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1.
Phytomedicine ; 92: 153763, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34601222

RESUMO

BACKGROUND: Misfolded proteins are formed in the endoplasmic reticulum (ER) due to diverse stimuli including oxidant production, calcium disturbance, and inflammatory factors. Accumulation of these non-native proteins in the ER evokes cellular stress involving the activation of unfolded protein response (UPR) and the execution of ER-associated degradation (ERAD). Naturally-occurring plant compounds are known to interfere with UPR due to their antioxidant and anti-inflammatory activities, leading to inhibition of ER stress. However, there are few studies dealing with the protective effects of natural compounds on the functionality of ERAD. PURPOSE: The current study examined whether asaronic acid enhanced ubiquitin-proteasomal degradation in J774A.1 murine macrophages exposed to 7ß-hydroxycholesterol, a risk factor for atherosclerosis. Asaronic acid (2,4,5-trimethoxybenzoic acid), identified as one of purple perilla constituents, has anti-diabetic and anti-inflammatory effects. Little is known regarding the effects of asaronic acid on the ERAD process and the ubiquitin-proteasomal degradation. METHODS AND RESULTS: Murine macrophages were incubated with 28 µM 7ß-hydroxycholesterol in absence and presence of 1-20 µΜ asaronic acid for up to 24 h. Nontoxic asaronic acid in macrophage diminished the activation of the ER stress sensors of ATF6, IRE1 and PERK stimulated by 7ß-hydroxycholesterol. This methoxybenzoic acid down-regulated the oxysterol-induced expression of EDEM1, OS9, Sel1L-Hrd1 and p97/VCP1, all required for the recognition, recruitment and dislocation of misfolded proteins. On the other hand, asaronic acid enhanced the ubiquitin-proteasomal degradation of non-native proteins dislocated to the cytosol by 7ß-hydroxycholesterol, which entailed the induction of the chaperones of Hsp70 and CHIP and the increased colocalization of ubiquitin and proteasomes. Taken together, asaronic acid attenuated the induction of the UPR-associated sensors and the dislocation-linked transmembrane components in the ER. Conversely, this compound enhanced the proteasomal degradation of dislocated non-native proteins in concert with the chaperones of Hsp70 and CHIP through ubiquitination. CONCLUSION: These observations demonstrate that asaronic acid may be a potent atheroprotective agent as a natural chaperone targeting ER stress-associated macrophage injury.


Assuntos
Hidroxicolesteróis , Ubiquitina , Animais , Estresse do Retículo Endoplasmático , Degradação Associada com o Retículo Endoplasmático , Macrófagos , Camundongos
2.
Front Immunol ; 12: 724609, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603297

RESUMO

STAT3 activates transcription of genes that regulate cell growth, differentiation, and survival of mammalian cells. Genetic deletion of Stat3 in T cells has been shown to abrogate Th17 differentiation, suggesting that STAT3 is a potential therapeutic target for Th17-mediated diseases. However, a major impediment to therapeutic targeting of intracellular proteins such as STAT3 is the lack of efficient methods for delivering STAT3 inhibitors into cells. In this study, we developed a novel antibody (SBT-100) comprised of the variable (V) region of a STAT3-specific heavy chain molecule and demonstrate that this 15 kDa STAT3-specific nanobody enters human and mouse cells, and induced suppression of STAT3 activation and lymphocyte proliferation in a concentration-dependent manner. To investigate whether SBT-100 would be effective in suppressing inflammation in vivo, we induced experimental autoimmune uveitis (EAU) in C57BL/6J mice by active immunization with peptide from the ocular autoantigen, interphotoreceptor retinoid binding protein (IRBP651-670). Analysis of the retina by fundoscopy, histological examination, or optical coherence tomography showed that treatment of the mice with SBT-100 suppressed uveitis by inhibiting expansion of pathogenic Th17 cells that mediate EAU. Electroretinographic (ERG) recordings of dark and light adapted a- and b-waves showed that SBT-100 treatment rescued mice from developing significant visual impairment observed in untreated EAU mice. Adoptive transfer of activated IRBP-specific T cells from untreated EAU mice induced EAU, while EAU was significantly attenuated in mice that received IRBP-specific T cells from SBT-100 treated mice. Taken together, these results demonstrate efficacy of SBT-100 in mice and suggests its therapeutic potential for human autoimmune diseases.

3.
J Dent ; : 103848, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34656657

RESUMO

OBJECTIVES: The oral biofilm structure or composition can affect the penetration of remineralizing agents. Therefore, this study evaluated the remineralizing efficacy of fluoride using a pH-cycling model with oral microcosm biofilms. METHODS: Artificial carious lesions were formed in 80 bovine incisors. The pH-cycling conditions with or without oral microcosm biofilms were applied to 40 specimens each. The pH-cycling scheme was repeated for 12 days. Fluorescence loss (ΔF, %) of early carious lesions was measured for all specimens using a quantitative light-induced fluorescence-digital camera, before and after fluoride application. Biofilms on specimens were further analyzed for red fluorescence intensity (red/green ratios) and colony-forming unit counts. The effects of pH-cycling conditions and treatments on changes in ΔF (ΔΔF) and the effects of interactions between factors were analyzed using two-way analysis of variance. RESULTS: The fluoride-treated group with oral biofilms had an approximately 0.89-fold lower ΔΔF than the fluoride-treated group without oral biofilms (p < 0.0001). When oral biofilms were absent, the fluoride-treated group showed a 1.31-fold greater ΔΔF compared to that in the distilled water-treated group (p < 0.0001). When oral biofilms were present, the fluoride-treated group showed a 1.14-fold greater ΔΔF compared to that in the distilled water-treated group; however, this difference was not statistically significant. CONCLUSIONS: There was a significant difference in fluoride remineralizing efficacy based on the presence of biofilms on early carious lesions. Therefore, fluoride remineralization assessment in the absence of oral biofilms could lead to an overestimation of efficacy. CLINICAL SIGNIFICANCE: Fluoride application might not have a robust remineralization effect on early carious lesions in the presence of a mature biofilm on the tooth surface.

4.
Medicine (Baltimore) ; 100(40): e27439, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622859

RESUMO

ABSTRACT: Vascular access (VA) failure is an important problem for patients undergoing hemodialysis, and maintaining VA patency is challenging. In this study, we used a nationwide database to investigate the effects of nitrate, as a vasodilator, on VA failure in hemodialysis patients.We investigated the Korean insurance claims data of hemodialysis patients who underwent angioplasty for VA failure between January 2012 and December 2017. The patients were divided into 2 groups: those not receiving vasodilator therapy (controls) and those receiving any vasodilator administration (vasodilator treatment, VDT). The primary endpoint was VA primary patency, defined as the time between arteriovenous dialysis access creation and the first percutaneous transluminal angioplasty (PTA).During the study period, a total of 6350 patients were recruited, 409 (6.4%) patients assigned to the VDT group and 5941 (93.6%) controls. PTA was performed in 998 patients (15.7%), including 8 in the VDT group and 990 controls. The VA site PTA rate was significantly lower in the VDT group (2.0%) than in the control group (16.7%, P < .001). In the subgroup analysis, the patency rates associated with the different vasodilators were similar (P = .736). All vasodilators, except molsidomine, improved the patency rate by approximately 20%.In this large national database study, vasodilator administration was associated with higher VA primary patency, compared with controls, in hemodialysis patients. VDT may have a beneficial effect on maintaining VA patency in patients undergoing hemodialysis.


Assuntos
Diálise Renal/estatística & dados numéricos , Grau de Desobstrução Vascular/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Idoso , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , República da Coreia , Estudos Retrospectivos
5.
Medicina (Kaunas) ; 57(9)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34577809

RESUMO

Background and Objectives: Extracorporeal membrane oxygenation (ECMO) can be helpful in patients with cardiogenic shock associated with myocardial infarction, and its early use can improve the patient survival rate. In this study, we report a mortality rate-difference analysis that examined the time and location of shock occurrence. Materials and Methods: We enrolled patients who underwent ECMO due to cardiogenic shock related to myocardial infarction and assigned them to either a pre- or post-admission shock group. The primary outcome was the 1-month mortality rate; a subgroup analysis was conducted to assess the effect of bailout ECMO. Results: Of the 113 patients enrolled, 67 (38 with pre-admission shock, 29 with post-admission shock) were analysed. Asystole was more frequently detected in the pre-admission shock group than in the post-admission group. In both groups, the commonest culprit lesion location was in the left anterior descending artery. Cardiopulmonary resuscitation was performed significantly more frequently and earlier in the pre-admission group. The 1-month mortality rate was significantly lower in the pre-admission group than in the post-admission group. Male sex and ECMO duration (≥6 days) were factors significantly related to the reduced mortality rate in the pre-admission group. In the subgroup analysis, the mortality rate was lower in patients receiving bailout ECMO than in those not receiving it; the difference was not statistically significant. Conclusions: ECMO application resulted in lower short-term mortality rate among patients with out-of-hospital cardiogenic shock onset than with in-hospital shock onset; early cardiopulmonary resuscitation and ECMO might be helpful in select patients.


Assuntos
Oxigenação por Membrana Extracorpórea , Infarto do Miocárdio , Vasos Coronários , Humanos , Masculino , Estudos Retrospectivos , Choque Cardiogênico/terapia , Taxa de Sobrevida
6.
Theranostics ; 11(16): 8092-8111, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335982

RESUMO

Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification. Membranous c-Src causes cancer initiation and progression. Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown. Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models. Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form. The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530. The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation. Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies. Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo. Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation. Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma.


Assuntos
Proteína Tirosina Quinase CSK/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Membrana/metabolismo , Proteína Tirosina Quinase CSK/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Genes src/genética , Genes src/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Peptídeos/metabolismo , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Tetraspaninas/genética , Tetraspaninas/metabolismo
7.
Biomedicines ; 9(6)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200167

RESUMO

Diabetes induces bone deterioration, which leads to increased risk of fracture, osteopenia, and osteoporosis. Thus, diabetes-associated bone fragility has been recognized as a diabetic complication. However, the pathophysiological effects of hyperglycemia on bone turnover remain unclear. Literature evidence demonstrates that anti-diabetic medications increase the risk of fractures in individuals with type 2 diabetes. Scopoletin is a naturally occurring hydroxycoumarin potentially exhibiting anti-inflammatory and antioxidant activities and ameliorating insulin resistance as an anti-diabetic agent. However, little is known regarding the effects of scopoletin on the impairment of bone remodeling that is caused by diabetes. The aim of this study was to identify that scopoletin was capable of inhibiting the impairment of bone remodeling and turnover in a mouse model of type 2 diabetes. Submicromolar scopoletin accelerated the formation TRAP-positive multinucleated osteoclasts (40.0 vs. 105.1%) and actin ring structures impaired by 33 mM glucose. Further, 1-20 µM scopoletin enhanced bone resorption and the induction of matrix-degrading enzymes in diabetic osteoclasts. The oral administration of 10 mg/kg scopoletin elevated serum RANKL/OPG ratio and osteocalcin level reduced in db/db mice along with an increase in BMD by ~6-14%; however, it was not effective in lowering blood glucose and hemoglobin glycation. In addition, the supplementation of scopoletin elevated the formation of trabecular bones and collagen fibers in femoral epiphysis and metaphysis with a thicker epiphyseal plate and cortical bones. Furthermore, 1-20 µM scopoletin enhanced ALP activity (4.39 vs. 7.02 nmol p-nitrophenyl phosphate/min/mg protein) and deposits of mineralized bone nodules in cultured osteoblasts reduced by 33 mM glucose. The treatment of diabetic osteoblasts with scopoletin stimulated the cellular induction of BMP-2 and osteopontin and Runx2 transcription. Accordingly, the administration of scopoletin protected mice from type 2 diabetes-associated bone loss through boosting bone remodeling via the robust induction of bone turnover markers of both osteoclasts and osteoblasts. These findings suggest that scopoletin could be a potential osteoprotective agent for the treatment of diabetes-associated bone loss and fractures.

8.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200222

RESUMO

Collagen hydrolysates have been suggested as a favorable antiaging modality in skin photoaged by persistent exposure to ultraviolet radiation (UV). The current study evaluated the beneficial effect of collagen hydrolysates (fsCH) extracted from Pangasius hypophthalmus fish skin on wrinkle formation and moisture preservation in dorsal skin of hairless mice challenged with UV-B. Inter-comparative experiments were conducted for anti-photoaging among fsCH, retinoic acid (RA), N-acetyl-D-glucosamine (NAG), and glycine-proline-hydroxyproline (GPH). Treating human HaCaT keratinocytes with 100-200 µg/mL fsCH reciprocally ameliorated the expression of aquaporin 3 (AQP3) and CD44 deranged by UV-B. The UV-B-induced deep furrows and skin thickening were improved in parched dorsal skin of mice supplemented with 206-412 mg/kg fsCH as well as RA and GPH. The UV-B irradiation enhanced collagen fiber loss in the dorsal dermis, which was attenuated by fsCH through enhancing procollagen conversion to collagen. The matrix metalloproteinase expression by UV-B in dorsal skin was diminished by fsCH, similar to RA and GPH, via blockade of collagen degradation. Supplementing fsCH to UV-B-irradiated mice decreased transepidermal water loss in dorsal skin with reduced AQP3 level and restored keratinocyte expression of filaggrin. The expression of hyaluronic acid synthase 2 and hyaluronidase 1 by UV-B was remarkably ameliorated with increased production of hyaluronic acid by treating fsCH to photoaged mice. Taken together, fsCH attenuated photoaging typical of deep wrinkles, epidermal thickening, and skin water loss, like NAG, RA, or GPH, through inhibiting collagen destruction and epidermal barrier impairment.


Assuntos
Colágeno/farmacologia , Proteínas na Dieta/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Dermatopatias/tratamento farmacológico , Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Animais , Masculino , Camundongos , Camundongos Pelados , Pele/patologia , Pele/efeitos da radiação , Envelhecimento da Pele/patologia , Envelhecimento da Pele/efeitos da radiação , Dermatopatias/etiologia , Dermatopatias/patologia
9.
Cardiovasc Ultrasound ; 19(1): 20, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090472

RESUMO

AIMS: The purpose of this study were to identify the usefulness of screening for PFO using agitated saline echocardiography (ASE) and characteristics and prognosis of patients with suggestive of patent foramen ovale (PFO). METHODS: Three hundred three patients (mean age, 53 ± 9 years; 199 [66%] men) admitted with acute stroke or suspicion of stroke were included. Patients were classified into those with and without right-to-left shunt (RLS) according to the ASE results (positive ASE [n = 92] vs. negative ASE [n = 211]). Fifty-one out of ninety-two patients with positive ASE and twenty-one out of two hundred eleven patients with negative ASE underwent TEE with ASE to confirm PFO. RESULTS: Ninety-two were positive for ASE and thirty-six of the fifty-one patients who underwent TEE were confirmed as having PFO. Of the patients with RLS grade 1, 50% were diagnosed with PFO and all patients with RLS grade ≥ 2 were diagnosed with PFO. All patients with negative ASE had no PFO (sensitivity of 100% and specificity of 58%). Patients with positive ASE were younger, had a lower body mass, and a lower prevalence of hypertension. The positive ASE patients had a higher mean S' velocity and better diastolic function. Four of ninety-one patients with positive ASE and thirteen of one hundred seventy-seven showed recurrence of stroke and suspicion of stroke. CONCLUSION: Transthoracic ASE is a good method to screen for PFO. Patients with suggestive of PFO had lower risk factors, less atherosclerosis, and better cardiac performance.


Assuntos
Forame Oval Patente , AVC Isquêmico , Acidente Vascular Cerebral , Adulto , Ecocardiografia , Ecocardiografia Transesofagiana , Forame Oval Patente/diagnóstico , Forame Oval Patente/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia
10.
Clin Case Rep ; 9(5): e03195, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34084469

RESUMO

The Rotarex® device is used for thrombectomy as well as atherectomy in patients with PAD. It is important to carefully consider the wire position of the Rotarex® device during the procedure. As possible as the wire should be located in a lesion-free area.

11.
PLoS One ; 16(5): e0250653, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33951046

RESUMO

BACKGROUND AND AIMS: Cardiovascular (CV) disease is the major cause of death in patients with end-stage kidney disease (ESKD). Left ventricular (LV) diastolic dysfunction reflects LV pressure overload and is common in patients with ESKD. Recently, there have been studies on the usefulness of central blood pressure (BP); however, the relationship between central BP and LV diastolic dysfunction is not clear in dialysis patients with preserved systolic function. The purpose of this study was to investigate the clinical implication of central BP on LV diastolic dysfunction and CV mortality in the ESKD patients with preserved LV systolic function. METHODS: This prospective observational cohort study investigated the effect of LV diastolic dysfunction on CV mortality in the ESKD patients with preserved systolic function using echocardiography. Vascular calcification was evaluated using the abdominal aortic calcification score, and aortic stiffness was determined by measuring pulse wave velocity (PWV). The predictors of CV mortality were analyzed using Cox proportional hazard analysis. RESULTS: The subjects were comprised of 61 patients, with an average age of 54 years, 20 males (32.8%), and 25 diabetics (41.0%). There were 39 patients on hemodialysis and 22 patients receiving peritoneal dialysis treatment. During the mean follow-up period of 79.3 months, 16 patients (26.2%) died, and 7 patients (11.4%) died of CV events. The central systolic BP and diabetes were independent risk factors for LV diastolic dysfunction. In addition, patients with LV diastolic dysfunction had an increased CV mortality. When left atrial volume index and PWV were adjusted, the E/E' ratio was found to be a predictor of CV mortality. CONCLUSIONS: Central systolic BP and diabetes were found to be significant risk factors for LV diastolic dysfunction. LV diastolic dysfunction can independently predict CV mortality in dialysis patients with preserved LV systolic function.


Assuntos
Pressão Sanguínea , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Diástole/fisiologia , Sístole/fisiologia , Disfunção Ventricular Esquerda , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Nature ; 593(7857): 67-73, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953412

RESUMO

Transition metal (oxy)hydroxides are promising electrocatalysts for the oxygen evolution reaction1-3. The properties of these materials evolve dynamically and heterogeneously4 with applied voltage through ion insertion redox reactions, converting materials that are inactive under open circuit conditions into active electrocatalysts during operation5. The catalytic state is thus inherently far from equilibrium, which complicates its direct observation. Here, using a suite of correlative operando scanning probe and X-ray microscopy techniques, we establish a link between the oxygen evolution activity and the local operational chemical, physical and electronic nanoscale structure of single-crystalline ß-Co(OH)2 platelet particles. At pre-catalytic voltages, the particles swell to form an α-CoO2H1.5·0.5H2O-like structure-produced through hydroxide intercalation-in which the oxidation state of cobalt is +2.5. Upon increasing the voltage to drive oxygen evolution, interlayer water and protons de-intercalate to form contracted ß-CoOOH particles that contain Co3+ species. Although these transformations manifest heterogeneously through the bulk of the particles, the electrochemical current is primarily restricted to their edge facets. The observed Tafel behaviour is correlated with the local concentration of Co3+ at these reactive edge sites, demonstrating the link between bulk ion-insertion and surface catalytic activity.

13.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916310

RESUMO

Epidemiological evidence shows that smoking causes a thrombophilic milieu that may play a role in the pathophysiology of chronic obstructive pulmonary disease (COPD) as well as pulmonary thromboembolism. The increased nicotine level induces a prothrombotic status and abnormal blood coagulation in smokers. Since several anticoagulants increase bleeding risk, alternative therapies need to be identified to protect against thrombosis without affecting hemostasis. Astragalin is a flavonoid present in persimmon leaves and green tea seeds and exhibits diverse activities of antioxidant and anti-inflammation. The current study investigated that astragalin attenuated smoking-induced pulmonary thrombosis and alveolar inflammation. In addition, it was explored that molecular links between thrombosis and inflammation entailed protease-activated receptor (PAR) activation and oxidative stress-responsive mitogen-activated protein kinase (MAPK)-signaling. BALB/c mice were orally administrated with 10-20 mg/kg astragalin and exposed to cigarette smoke for 8 weeks. For the in vitro study, 10 U/mL thrombin was added to alveolar epithelial A549 cells in the presence of 1-20 µM astragalin. The cigarette smoking-induced the expression of PAR-1 and PAR-2 in lung tissues, which was attenuated by the administration of ≥10 mg/kg astragalin. The oral supplementation of ≥10 mg/kg astragalin to cigarette smoke-challenged mice attenuated the protein induction of urokinase plasminogen activator, plasminogen activator inhibitor-1and tissue factor, and instead enhanced the induction of tissue plasminogen activator in lung tissues. The astragalin treatment alleviated cigarette smoke-induced lung emphysema and pulmonary thrombosis. Astragalin caused lymphocytosis and neutrophilia in bronchoalveolar lavage fluid due to cigarette smoke but curtailed infiltration of neutrophils and macrophages in airways. Furthermore, this compound retarded thrombin-induced activation of PAR proteins and expression of inflammatory mediators in alveolar cells. Treating astragalin interrupted PAR proteins-activated reactive oxygen species production and MAPK signaling leading to alveolar inflammation. Accordingly, astragalin may interrupt the smoking-induced oxidative stress-MAPK signaling-inflammation axis via disconnection between alveolar PAR activation and pulmonary thromboembolism.


Assuntos
Quempferóis/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Embolia Pulmonar/prevenção & controle , Enfisema Pulmonar/prevenção & controle , Receptores Ativados por Proteinase/antagonistas & inibidores , Animais , Fumar Cigarros/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Quempferóis/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Embolia Pulmonar/etiologia
14.
Molecules ; 26(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33799919

RESUMO

Herein, we investigated the surface characterization and biocompatibility of a denture-lining material containing Cnidium officinale extracts and its antifungal efficacy against Candida albicans. To achieve this, a denture-lining material containing various concentrations of C. officinale extract and a control group without C. officinale extract were prepared. The surface characterization and biocompatibility of the samples were investigated. In addition, the antifungal efficacy of the samples on C. albicans was investigated using spectrophotometric growth and a LIVE/DEAD assay. The results revealed that there was no significant difference between the biocompatibility of the experimental and control groups (p > 0.05). However, there was a significant difference between the antifungal efficiency of the denture material on C. albicans and that of the control group (p < 0.05), which was confirmed by the LIVE/DEAD assay. These results indicate the promising potential of the C. officinale extract-containing denture-lining material as an antifungal dental material.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Cnidium/química , Reembasadores de Dentadura , Extratos Vegetais/farmacologia , Antifúngicos/química , Antifúngicos/toxicidade , Linhagem Celular , Cor , Reembasadores de Dentadura/microbiologia , Fibroblastos/efeitos dos fármacos , Humanos , Teste de Materiais , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Propriedades de Superfície
15.
Artigo em Inglês | MEDLINE | ID: mdl-33800982

RESUMO

Nurses have reported higher rates of sickness presenteeism than other workers, which is particularly problematic because this problem is linked to care quality and patient safety. This secondary data analysis study aimed to identify the prevalence of sickness presenteeism and explore related factors among shift and non-shift nurses using the Fifth Korean Working Conditions Survey. A total of 272 nurses in Korean hospitals were included. The survey included questions on working conditions, health status, and sickness presenteeism. A multivariate logistic regression was used to identify associated factors of sickness presenteeism. Overall, 21.8% of the participants reported experiencing sickness presenteeism; shift nurses experienced more sickness presenteeism than non-shift nurses. Sickness presenteeism was greater in shift nurses who did not have rest breaks during work and in nurses who experienced quick return. Additionally, the odds of sickness presenteeism were approximately four times greater in shift nurses who experienced sleep disturbance and about four times higher in shift nurses who experienced health problems. Among non-shift nurses, the odds of sickness presenteeism were about 15 times greater in those who worked ≥53 h per week. Nurse managers and administrators should prevent sickness presenteeism in hospital nurses to provide quality care and enhance productivity.


Assuntos
Nível de Saúde , Presenteísmo , Estudos Transversais , Eficiência , Humanos , República da Coreia/epidemiologia , Inquéritos e Questionários
16.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803441

RESUMO

Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.


Assuntos
Doenças Autoimunes , Linfócitos T CD4-Positivos , Diferenciação Celular , Deleção de Genes , Fatores Reguladores de Interferon/deficiência , Transcrição Genética/imunologia , Uveíte , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Knockout , Uveíte/genética , Uveíte/imunologia , Uveíte/metabolismo , Uveíte/patologia
17.
Antioxidants (Basel) ; 10(3)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809902

RESUMO

Particulate matter (PM) is a mixture of solid and liquid air pollutant particles suspended in the air, varying in composition, size, and physical features. PM is the most harmful form of air pollution due to its ability to penetrate deep into the lungs and blood streams, causing diverse respiratory diseases. Aesculetin, a coumarin derivative present in the Sancho tree and chicory, is known to have antioxidant and anti-inflammatory effects in the vascular and immune system. However, its effect on PM-induced airway thickening and mucus hypersecretion is poorly understood. The current study examined whether naturally-occurring aesculetin inhibited airway thickening and mucus hypersecretion caused by urban PM10 (uPM10, particles less than 10 µm). Mice were orally administrated with 10 mg/kg aesculetin and exposed to 6 µg/mL uPM10 for 8 weeks. To further explore the mechanism(s) involved in inhibition of uPM10-induced mucus hypersecretion by aesculetin, bronchial epithelial BEAS-2B cells were treated with 1-20 µM aesculetin in the presence of 2 µg/mL uPM10. Oral administration of aesculetin attenuated collagen accumulation and mucus hypersecretion in the small airways inflamed by uPM10. In addition, aesculetin inhibited uPM10-evoked inflammation and oxidant production in lung tissues. Further, aesculetin accompanied the inhibition of induction of bronchial epithelial toll-like receptor 4 (TLR4) and epidermal growth factor receptor (EFGR) elevated by uPM10. The inhibition of TLR4 and EGFR accompanied bronchial mucus hypersecretion in the presence of uPM10. Oxidative stress was responsible for the epithelial induction of TLR4 and EGFR, which was disrupted by aesculetin. These results demonstrated that aesculetin ameliorated airway thickening and mucus hypersecretion by uPM10 inhalation by inhibiting pulmonary inflammation via oxidative stress-stimulated TLR4 and EGFR. Therefore, aesculetin may be a promising agent for treating airway mucosa-associated disorders elicited by urban coarse particulates.

18.
Nat Mater ; 20(7): 1000-1006, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33737727

RESUMO

Understanding how the bulk structure of a material affects catalysis on its surface is critical to the development of actionable catalyst design principles. Bulk defects have been shown to affect electrocatalytic materials that are important for energy conversion systems, but the structural origins of these effects have not been fully elucidated. Here we use a combination of high-resolution scanning electrochemical cell microscopy and electron backscatter diffraction to visualize the potential-dependent electrocatalytic carbon dioxide [Formula: see text] electroreduction and hydrogen [Formula: see text] evolution activity on Au electrodes and probe the effects of bulk defects. Comparing colocated activity maps and videos to the underlying microstructure and lattice deformation supports a model in which CO2 electroreduction is selectively enhanced by surface-terminating dislocations, which can accumulate at grain boundaries and slip bands. Our results suggest that the deliberate introduction of dislocations into materials is a promising strategy for improving catalytic properties.

19.
J Pathol ; 253(1): 55-67, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32918742

RESUMO

Nonalcoholic fatty liver disease is a chronic condition involving steatosis, steatohepatitis and fibrosis, and its progression remains unclear. Although the tetraspanin transmembrane 4 L six family member 5 (TM4SF5) is involved in hepatic fibrosis and cancer, its role in nonalcoholic steatohepatitis (NASH) progression is unknown. We investigated the contribution of TM4SF5 to liver pathology using transgenic and KO mice, diet- or drug-treated mice, in vitro primary cells, and in human tissue. TM4SF5-overexpressing mice exhibited nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and liver tissue exhibited lipid accumulation, decreased Sirtuin 1 (SIRT1), increased sterol regulatory-element binding proteins (SREBPs) and inactive STAT3 via suppressor of cytokine signaling (SOCS)1/3 upregulation. In older mice, TM4SF5 promoted inflammatory factor induction, SIRT1 expression and STAT3 activity, but did not change SOCS or SREBP levels, leading to active STAT3-mediated ECM production for NASH progression. A TM4SF5-associated increase in chemokines promoted SIRT1 expression and progression to NASH with fibrosis. Suppression of the chemokine CCL20 reduced immune cell infiltration and ECM production. Liver tissue from high-fat diet- or CCl4 -treated mice and human patients exhibited TM4SF5-dependent steatotic or steatohepatitic livers with links between TM4SF5-mediated SIRT1 modulation and SREBP or SOCS/STAT3 signaling axes. TM4SF5-mediated STAT3 activation in fibrotic NASH livers increased collagen I and laminin γ2. Both collagen I α1 and laminin γ2 suppression resulted in reduced SIRT1 and active STAT3, but no change in SREBP1 or SOCS, and abolished CCl4 -mediated mouse liver damage. TM4SF5-mediated signaling pathways that involve SIRT1, SREBPs and SOCS/STAT3 promoted progression to NASH. Therefore, TM4SF5 and its downstream effectors may be promising therapeutic targets to treat nonalcoholic fatty liver disease. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Matriz Extracelular/enzimologia , Metabolismo dos Lipídeos , Cirrose Hepática Experimental/enzimologia , Fígado/enzimologia , Proteínas de Membrana/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Sirtuína 1/metabolismo , Animais , Tetracloreto de Carbono , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dieta Hiperlipídica , Progressão da Doença , Matriz Extracelular/patologia , Humanos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Proteínas de Membrana/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais
20.
Korean J Intern Med ; 36(Suppl 1): S80-S89, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32872739

RESUMO

BACKGROUND/AIMS: Prolonged dual antiplatelet therapy (DAPT) with aspirin and clopidogrel beyond 1 year has been shown to reduce ischemic events at the expense of increased bleeding. However, limited data are available on the clinical significance of platelet reactivity (PR) at 1 year. METHODS: We retrospectively identified 331 patients who underwent percutaneous coronary intervention (PCI) and assessed the on-clopidogrel PR using VerifyNow P2Y12 assay at 1 year in a single center. Two hundred eleven patients were on DAPT for > 1 year. The relationship between high on-treatment platelet reactivity (HPR) at 1 year and clinical outcomes beyond 1 year, as well as the longitudinal change in PR was analyzed. RESULTS: At 1 year, 135 (64%) patients showed HPR and 76 (36%) did not. There was a significant increase in ischemic endpoint events, including cardiovascular death, non-fatal myocardial infarction, and stroke/transient ischemic attack in patients with compared to without HPR at 1 year (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.06 to 6.77; p = 0.036). However, the incidence of any Bleeding Academic Research Consortium bleeding was significantly lower in the HPR group (HR, 0.11; 95% CI, 0.02 to 0.65; p = 0.015). In the longitudinal analysis, PR significantly decreased from post-load to 1 year after index PCI in the non-HPR group. Conversely, the HPR group showed high PR from baseline through 1 year. CONCLUSION: HPR at 1 year may be a useful surrogate for predicting ischemic and bleeding events in patients on prolonged DAPT. Patients with and without HPR at 1 year showed different patterns of longitudinal change in PR.


Assuntos
Intervenção Coronária Percutânea , Plaquetas , Clopidogrel/efeitos adversos , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária , Estudos Retrospectivos , Resultado do Tratamento
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