efeitos adversos , Xantomatose , Humanos , Criança , Lipoproteínas/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Fitosteróis/genética , Colesterol , Ezetimiba/uso terapêutico
8.
Mar Drugs ; 22(7)2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39057432

RESUMO

Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild populations and harm to local environments. To fully utilize aquaculture as a source of biologically active products, a cell-free system was established to target molecular components with protein-modulating activity, including topoisomerase II, HDAC, and tubulin polymerization, using extracts from aquaculture corals. Subsequent in vitro studies were performed, including MTT assays, flow cytometry, confocal microscopy, and Western blotting, along with in vivo xenograft models, to verify the efficacy of the active extracts and further elucidate their cytotoxic mechanisms. Regulatory proteins were clarified using NGS and gene modification techniques. Molecular docking and SwissADME assays were performed to evaluate the drug-likeness and pharmacokinetic and medicinal chemistry-related properties of the small molecules. The extract from Lobophytum crassum (LCE) demonstrated potent broad-spectrum activity, exhibiting significant inhibition of tubulin polymerization, and showed low IC50 values against prostate cancer cells. Flow cytometry and Western blotting assays revealed that LCE induced apoptosis, as evidenced by the increased expression of apoptotic protein-cleaved caspase-3 and the populations of early and late apoptotic cells. In the xenograft tumor experiments, LCE significantly suppressed tumor growth and reduced the tumor volume (PC3: 43.9%; Du145: 49.2%) and weight (PC3: 48.8%; Du145: 7.8%). Additionally, LCE inhibited prostate cancer cell migration, and invasion upregulated the epithelial marker E-cadherin and suppressed EMT-related proteins. Furthermore, LCE effectively attenuated TGF-ß-induced EMT in PC3 and Du145 cells. Bioactivity-guided fractionation and SwissADME validation confirmed that LCE's main component, 13-acetoxysarcocrassolide (13-AC), holds greater potential for the development of anticancer drugs.


Assuntos
Antozoários , Antineoplásicos , Apoptose , Aquicultura , Produtos Biológicos , Animais , Antozoários/química , Antineoplásicos/farmacologia , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Camundongos , Desenvolvimento de Medicamentos , Ensaios Antitumorais Modelo de Xenoenxerto , Simulação de Acoplamento Molecular , Masculino , Tubulina (Proteína)/metabolismo , Camundongos Nus
9.
Int Wound J ; 21(2): e14744, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38358070

RESUMO

An association between venous leg ulcers (VLU) and chronic heart failure (CHF) has been suggested by observational research. This study used Mendelian randomization (MR) methods to look into any possible bidirectional causal links between VLU and CHF. The 'TwoSampleMR' R package was employed for MR analyses. The association of VLU and CHF was assessed via methods of inverse variance weighted (IVW), weighted mode, MR Egger and weighted median. Results of IVW suggested no association between VLU and CHF (ß 0.008356; SE 0.01889; p = 0.6582). The weighted median estimator (ß -0.005777; SE 0.02059, p = 0.7791), MR-Egger (ß -0.08955; SE 0.04557; p = 0.07296) and weighted mode (ß -0.01202; SE 0.02467; p = 0.6341) showed consistent results. Conversely, evidence indicating that the presence of CHF increased the risk of VLU was lacking. In conclusion, there is no bidirectional causal relationship between VLU and CHF. Further studies are required to validate the findings of this study.


Assuntos
Insuficiência Cardíaca , Úlcera Varicosa , Humanos , Análise da Randomização Mendeliana , Doença Crônica , Insuficiência Cardíaca/genética , Úlcera Varicosa/genética
10.
Zhongguo Zhong Yao Za Zhi ; 48(24): 6702-6710, 2023 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-38212030

RESUMO

This study aims to explore the influence of Polygonati Rhizoma on the pyroptosis in the rat model of diabetic macroangiopathy via the NOD-like receptor thermal protein domain associated protein 3(NLRP3)/cysteinyl aspartate specific proteinase-1(caspase-1)/gasdermin D(GSDMD) pathway. The rat model of diabetes was established by intraperitoneal injection of streptozotocin(STZ) combined with a high-fat, high-sugar diet. The blood glucose meter, fully automated biochemical analyzer, hematoxylin-eosin(HE) staining, enzyme-linked immunosorbent assay, immunofluorescence, immunohistochemistry, and Western blot were employed to measure blood glucose levels, lipid levels, vascular thickness, inflammatory cytokine levels, and expression levels of pyroptosis-related proteins. The mechanism of pharmacological interventions against the injury in the context of diabetes was thus explored. The results demonstrated the successful establishment of the model of diabetes. Compared with the control group, the model group showed elevated levels of fasting blood glucose, total cholesterol(TC), triglycerides(TG) and low-density lipoprotein cholesterol(LDL-c), lowered level of high-density lipoprotein cholesterol(HDL-c), thickened vascular intima, and elevated serum and aorta levels of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß) and interleukin-18(IL-18). Moreover, the model group showed increased NLRP3 inflammasomes and up-regulated levels of caspase-1 and GSDMD in aortic vascular cells. Polygonati Rhizoma intervention reduced blood glucose and lipid levels, inhibited vascular thickening, lowered the levels of TNF-α, IL-1ß, IL-18 in the serum and aorta, attenuated NLRP3 inflammasome expression, and down-regulated the expression levels of caspase-1 and GSDMD, compared with the model group. In summary, Polygonati Rhizoma can slow down the progression of diabetic macroangiopathy by inhibiting pyroptosis and alleviating local vascular inflammation.


Assuntos
Complicações do Diabetes , Diabetes Mellitus , Doenças Vasculares , Animais , Ratos , Caspase 1/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Interleucina-18 , Glicemia , Piroptose , Fator de Necrose Tumoral alfa , Inflamassomos , Colesterol , Lipídeos
11.
Front Nutr ; 11: 1347712, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38650639

RESUMO

Background: Periodontitis is a prevalent inflammatory periodontal disease that has an impact on the overall quality of life. Although several studies have indicated an association between individual vitamin intake and periodontitis risk, the associations of the multivitamins with periodontitis risk remain unclear. Aim: This study aimed to explore the joint effect of multivitamins (including vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, and vitamin K) on periodontitis. Methods: For this cross-sectional study, data were collected from participants aged ≥ 30 years in the National Health and Nutrition Examination Surveys 2009-2014 (n = 9,820). We employed weighted multivariate logistic regression models to evaluate the single association between individual vitamin intakes and periodontitis, and Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression, and quantile g-computation (qgcomp) models to assess the joint effect of nine vitamins on periodontitis. Results: The overall prevalence of periodontitis was approximately 35.97%. After adjustment of covariates, vitamin B6 [odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.72-0.94] and vitamin E (OR = 0.79, 95%CI: 0.69-0.92) were negatively related to the likelihood of developing periodontitis, respectively. The result of three models indicated that, mixture of vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, and vitamin K had a significant negative combined effect on the risk of periodontitis. In the BKMR model, when all remaining vitamins were at their median levels, the periodontitis risk decreased with increased concentration levels of vitamin E and vitamin B2. WQS analysis indicated the highest weighted chemical was vitamin E, followed by vitamin B12 and vitamin D. In the qgcomp model, vitamin E received the highest negative weights for the periodontitis risk, followed by vitamin B2 and vitamin D, respectively. Conclusion: Both dietary vitamin B6 and vitamin E were associated with decreased odds of periodontitis. Additionally, the mixture-exposed analyses consistently showed the negative correlations between nine dietary vitamins mixtures and periodontitis.

12.
Heliyon ; 10(13): e34150, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39071617

RESUMO

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) significantly impacts patients with type 2 diabetes mellitus (T2DM), where current non-invasive assessment methods show limited predictive power for future fibrotic progression. This study aims to develop an enhanced deep learning (DL) model that integrates ultrasound elastography images with clinical data, refining the prediction of fibrotic progression in T2DM patients with MASLD who initially exhibit no signs of hepatic fibrosis. Methods: We enrolled 946 diabetic MASLD patients without advanced fibrosis, confirmed by initial liver stiffness measurements (LSM) below 6.5 kPa. Patients were divided into a training dataset of 671 and a testing dataset of 275. Hepatic shear wave elastography (SWE) images measured liver stiffness, classifying participants based on progression. A DL integrated model (DI-model) combining SWE images and clinical data was trained and its predictive performance compared with individual Image and Tabular models, as well as a logistic regression model on the testing dataset. Results: Fibrotic progression was observed in 18.1 % of patients over three years. During the training phase, the DI-model outperformed other models, achieving the lowest validation loss of 0.161 and highest accuracy of 0.933 through cross-validation. In the testing phase, it demonstrated robust discrimination with AUCs of 0.884 and 0.903 for the receiver operating characteristic and precision-recall curves, respectively, clearly outperforming other models. Shapley analysis identified BMI, LSM, and glycated hemoglobin as critical predictors. Conclusion: The DI-model significantly enhances the prediction of future fibrotic progression in diabetic MASLD patients, demonstrating the benefit of combining clinical and imaging data for early diagnosis and intervention.

13.
Neurol Clin Pract ; 14(2): e200260, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38585442

RESUMO

Background and Objectives: Among health care providers (HCPs), neurologists have one of the highest rates of burnout in the United States, compromising the quality and accessibility of patient care. Patients with refractory epilepsy are especially challenging to treat. This study aims to understand the burnout level in neurologists treating patients with refractory epilepsy and identify key contributing factors. Methods: US board-certified pediatric/adult neurologists who devote ≥50% of their time to clinical practice and treat ≥10 unique patients with refractory epilepsy annually were invited to take a noninterventional quantitative survey, designed to capture key elements of the HCP's background, burnout level, current practice, burden domains, and satisfaction with current antiseizure medications (ASMs). Burnout in 3 domains (emotional exhaustion, depersonalization, and personal accomplishment) was assessed by the validated Maslach Burnout Inventory-Human Services Survey. Results: From March 11, 2022, to April 10, 2022, a total of 138 neurology-specialist HCPs participated in the survey, divided between adult epileptologists (n = 44), adult neurologists (n = 41), pediatric epileptologists (n = 36), and pediatric neurologists (n = 17). Of participating HCPs, 61% experienced at least some burnout (≥1 of 3 burnout domains categorized as high), and 4% experienced high burnout (3 of 3 burnout domains categorized as high). High burnout levels were driven by high pediatric and inpatient caseloads and unexpected pediatric patient reluctance to transition to adult care. HCPs with high burnout had a higher yearly caseload of patients with refractory epilepsy. Most HCPs (approximately 90%) indicated that patients with refractory epilepsy were more difficult to manage than those with nonrefractory epilepsy. The proportion of HCPs satisfied or extremely satisfied with ASMs was lower for patients with refractory epilepsy (20%) than that for patients with nonrefractory epilepsy (73%). Dissatisfaction was mostly due to workload and latency of the insurance approval process, out-of-pocket costs, and poor efficacy, safety, and tolerability. For 32% of HCPs, stopping practicing or moving to another practice within 5 years was probable or very probable. Discussion: Some burnout is common among HCPs who treat patients with refractory epilepsy. However, management of refractory epilepsy is challenging, and satisfaction with available ASMs is low. Thus, addressing these contributing factors may help to alleviate HCP burnout.

14.
Int J Biol Macromol ; 277(Pt 2): 134360, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39094855

RESUMO

Two novel sulfated polysaccharides (SPs), N10 and K5 were isolated from ammonium sulfate or potassium sulfate at concentrations of 10 mM and 5 mM in liquid cultures of Antrodia cinnamomea, respectively. N10 and K5 were galactoglucans with a galactose:glucose molar ratio of approximately 1:3. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, N10 and K5 exhibited strong anti-inflammatory potential, of 56 % and 23 % maximal inhibition of IL-6 and TNF-α production, respectively. Mechanical analysis revealed differences between N10 and K5, with N10 inhibiting the LPS-stimulated phosphorylation of ERK and p38 in RAW264.7 cells. K5 inhibited the LPS-stimulated phosphorylation of AKT and TGFßR-II. N10 and K5 were fragmented into F1, F2, and F3, the molecular weights of which were 455, 24, 0.9, and 327, 36, 1.9 kDa, respectively. K5 F2 and K5 F3 exhibited high degrees of sulfation of 1:3 and 1:8, resulting in strong anti-inflammation, of 83 % and 37 % highest inhibition of IL-6 and TNF-α production, respectively. Therefore, low-molecular-weight and high-sulfation-degree SPs exhibited strong anti-inflammatory activity. Specifically, K5 F2 inhibited the phosphorylation of p38, and K5 F3 suppressed the signaling pathway of p38/JNK. Overall, the sulfation degree of SPs is concluded to affect the anti-inflammatory responses.

15.
Foods ; 13(6)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38540805

RESUMO

Polygonatum cyrtonema Hua, an edible resource and medical material, is mainly consumed as a food in China. However, few published studies have comprehensively assessed its nutritional components. In this study, the proximate, carbohydrate, and dietary fiber contents as well as the mineral, vitamin, and amino acid compositions of five sources of P. cyrtomena grown in Yuhang district, Hangzhou city, Zhejiang province, were investigated. The nutritional profile of the five germplasms was investigated using analytical chemistry methods. All germplasms had a low starch content and contained greater amounts of carbohydrates (23.25-34.29%), protein (2.96-5.40%), Ca (195.08-282.08 mg/100 g), Fe (29.68-59.37 mg/100 g), and vitamin C (60.49-149.86 mg/100 g) in comparison to ginger, yam, and potatoes. The polysaccharide content ranged from 16.92% to 28.48%, representing the main source of carbohydrates. Fructose, a desirable sweetener, was the most abundant monosaccharide, representing 1.06% to 4.88% of the content. P. cyrtonema was found to be high in dietary fiber, with pectin and resistant starch being the major soluble components and hemicellulose being the dominant insoluble dietary fiber. A correlation analysis (CA) revealed significant correlations for the carbohydrate components and dietary fiber fractions with other nutrients. A principal component analysis (PCA) identified significant differences between the nutritional characteristics of the five germplasms, with Huanggang having the highest comprehensive quality scores. Moreover, ten nutrient components were selected as potential indicators that could be used to further evaluate the nutritional quality of P. cyrtomena. Our results demonstrate the rich nutrient composition and characteristics of P. cyrtonema and provide a valuable reference for the future development and utilization of Polygonatum.

16.
Front Microbiol ; 15: 1347204, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38559348

RESUMO

Introduction: With the increasing demand for health products derived from Polygonati rhizoma (PR), people begin to artificially plant Polygonatum cyrtonema Hua (P. cyrtonema) in the middle and lower reaches of the Yangtze River. To promote P. cyrtonema cultivation and increase farmers' income, efforts are needed to understand the ways to obtain high-quality PR under artificial cultivation conditions. Methods: Rhizomes of artificial planting P. cyrtonema and rhizosphere soils were collected across five regions in Zhejiang Province, China. Subsequently, the contents of the main active ingredients of P. cyrtonema and soil properties were analyzed, and both rhizosphere and endophytic bacteria of P. cyrtonema were detected by 16S rDNA sequencing. The relationship between the active ingredients and soil properties, and the dominant bacteria were investigated by correlation analysis. Results: The content of active ingredients of P. cyrtonema from the five regions varied significantly, especially polysaccharides and saponins. High-throughput sequencing demonstrated that Proteobacteria was the dominant bacterial phylum in all samples, and Burkholderia-Caballeronia-Paraburkholderia was the main endophytic bacterial genus in rhizome. In addition, the bacterial diversity and richness of rhizosphere soil samples were higher than those of rhizome samples. Soil physicochemical properties and enzyme activities were significantly different across regions, leading to notable variations in the community structures of rhizosphere and endophytic bacteria. Redundancy analysis (RDA) displayed that pH and urease (UE) were the major factors altering shifting rhizosphere bacteria community structure. Moreover, the composition and diversity of rhizome endophytic bacteria were principally affected by both soil physicochemical properties and soil enzyme activities. Soil properties and bacteria from rhizosphere soil and rhizome had a considerable impact on certain active ingredients in P. cyrtonema under artificial cultivation conditions after Pearson correlation analysis. Polysaccharides were significantly correlated with nutrient-rich soil and endophytic bacteria, such as Burkholderia-Caballeronia-Paraburkholderia, Pseudomonas, Ralstonia, and Bacillus. However, flavonoids were associated with nutrient-poor soil. Saponins were positively correlated with OM and available phosphorous (AP) and were significantly negatively affected by rhizosphere bacterial communities. Conclusion: The study demonstrated that bacterial microorganisms were involved in the accumulation of active ingredients of P. cyrtonema together with soil physicochemical properties and enzyme activities, which provided a theoretical basis for the scientific and effective artificial cultivation of high-quality P. cyrtonema.

17.
World J Psychiatry ; 14(3): 445-455, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38617985

RESUMO

BACKGROUND: Epidemiological studies have revealed a correlation between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D). Insulin resistance in the brain is a common feature in patients with T2D and AD. KAT7 is a histone acetyltransferase that participates in the modulation of various genes. AIM: To determine the effects of KAT7 on insulin patients with AD. METHODS: APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes, respectively. An in vitro model of AD was established by Aß stimulation. Insulin resistance was induced by chronic stimulation with high insulin levels. The expression of microtubule-associated protein 2 (MAP2) was assessed using immunofluorescence. The protein levels of MAP2, Aß, dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), IRS-1, p-AKT, total AKT, p-GSK3ß, total GSK3ß, DYRK1A, and KAT7 were measured via western blotting. Accumulation of reactive oxygen species (ROS), malondialdehyde (MDA), and SOD activity was measured to determine cellular oxidative stress. Flow cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation, respectively. Relative RNA levels of KAT7 and DYRK1A were examined using quantitative PCR. A chromatin immunoprecipitation assay was conducted to detect H3K14ac in DYRK1A. RESULTS: KAT7 expression was suppressed in the AD mice. Overexpression of KAT7 decreased Aß accumulation and MAP2 expression in AD brains. KAT7 overexpression decreased ROS and MDA levels, elevated SOD activity in brain tissues and neurons, and simultaneously suppressed neuronal apoptosis. KAT7 upregulated levels of p-AKT and p-GSK3ß to alleviate insulin resistance, along with elevated expression of DYRK1A. KAT7 depletion suppressed DYRK1A expression and impaired H3K14ac of DYRK1A. HMGN1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 depletion. CONCLUSION: We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylation. Our findings suggest that KAT7 is a novel and promising therapeutic target for the resistance in AD.

18.
J Dermatol Sci ; 114(1): 2-12, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38514279

RESUMO

BACKGROUND: Keratinocyte dysdifferentiation and proinflammatory cytokine production play a central role in psoriatic inflammation. According to recent studies, the Rh family C glycoprotein (RHCG) enhances cell proliferation and disrupts cell differentiation. However, the specific role of RHCG psoriasis development remains unclear. OBJECTIVE: We here explored the effect of RHCG on keratinocytes under psoriatic inflammation. METHODS: The cell counting kit­8 assay was conducted to assess proliferation. RHCG protein expression was assessed through western blotting and enzyme-linked immunosorbent assays. The expression of proinflammatory cytokines and differentiation markers was analyzed through a quantitative reverse-transcription polymerase chain reaction. RESULTS: Both RHCG mRNA and protein levels increased in psoriatic skin. Notably, cultured keratinocytes treated with an M5 cocktail, which mimics psoriatic inflammation, exhibited higher RHCG expression. Furthermore, RHCG overexpression promoted keratinocyte proliferation, accompanied by an increase in the production of interleukin (IL)-1ß, IL-6, and IL-8, and tumor necrosis factor-α. RHCG overexpression also resulted in higher expression of keratin 17, a differentiation marker. Conversely, RHCG gene knockdown reduced keratinocyte proliferation and cytokine secretion. RHCG inhibition in cells recovered both keratin 1 and loricrin expression. Additionally, RHCG overexpression facilitated the phosphorylation of nuclear factor-kappa B and extracellular signal-regulated protein kinase signaling pathways. Importantly, when these signaling pathways were inhibited, the effect of RHCG on keratinocytes was attenuated. CONCLUSION: These findings support the substantial role of RHCG in psoriatic inflammation development and suggest that RHCG serves as a potential target for psoriasis treatment.


Assuntos
Diferenciação Celular , Proliferação de Células , Citocinas , Queratinócitos , Psoríase , Humanos , Queratinócitos/metabolismo , Psoríase/patologia , Psoríase/imunologia , Psoríase/metabolismo , Citocinas/metabolismo , Feminino , Masculino , Células Cultivadas , Pele/patologia , Pele/imunologia , Pele/metabolismo , Pele/citologia , Adulto , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transdução de Sinais
19.
Vet Microbiol ; 295: 110163, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38959807

RESUMO

Avian influenza virus (AIV) infection and vaccination against live attenuated infectious bronchitis virus (aIBV) are frequent in poultry worldwide. Here, we evaluated the clinical effect of H9N2 subtype AIV and QX genotype aIBV co-infection in specific-pathogen-free (SPF) white leghorn chickens and explored the potential mechanisms underlying the observed effects using by 4D-FastDIA-based proteomics. The results showed that co-infection of H9N2 AIV and QX aIBV increased mortality and suppressed the growth of SPF chickens. In particular, severe lesions in the kidneys and slight respiratory signs similar to the symptoms of virulent QX IBV infection were observed in some co-infected chickens, with no such clinical signs observed in single-infected chickens. The replication of H9N2 AIV was significantly enhanced in both the trachea and kidneys, whereas there was only a slight effect on the replication of the QX aIBV. Proteomics analysis showed that the IL-17 signaling pathway was one of the unique pathways enriched in co-infected chickens compared to single infected-chickens. A series of metabolism and immune response-related pathways linked with co-infection were also significantly enriched. Moreover, co-infection of the two pathogens resulted in the enrichment of the negative regulation of telomerase activity. Collectively, our study supports the synergistic effect of the two pathogens, and pointed out that aIBV vaccines might increased IBV-associated lesions due to pathogenic co-infections. Exacerbation of the pathogenicity and mortality in H9N2 AIV and QX aIBV co-infected chickens possibly occurred because of an increase in H9N2 AIV replication, the regulation of telomerase activity, and the disturbance of cell metabolism and the immune system.


Assuntos
Galinhas , Coinfecção , Infecções por Coronavirus , Vírus da Bronquite Infecciosa , Vírus da Influenza A Subtipo H9N2 , Influenza Aviária , Doenças das Aves Domésticas , Animais , Galinhas/virologia , Vírus da Influenza A Subtipo H9N2/patogenicidade , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Bronquite Infecciosa/patogenicidade , Vírus da Bronquite Infecciosa/genética , Coinfecção/virologia , Coinfecção/veterinária , Influenza Aviária/virologia , Doenças das Aves Domésticas/virologia , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Organismos Livres de Patógenos Específicos , Replicação Viral , Vacinas Atenuadas/imunologia , Genótipo , Virulência , Proteômica , Rim/virologia , Rim/patologia
20.
Antioxidants (Basel) ; 13(5)2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38790708

RESUMO

Blue light is the higher-energy region of the visible spectrum. Excessive exposure to blue light is known to induce oxidative stress and is harmful to the eyes. The stems of Dendrobium nobile Lindl. (Orchidaceae), named Jinchaishihu, have long been used in traditional Chinese medicine (TCM) for nourishing yin, clearing heat, and brightening the eyes. The polysaccharide is one of the major components in D. nobile. However, the effect on ocular cells remains unclear. This study aimed to investigate whether the polysaccharide from D. nobile can protect the eyes from blue light-induced injury. A crude (DN-P) and a partially purified polysaccharide (DN-PP) from D. nobile were evaluated for their protective effects on blue light-induced damage in ARPE-19 and 661W cells. The in vivo study investigated the electroretinographic response and the expression of phototransduction-related genes in the retinas of a Drosophila model. The results showed that DN-P and DN-PP could improve blue light-induced damage in ARPE-19 and 661W cells, including cell viability, antioxidant activity, reactive oxygen species (ROS)/superoxide production, and reverse opsin 3 protein expression in a concentration-dependent manner. The in vivo study indicated that DN-P could alleviate eye damage and reverse the expression of phototransduction-related genes, including ninaE, norpA, Gαq, Gß76C, Gγ30A, TRP, and TRPL, in a dose-dependent manner in blue light-exposed Drosophila. In conclusion, this is the first report demonstrating that D. nobile polysaccharide pretreatment can protect retinal cells and retinal photoreceptors from blue light-induced damage. These results provide supporting evidence for the beneficial potential of D. nobile in preventing blue light-induced eye damage and improving eyesight.

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