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Diabetic foot ulcers (DFUs) are a serious vascular disease. Currently, no effective methods are available for treating DFUs. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid levels to promote atherosclerosis. However, the role of PCSK9 in DFUs remains unclear. In this study, we found that the expression of PCSK9 in endothelial cells (ECs) increased significantly under high glucose (HG) stimulation and in diabetic plasma and vessels. Specifically, PCSK9 promotes the E3 ubiquitin-protein ligase NEDD4 binding to vascular endothelial growth factor receptor 2 (VEGFR2), which led to the ubiquitination of VEGFR2, resulting in its degradation and downregulation in ECs. Furthermore, PCSK9 suppresses the expression and activation of AKT, endothelial nitric oxide synthase (eNOS), and ERK1/2, leading to decreased nitric oxide (NO) production and increased superoxide anion (O2._) generation, which impairs vascular endothelial function and angiogenesis. Importantly, using evolocumab to limit the increase in PCSK9 expression blocked the HG-induced inhibition of NO production and the increase in O2._ production, as well as inhibited the phosphorylation and expression of AKT, eNOS, and ERK1/2. Moreover, evolocumab improved vascular endothelial function and angiogenesis, and promoted wound healing in diabetes. Our findings suggest that targeting PCSK9 is a novel therapeutic approach for treating DFUs.
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Statins, the first-line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short-term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of statin-induced diabetes. Statin medication raises the expression of progesterone and adiponectin receptor 9 (PAQR9) in liver, which inhibits insulin signaling through degradation of protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α) to activate ERK pathway. STIP1 homology and U-box containing protein 1 (STUB1) is found to mediate ubiquitination of PPM1α promoted by PAQR9. On the other hand, decreased activity of hepatocyte nuclear factor 4 alpha (HNF4α) seems to be the cause of PAQR9 expression under statin therapy. The interventions on PAQR9, including deletion of PAQR9, caloric restriction and HNF4α activation, are all effective treatments for statin-induced diabetes, while liver specific over-expression of PPM1α is another possible tactic. The results reveal the importance of HNF4α-PAQR9-STUB1-PPM1α axis in controlling the statin-induced hepatic insulin resistance, offering a fresh insight into the molecular mechanisms underlying statin therapy.
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AIM: In Taiwan, over 90% of dementia patients received home care. Severe dementia-linked food refusal significantly affects nutrition, thereby straining caregivers. Family caregivers can reduce their burden by learning feeding and dementia nutrition online, thus preserving patient oral feeding. The study aim for family caregivers learn online Hand-Under-Hand (UH) techniques to ease feeding in severe dementia, enhancing nutrition and reducing their burden. METHODS: In this quasi-experimental study, participants in the experimental group received 2-h UH courses online, while the control group received their usual care. The primary outcome indicators were abnormal eating behavior, nutritional status, and caregiver burden, with outcomes tracked at 0, 1, and 3 months. At the neurology outpatient clinic of a medical center in Taipei, 65 dyads-comprising patients with severe dementia and their caregivers-were randomly assigned to groups. RESULTS: The study participants comprised 36 female and 29 male caregivers, with an average age of 58.09 years. The patient group included 43 females and 22 males, with a mean age of 83.32 years. Patients in the experimental group exhibited reduced abnormal eating behavior, and caregiver burden was reduced at 1 and 3 months, patients demonstrated improved nutritional status by month 3. CONCLUSIONS: The accessibility and convenience of online courses enabled family caregivers to use UH feeding techniques to effectively improve the nutritional status and correct the abnormal eating behavior of patients with dementia, while also decreasing caregiver burden. Geriatr Gerontol Int 2024; â¢â¢: â¢â¢-â¢â¢.
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The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates ß-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-ß signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.
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Envejecimiento , Aneurisma de la Aorta , Disección Aórtica , Senescencia Celular , MicroARNs , Músculo Liso Vascular , Quinasa de Cadena Ligera de Miosina , Transducción de Señal , Animales , Femenino , Humanos , Masculino , Ratones , Envejecimiento/genética , Envejecimiento/metabolismo , Angiotensina II/metabolismo , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/patología , Disección Aórtica/metabolismo , Disección Aórtica/genética , Disección Aórtica/patología , Proteínas de Unión al Calcio , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Quinasa de Cadena Ligera de Miosina/metabolismo , Quinasa de Cadena Ligera de Miosina/genética , Factor de Crecimiento Transformador beta/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Conjunctival fibrosis is a common postoperative complication of glaucoma filtration surgery, resulting in uncontrolled intraocular pressure and surgery failure. Therefore, there is an urgent need to understand the molecular mechanisms underlying conjunctival fibrosis and to explore novel pharmacologic anti-fibrosis therapies for glaucoma filtration surgery. Herein, the 4-dimensional data-independent acquisition (4D-DIA) quantitative proteomic results, coupled with experimental data, revealed the activation of the Wnt/ß-catenin pathway in transforming growth factor (TGF)-ß1-induced human conjunctival fibroblasts (HConFs). Treatment with ICG-001, a Wnt/ß-catenin inhibitor, effectively inhibited cell proliferation and migration in TGFß1-treated HConFs. ICG-001 treatment alleviated the increased generation of extracellular matrix proteins induced by TGFß1. In addition, ICG-001 reduced the expression level of α smooth muscle actin (α-SMA) and inhibited cell contractility in TGFß1-treated HConFs. Proteomics data further suggested that αB-crystallin (CRYAB) was a downstream target of Wnt/ß-catenin, which was up-regulated by TGFß1 and down-regulated by ICG-001. Immunoblotting assay also indicated that ICG-001 reduced the expressions of ubiquitin and ß-catenin in TGFß1-treated HConFs, implying that CRYAB stabilized ß-catenin by inhibiting its ubiquitination degradation. Exogenous CRYAB promoted cell viability, increased extracellular matrix protein levels, and up-regulated α-SMA expression of HConFs under TGFß1 stimulation. CRYAB rescued TGFß1-induced fibrotic responses that were suppressed by ICG-001. In conclusion, this study elucidates the regulatory mechanism of the Wnt/ß-catenin/CRYAB pathway in conjunctival fibrosis, offering promising therapeutic targets for mitigating bleb scarring after glaucoma filtration surgery.
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Conjuntiva , Fibroblastos , Fibrosis , Factor de Crecimiento Transformador beta1 , Vía de Señalización Wnt , Humanos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Conjuntiva/patología , Conjuntiva/metabolismo , Conjuntiva/efectos de los fármacos , beta Catenina/metabolismo , Proliferación Celular/efectos de los fármacos , Proteómica/métodos , Pirimidinonas/farmacología , Compuestos Bicíclicos Heterocíclicos con PuentesRESUMEN
Introduction: Anxiety and depressive disorders are highly prevalent mental health conditions worldwide. However, little is known about their specific prevalence in primary care settings. This study aimed to determine the prevalence of depression and anxiety in the primary care population and identify associated patient characteristics. Method: We conducted a cross-sectional study using stratified sampling by age with a self-administered questionnaire survey in Singapore's National Health-care Group Polyclinics from December 2021 to April 2022. A total score of Patient Health Questionnaire-9 (PHQ-9) ≥10 represents clinical depression, and a total score of Generalised Anxiety Disorder-7 (GAD-7) ≥10 indicates clinical anxiety. Multivariable logistic regression was used to identify the factors associated with depression and anxiety. Results: A total of 5694 patients were approached and 3505 consented to the study (response rate=61.6%). There was a higher prevalence of coexisting clinical depression and anxiety (DA) (prevalence=5.4%) compared to clinical depression only (3.3%) and clinical anxiety only (1.9%). The odds of having DA were higher among those aged 21-39 years (odds ratio [OR] 13.49; 95% confidence interval [CI] 5.41-33.64) and 40-64 years (OR 2.28; 95% CI 1.03-5.03) compared to those ≥65 years. Women had higher odds of having DA (OR 2.33; 95% CI 1.54-3.50) compared to men. Respondents with diabetes had higher odds of having DA (OR 1.78; 95% CI 1.07-2.94) compared to those without diabetes. Conclusion: Coexisting clinical depression and anxiety are significantly present in the primary care setting, especially among younger individuals, patients with diabetes and women. Mental health screening programmes should include screening for both depression and anxiety, and target these at-risk groups.
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Depresión , Atención Primaria de Salud , Humanos , Atención Primaria de Salud/estadística & datos numéricos , Persona de Mediana Edad , Prevalencia , Adulto , Estudios Transversales , Femenino , Masculino , Singapur/epidemiología , Factores de Riesgo , Adulto Joven , Depresión/epidemiología , Anciano , Ansiedad/epidemiología , Trastornos de Ansiedad/epidemiología , Adolescente , Factores de Edad , Cuestionario de Salud del Paciente , Modelos Logísticos , Encuestas y Cuestionarios , Trastorno Depresivo/epidemiologíaRESUMEN
Home exercise programs are beneficial in managing frozen shoulder (FS), yet adherence remains challenging. This pilot study introduces the remote app, Defrozen, designed for home exercises and assesses its feasibility and clinical outcomes in FS patients undergoing intra-articular and sub-acromial corticosteroid treatment. Over a four-week period, patients used the Defrozen-app, engaging in guided exercises. The feasibility of the intervention was assessed through several measurement scales, including adherence, the Technology Acceptance Model 2 (TAM2), the System Usability Scale (SUS), and User Satisfaction and Engagement (USE). Clinical outcomes included pain scale, Oxford Shoulder Score (OSS), Quick Disability of the Arm, Shoulder, and Hand (QuickDASH) Score, and passive range of motion. The TAM2 results indicated high perceived usefulness (4.5/5), ease of use (4.8/5), and intention to use (4.4/5); the SUS score was high at 81.7/100, complemented by USE scores reflecting ease of learning (4.9/5) and satisfaction (4.3/5). Clinical outcomes showed significant pain reduction, improved shoulder function, reduced shoulder-related disability, and increased shoulder range of motion. These findings suggest the Defrozen-app as a promising solution for FS, significantly improving adherence and showing potential to enhance clinical outcomes. However, these clinical outcome results are preliminary and necessitate further validation through a large-scale randomized controlled trial to definitively confirm efficacy and assess long-term benefits.
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Purpose: To investigate the potential effects and mechanism of nicotinamide riboside (NR) on the oxidative stress and fibrosis model of human trabecular meshwork (HTM) cell line cells. Methods: HTM cells were pretreated with NR, followed by the induction of oxidative injury and fibrosis by hydrogen peroxide (H2O2) and TGF-ß2, respectively. Cell viability was tested using Hoechst staining and MTT assays, cell proliferation was assessed by EdU assay, and cell apoptosis was detected by flow cytometry and western blotting. DCFH-DA and DHE probes were used to measure the level of reactive oxygen species (ROS), and MitoTracker staining was used to measure the mitochondrial membrane potential (MMP). Fibrotic responses, including cell migration and deposition of extracellular matrix (ECM) proteins, were detected via Transwell assays, qRT-PCR, and immunoblotting. Results: NR pretreatment improved the viability, proliferation, and MMP of H2O2-treated HTM cells. Compared to cells treated solely with H2O2, HTM cells treated with both NR and H2O2, exhibited a reduced rate of apoptosis and generation of ROS. Compared with H2O2 pretreatment, NR pretreatment upregulated expression of the JAK2/Stat3 pathway but inhibited mitogen-activated protein kinase (MAPK) pathway expression. Moreover, 10-ng/mL TGF-ß2 promoted cell proliferation and migration, which were inhibited by NR pretreatment. Both qRT-PCR and immunoblotting showed that NR inhibited the expression of fibronectin in a TGF-ß2-induced fibrosis model. Conclusions: NR has a protective effect on oxidative stress and fibrosis in HTM cells, which may be related to the JAK2/Stat3 pathway and MAPK pathway. Translational Relevance: Our research provides the ongoing data for potential therapy of NAD+ precursors in glaucoma.
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Niacinamida/análogos & derivados , Compuestos de Piridinio , Malla Trabecular , Factor de Crecimiento Transformador beta2 , Humanos , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/farmacología , Factor de Crecimiento Transformador beta2/metabolismo , Factor de Crecimiento Transformador beta2/farmacología , Malla Trabecular/metabolismo , Malla Trabecular/patología , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/metabolismo , Estrés Oxidativo/fisiología , FibrosisRESUMEN
BACKGROUND: Peroxiredoxin 2 (Prx2), an intracellular protein that regulates redox reactions, released from red blood cells is involved in inflammatory brain injury after intracerebral hemorrhage (ICH). Toll-like receptor 4 (TLR4) may be crucial in this process. This study investigated the role of the Prx2-TLR4 inflammatory axis in brain injury following experimental ICH in mice. METHODS: First, C57BL/6 mice received an intracaudate injection of autologous arterial blood or saline and their brains were harvested on day 1 to measure Prx2 levels. Second, mice received an intracaudate injection of either recombinant mouse Prx2 or saline. Third, the mice were co-injected with autologous arterial blood and conoidin A, a Prx2 inhibitor, or vehicle. Fourth, the mice received a Prx2 injection and were treated with TAK-242, a TLR4 antagonist, or saline (intraperitoneally). Behavioral tests, magnetic resonance imaging, western blot, immunohistochemistry/immunofluorescence staining, and RNA sequencing (RNA-seq) were performed. RESULTS: Brain Prx2 levels were elevated after autologous arterial blood injection. Intracaudate injection of Prx2 caused brain swelling, microglial activation, neutrophil infiltration, neuronal death, and neurological deficits. Co-injection of conoidin A attenuated autologous arterial blood-induced brain injury. TLR4 was expressed on the surface of microglia/macrophages and neutrophils and participated in Prx2-induced inflammation. TAK-242 treatment attenuated Prx2-induced inflammation and neurological deficits. CONCLUSIONS: Prx2 can cause brain injury following ICH through the TLR4 pathway, revealing the Prx2-TLR4 inflammatory axis as a potential therapeutic target.
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Lesiones Encefálicas , Sulfonamidas , Receptor Toll-Like 4 , Animales , Ratones , Lesiones Encefálicas/etiología , Hemorragia Cerebral/metabolismo , Inflamación/etiología , Inflamación/patología , Ratones Endogámicos C57BL , Peroxirredoxinas/metabolismo , Peroxirredoxinas/farmacología , Peroxirredoxinas/uso terapéutico , Receptor Toll-Like 4/metabolismoRESUMEN
The QuEChERS (quick, easy, cheap, effective, rugged and safe) conditions were optimized for efficient determination of the U.S. Environmental Protection Agency (US EPA) and European Union (EU) priority polycyclic aromatic hydrocarbons (PAHs) for the categories of grains, tuber & starchy vegetables, soy beans and products, fish & seafood, and poultry & meat, including raw materials and their corresponding products. The PAHs were analyzed using ultrahigh-performance liquid chromatography with temperature-controlled fluorescence detection and gas chromatography with tandem mass spectrometry. The established conditions had good accuracy, repeatability, and precision. Environmental pollution and processing methods influence the level of PAHs in samples. The low molecular weight PAHs were present in all raw materials, and processing increased high and low molecular weight PAHs in the products. The excess cancer risk for consumption of PAHs in cooked samples was mostly acceptable; a small number of samples might be of slight concern in certain age groups.
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Hidrocarburos Policíclicos Aromáticos , Animales , Estados Unidos , Cromatografía de Gases y Espectrometría de Masas/métodos , Unión Europea , Hidrocarburos Policíclicos Aromáticos/análisis , United States Environmental Protection Agency , Espectrometría de Masas en Tándem/métodosRESUMEN
INTRODUCTION: Rhegmatogenous retinal detachment (RRD) is one of the most common fundus diseases. Many rural areas of China have few ophthalmologists, and ophthalmologic ultrasound examination is of great significance for remote diagnosis of RRD. Therefore, this study aimed to develop and evaluate a deep learning (DL) model, to be used for automated RRD diagnosis based on ophthalmologic ultrasound images, in order to support timely diagnosis of RRD in rural and remote areas. METHODS: A total of 6,000 ophthalmologic ultrasound images from 1,645 participants were used to train and verify the DL model. A total of 5,000 images were used for training and validating DL models, and an independent testing set of 1,000 images was used to test the performance of eight DL models trained using four different DL model architectures (fully connected neural network, LeNet5, AlexNet, and VGG16) and two preprocessing techniques (original, original image augmented). Receiver operating characteristic (ROC) curves were used to analyze their performance. Heatmaps were generated to visualize the process of the best DL model in the identification of RRD. Finally, five ophthalmologists were invited to diagnose RRD independently on the same test set of 1,000 images for performance comparison with the best DL model. RESULTS: The best DL model for identifying RRD achieved an area under the ROC curve (AUC) of 0.998 with a sensitivity and specificity of 99.2% and 99.8%, respectively. The best preprocessing method in each model architecture was the application of original image augmentation (average AUC = 0.982). The best model architecture in each preprocessing method was VGG16 (average AUC = 0.998). CONCLUSION: The best DL model determined in this study has higher accuracy, sensitivity, and specificity than the ophthalmologists' diagnosis in identifying RRD based on ophthalmologic ultrasound images. This model may provide support for timely diagnosis in locations without access to ophthalmologic care.
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Aprendizaje Profundo , Desprendimiento de Retina , Humanos , Desprendimiento de Retina/diagnóstico , Redes Neurales de la Computación , Fondo de Ojo , Curva ROCRESUMEN
Pregnant women, infants, and children are particularly vulnerable to perfluoroalkyl substances (PFASs), yet little is known about related health risks. Here, we aimed to study the four main PFASs: perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS), and assess the mixture risks of co-exposure to PFASs for pregnant women and children as well as for infants associated with maternal PFAS exposure at national and global scales, based on biomonitoring data on serum. We conducted a literature search and aggregated 69 data sources across 22 countries/regions from 2010 to 2020 to profile the serum concentrations of these four PFASs in pregnant women and children. Based on toxicity assessments by regulatory authorities, we determined conservative reference levels (RfLs) in the serum for the primary adverse effects of PFASs, including hepatic, developmental, and immune effects. The cumulative hazard quotient (HQ) was combined with probabilistic analysis to compare serum levels with RfLs and to quantify mixture risks. Our analysis revealed that PFOS was the dominant PFAS in maternal and child serum worldwide, with median levels 2.5-10 times higher than those of PFOA, PFNA, and PFHxS. The estimated global median serum levels of PFOS were 6.17 ng/mL for pregnant women and 4.85 ng/mL for children, and their immune effects in pregnant women and children are concerning as their cumulative HQs could exceed 1. For infants, the cumulative HQs for both developmental and immune effects could also be > 1, suggesting that maternal exposure to PFASs during pregnancy and breastfeeding may pose concerns for infant development and immunity. Our national and global serum database and risk assessment offer additional insights into PFAS exposures and mixture risks in susceptible populations, serving as a reference for evaluating the effectiveness of ongoing regulatory mitigation measures.
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Ácidos Alcanesulfónicos , Contaminantes Ambientales , Fluorocarburos , Humanos , Niño , Femenino , Lactante , Embarazo , Mujeres Embarazadas , Exposición Materna/efectos adversos , Fluorocarburos/toxicidad , Medición de RiesgoRESUMEN
Taiwan is an island and therefore has a considerable amount of coastal land. Drowning or near-drowning incidents often occur in coastal recreational areas. To reduce the risk of drowning or near-drowning associated with marine recreational activities in Taiwan, this study collected data on the risk associated with marine recreational activities. It selected risk factors using a modified Delphi panel method, with an expert panel used to obtain probability values for each risk factor. A Bayesian network for risk assessment was then established. The results of this study can serve as a reference for stakeholders involved in marine recreational activities. Severe weather conditions increase wave height and current speed, resulting in an increased risk of drowning or near-drowning when coastal recreational activities occur under these conditions. Individuals who undertake marine recreational activities without safety awareness are more likely to exhibit risky behaviors. When self-rescue ability is insufficient to prevent possible danger, the probability of drowning or near-drowning is higher. Serious incidents may lead to death, and therefore, marine recreational activities should be avoided when weather conditions are poor. In addition, the safety awareness and self-rescue ability of individuals undertaking coastal recreational activities should be improved. This study did not explore emergency response measures or postincident policy management.
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BRICS-Plus countries (Brazil, Russia, India, China, South Africa, and 30 other countries) is a group of 35 countries with emerging economies making up more than half of the world's population. We explored epidemiological trends of cardiovascular disease (CVD) mortality attributable to modifiable risk factors and its association with period and birth cohort effects and sociodemographic index (SDI) across BRICS-Plus countries by using joinpoint regression and age-period-cohort modeling from 1990 to 2019. Between 1990 and 2019, the all-ages CVD deaths increased by 85.2% (6.1 million to 11.3 million) across BRICS-Plus countries. The CVD age-standardized mortality rate attributable to dietary risks and smoking significantly decreased across BRICS-Plus countries, with some exceptions. However, four-fifths of BRICS-Plus countries observed a remarkable increasing trend of high body mass-index (BMI)-related CVD deaths, in particular, among younger adults (25-49 years). Early birth cohorts and individuals aged greater than 50 years showed a higher risk of CVD mortality. Both the China-ASEAN FTA and Mercosur regions stand out for their successful sociodemographic transition, with a significant reduction in CVD mortality over the study period. Singapore and Brazil achieved great progress in CVD mortality reduction and the other BRICS-Plus countries should follow their lead in adopting public health policies and initiatives into practice.
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Enfermedades Cardiovasculares , Sistema Cardiovascular , Adulto , Humanos , Anciano , Factores de Riesgo , Fumar , Cohorte de NacimientoRESUMEN
In mammals, mitofusin 2 (MFN2) is involved in mitochondrial fusion, and suppresses the virus-induced RIG-I-like receptor (RLR) signaling pathway. However, little is known about the function of MFN2 in non-mammalian species. In the present study, we cloned an MFN2 ortholog (LcMFN2) in large yellow croaker (Larimichthys crocea). Phylogenetic analysis showed that MFN2 emerged after the divergence of amphioxus and vertebrates. The protein sequences of MFN2 were well conserved from fish to mammals. LcMFN2 was expressed in all the tissues/organs examined at different levels, and its expression was upregulated in response to poly(I:C) stimulation. Overexpression of LcMFN2 inhibited MAVS-induced type I interferon (IFN) promoter activation and antiviral gene expression. In contrast, knockdown of endogenous LcMFN2 enhanced poly(I:C) induced production of type I IFNs. Additionally, LcMFN2 enhanced K48-linked polyubiquitination of MAVS, promoting its degradation. Also, overexpression of LcMFN2 impaired the cellular antiviral response, as evidenced by the increased expression of viral genes and more severe cytopathic effects (CPE) in cells infected with spring viremia of carp virus (SVCV). These results indicated that LcMFN2 inhibited type I IFN response by degrading MAVS, suggesting its negative regulatory role in cellular antiviral response. Therefore, our study sheds a new light on the regulatory mechanisms of the cellular antiviral response in teleosts. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00189-8.
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Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis.
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Lipoproteínas HDL , ARN Largo no Codificante , Ratones , Animales , Humanos , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Antígeno Nuclear de Célula en Proliferación , ARN Largo no Codificante/genética , Células Endoteliales/metabolismo , Neovascularización Fisiológica/genéticaRESUMEN
Progesterone and adipoQ receptor 9 (PAQR9) is an endoplasmic reticulum (ER)-localized membrane protein that is involved in protein quality control of ER by interacting with BAG6. One of the physiological functions of PAQR9 is regulation of fasting-induced ketogenesis and fatty acid oxidation in the liver via modulating protein degradation of PPARα. However, it is currently unknown whether or not PAQR9 impacts glucose homeostasis. We addressed this question using a Paqr9-deleted mouse model in which type 1 diabetes was induced by streptozotocin injection and type 2 diabetes was induced by high-fat diet (HFD) with streptozotocin injection. Paqr9 deletion improved hyperglycemia and glucose tolerance in both of the diabetic mouse models. In the pancreatic islets, Paqr9 deletion reduced apoptosis of ß cells in type 2 diabetic mice. Paqr9 deletion also reduced HFD-induced hepatic steatosis and adiposity of white adipose tissue. In Min6 cells, overexpression of DUF3538 domain of BAG6 to block the interaction of PAQR9 with BAG6 was able to enhance glucose-stimulated insulin secretion upon treatment with inflammatory factors or thapsigargin, an ER stress inducer. Thapsigargin-induced ER stress markers were also reduced by overexpression of DUF3538 domain. Collectively, these results indicate that PAQR9 has a modulatory role in glucose homeostasis, associated with regulation on insulin secretion of ß cells in vitro under stress conditions.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Ratones , Animales , Secreción de Insulina , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Estreptozocina , Tapsigargina/metabolismo , Células Secretoras de Insulina/metabolismo , Glucosa/metabolismo , Modelos Animales de Enfermedad , Dieta Alta en Grasa , Homeostasis , Estrés del Retículo EndoplásmicoRESUMEN
The optimal conditions for simultaneous determination of the U.S. Environmental Protection Agency (US EPA) and European Union (EU) priority polycyclic aromatic hydrocarbons (PAHs) in coffee beans and coffee brews were developed. The QuEChERS (quick, easy, cheap, effective, rugged and safe) technology combined with high performance liquid chromatography - temperature-controlled fluorescence detection and gas chromatography - tandem mass spectrometry were used in the investigation. PAHs could be determined in commercially available green coffee beans (possibly caused by environmental contamination), and their PAHs content increased with the degree of roasting. Coffee beans brewed with the coffee machine released more PAHs into their brews than those brewed with the drip bag. The PAHs consumption risk of the brewed coffee samples was not high due to their low PAH level. Nevertheless, the methods of roasting and brewing and the amount of drinking could still be considered to reduce the intake of PAHs.
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Hidrocarburos Policíclicos Aromáticos , Estados Unidos , Unión Europea , Cromatografía de Gases y Espectrometría de Masas/métodos , Hidrocarburos Policíclicos Aromáticos/análisis , United States Environmental Protection Agency , Cromatografía Líquida de Alta PresiónRESUMEN
Some public officials have expressed concern that policies mandating collective public health behaviors (e.g., national/regional "lockdown") may result in behavioral fatigue that ultimately renders such policies ineffective. Boredom, specifically, has been singled out as one potential risk factor for noncompliance. We examined whether there was empirical evidence to support this concern during the COVID-19 pandemic in a large cross-national sample of 63,336 community respondents from 116 countries. Although boredom was higher in countries with more COVID-19 cases and in countries that instituted more stringent lockdowns, such boredom did not predict longitudinal within-person decreases in social distancing behavior (or vice versa; n = 8,031) in early spring and summer of 2020. Overall, we found little evidence that changes in boredom predict individual public health behaviors (handwashing, staying home, self-quarantining, and avoiding crowds) over time, or that such behaviors had any reliable longitudinal effects on boredom itself. In summary, contrary to concerns, we found little evidence that boredom posed a public health risk during lockdown and quarantine. (PsycInfo Database Record (c) 2023 APA, all rights reserved).