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1.
BMJ Open Gastroenterol ; 8(1)2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34789472

RESUMO

RESEARCH OBJECTIVES: Clostriodiodes difficile infection (CDI) is a major cause of healthcare-associated diarrhoea with high mortality. There is a lack of validated predictors for severe outcomes in CDI. The aim of this study is to derive and validate a clinical prediction tool for CDI in-hospital mortality using a large critical care database. METHODOLOGY: The demographics, clinical parameters, laboratory results and mortality of CDI were extracted from the Medical Information Mart for Intensive Care-III (MIMIC-III) database. We subsequently trained three machine learning models: logistic regression (LR), random forest (RF) and gradient boosting machine (GBM) to predict in-hospital mortality. The individual performances of the models were compared against current severity scores (Clostridiodes difficile Associated Risk of Death Score (CARDS) and ATLAS (Age, Treatment with systemic antibiotics, leukocyte count, Albumin and Serum creatinine as a measure of renal function) by calculating area under receiver operating curve (AUROC). We identified factors associated with higher mortality risk in each model. SUMMARY OF RESULTS: From 61 532 intensive care unit stays in the MIMIC-III database, there were 1315 CDI cases. The mortality rate for CDI in the study cohort was 18.33%. AUROC was 0.69 (95% CI, 0.60 to 0.76) for LR, 0.71 (95% CI, 0.62 to 0.77) for RF and 0.72 (95% CI, 0.64 to 0.78) for GBM, while previously AUROC was 0.57 (95% CI, 0.51 to 0.65) for CARDS and 0.63 (95% CI, 0.54 to 0.70) for ATLAS. Albumin, lactate and bicarbonate were significant mortality factors for all the models. Free calcium, potassium, white blood cell, urea, platelet and mean blood pressure were present in at least two of the three models. CONCLUSION: Our machine learning derived CDI in-hospital mortality prediction model identified pertinent factors that can assist critical care clinicians in identifying patients at high risk of dying from CDI.

2.
Ann Palliat Med ; 10(9): 9993-10004, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34628923

RESUMO

BACKGROUND: The prognosis of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) between patients with diabetes mellitus (DM) and those without DM is unknown. This study aimed to investigate whether DM has adverse effects on CTO PCI patients. METHODS: This single-center retrospective study included consecutive patients who underwent PCI for CTO at the China-Japan Friendship Hospital (Beijing, China) between January 2016 and April 2019. The clinical outcomes during follow-up were compared between patients with DM and those without DM. RESULTS: The analysis included 187 patients (152 males) aged 62.6±11.5 years. A total of 99 participants (52.9%) had DM, which involved a higher body mass index (BMI) and triglyceride level than those without DM (P<0.05). Participants with DM and those without DM had similar PCI success rates (89.9% vs. 95.4%, respectively) and complete revascularization rates (82.8% vs. 84.1%, respectively). There were no significant differences between groups in the rates of all-cause mortality, cardiac death, major adverse cardiovascular events (MACEs), readmission, recurrence of angina, target vessel revascularization (TVR), or myocardial infarction (MI) during a median follow-up of 20.5 months. Multivariable logistic regression revealed that CTO in a coronary branch vessel was associated with higher odds of all-cause death (odds ratio (OR): 53.56; 95% confidence interval (CI): 2.48 to 1,155.41; P<0.05) and failure of PCI for CTO (OR: 5.40; 95% CI: 1.263 to 23.098; P<0.05). Additionally, PCI for single CTO was associated with lower odds of MACEs (OR: 0.300; 95% CI: 0.118 to 0.765; P<0.05). CONCLUSIONS: The performance of PCI for CTO has a high success rate in both patients with DM and those without DM, and clinical outcomes are comparable between groups.


Assuntos
Oclusão Coronária , Diabetes Mellitus , Intervenção Coronária Percutânea , Doença Crônica , Angiografia Coronária , Oclusão Coronária/cirurgia , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
3.
J Invasive Cardiol ; 33(11): E877-E883, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34653957

RESUMO

BACKGROUND AND AIM: Patients with chronic dialysis dependency undergoing percutaneous coronary intervention (PCI) are at a greater risk of hemorrhagic and ischemic events. Due to their exclusion from randomized clinical trials, the optimal antithrombotic regimen for this population remains unknown. Bivalirudin has been associated with fewer hemorrhagic complications than unfractionated heparin (UFH) in patients undergoing PCI. We evaluated major adverse cardiac event (MACE) and hemorrhagic event rates for an antithrombotic regimen using bivalirudin or UFH during PCI in acute coronary syndrome (ACS) patients with chronic dialysis dependency. METHODS: A retrospective study was performed, including 211 patients on dialysis undergoing PCI due to ACS from January 2014 to April 2019 at the China-Japan Friendship Hospital. Patients were divided into 2 groups based on anticoagulation regimen: the bivalirudin group (86 cases) or the UFH group (125 cases) during and after PCI. Statistical analyses were used to compare MACE and hemorrhagic events between groups at 30 days after PCI. RESULTS: No patients experienced stent thrombosis within 30 days after PCI regardless of anticoagulant. There was no difference in the incidence of MACE in the bivalirudin group compared with the UFH group (6.98% vs 8.80%, respectively; P>.05). The rate of hemorrhagic events in the bivalirudin group was significantly lower than in the UHP group (5.81% vs 18.4%, respectively; P<.05), particularly for rates of mild bleeding (4.65% vs 15.2%, respectively; P<.05). There were no significant differences in rates of severe bleeding between the bivalirudin and UFH groups (1.16% vs 4.00%, respectively; P>.05), although fewer severe hemorrhagic events occurred in the bivalirudin group. CONCLUSION: Bivalirudin was associated with fewer bleeding events following PCI in individuals with end-stage renal disease on dialysis.


Assuntos
Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/cirurgia , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , Heparina/efeitos adversos , Hirudinas/efeitos adversos , Humanos , Fragmentos de Peptídeos/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Proteínas Recombinantes , Diálise Renal/efeitos adversos , Estudos Retrospectivos
4.
Histol Histopathol ; : 18381, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34668176

RESUMO

Cardiomyocyte apoptosis is a fundamental pathogenic factor leading to myocardial ischemia/reperfusion (MI/R) injury. The long non-coding RNA (IncRNA) TUG1 regulates apoptosis in various cell types. We report here that TUG1 expression is induced in mouse heart following MI/R injury as well as in cardiomyocytes subjected to simulated ischemia/reperfusion (SI/R) in vitro. Clinically, TUG1 expression is also elevated in plasma from patients with acute myocardial infarction (AMI), which implies its potential application as a disease biomarker. Functionally, TUG1 overexpression promotes, and its knockdown reduces SI/R-induced lactate dehydrogenase (LDH) release and caspase-3 activity in cardiomyocytes in vitro, illustrating that TUG1 exacerbates SI/R-induced apoptosis. Furthermore, in vivo, TUG1 aggravates MI/R injury in a mouse model, and subsequent observations show concurrent increased apoptosis of cardiomyocytes. Hence, this study unveils a clinical relevance and functional role of TUG1 in MI/R injury, and also implicates that targeting TUG1 may have therapeutic effects in treating MI/R injury.

5.
Aging (Albany NY) ; 13(19): 22843-22855, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607973

RESUMO

OBJECTIVES: Allicin is an allyl 2-propenethiosulfinate or diallyl thiosulfinate acid with cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury. This study aims to examine the underlying mechanism by which Allicin protects against MI/R. METHODS: C57BL6 mice were subjected to either sham or MI/R surgery, and mice in the Allicin group were injected with Allicin (5 mg/ml) before the induction of ischemia. The cardiac function and histopathology of experimental mice were evaluated by ultrasound quantification and Masson staining. We next measured the capillary angiogenesis of the peri-infarct area by Masson staining and immunohistochemical staining. The miRNA microarray was carried out to examine the expressed miRNAs in MI/R tissues and corresponding normal tissues. Real-time quantitative polymerase chain reaction (q-PCR) was performed to validate the selected miRNA-19α-3p gene expression. Besides, we evaluated the myocardial lactate dehydrogenase and COX-2 by immunofluorescence staining. The western blot analysis was used to evaluate the protein levels of p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein in the Allicin and Model group. In vitro study, LPS stimulated Tie2 expressing macrophages were cultured in an ischemic buffer. We evaluated the accumulation of VEGF by fura-2/AM fluorescence. Besides, Western blotting was performed to examine the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2. The PI3K inhibitor was applied to investigate whether Allicin-induced myocardial ischemia-reperfusion injury protection is mediated via the PI3K/AKT pathway. And the miR-19α-3p mimic/inhibitor were transfected to promote/inhibit the expression of miR-19a-3p for verifying the regulation of miR-19a-3p on PI3K pathway. RESULTS: Allicin pretreatment significantly improved I/R-induced cardiac function damage. Furthermore, Allicin could repress cardiac fibrosis, as evidenced by reduced areas of cardiac fibrosis. Allicin's effect on the MI/R was associated with increased capillary angiogenesis. Microarray analysis exposed that miR-19a-3p down-regulated PIK3CA (PI3K) expression by directly targeting the PIK3CA gene. The regulation of the angiogenesis pathway and gene miRNA-19a-3p might affect the Allicin-induced MI/R protection. Immunofluorescence staining revealed that COX-2 and myocardial lactate dehydrogenase were significantly increased after Allicin treatment. Furthermore, western blot analysis demonstrated that p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein levels were also increased in the Allicin group. In vitro study, the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2 were significantly increased in the Allicin-treated Tie2 expressing macrophages. These effects were partially reversed by PI3K inhibitor (Wortmannin) treatment. MiR-19α-3p plays an important role in myocardial I/R injury. It could regulate the activity of the PI3K-AKT pathway. And inhibition of miR-19a-3p promoted angiogenesis by regulating PI3K/AKT pathway. CONCLUSIONS: Allicin pretreatment protects against myocardial I/R and activating the miR-19a-3p/PI3K/AKT pathway.

6.
Acta Pharm Sin B ; 11(7): 1708-1720, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34386317

RESUMO

Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.

7.
Aging (Albany NY) ; 13(15): 19643-19656, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34343971

RESUMO

PURPOSE: To investigate the protective effect and mechanism of allicin on myocardial ischemia-reperfusion (MI/R) injury. METHODS: We investigated the mechanisms by which allicin attenuated the MI/R injury by focusing on phosphoinositide 3-kinase, G protein coupled receptor kinases 2, phospholipase Cγ and cardiomyocyte apoptosis. Sixty male mice were randomly assigned into three groups: repeated MI/R (model), sham-operated (control), and MI/R+ allicin group (allicin). Ultrasound examination was used to examine the cardiac function. Masson staining was used to evaluate the myocardial infarct area. TUNEL assay was performed to examine the anti-apoptotic effect of allicin. Differentially expressed genes (DEGs) and pathways were analyzed by mRNA microarray analysis. Immunofluorescence staining and western blot were carried out to detect the effect of allicin on the PI3K. A pan-PLC activator, m-3M3FBS, was applied to investigate whether allicin induced cardiomyocyte apoptosis was via the GRK2/PLC/IP3R signaling pathway. RESULTS: Masson staining and the TUNEL assay revealed that allicin reduced infarct size and played an anti-apoptotic role in M/IR. Ultrasound examination revealed that allicin improved cardiac function after M/IR injury. Gene ontology analysis indicated that the calcium signaling pathway and PI3KCA(PI3K) were selected. Immunofluorescence staining and western blot exposed that PI3K was activated by allicin during MI/R injury. Fura-2AM staining revealed that the PI3K -mediated GRK2/PLC-γ/IP3R pathway may be involved in the protective effect of allicin on MI/R injury. CONCLUSIONS: Allicin has a protective effect on MI/R injury. This effect might be associated with the inhibition of Ca2+ overload-induced apoptosis and the inhibition of the PI3K -mediated GRK2/PLC-γ/IP3R signaling pathway.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34152510

RESUMO

PURPOSE: It has been established that obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. Chronic intermittent hypoxia (CIH) activates sympathoadrenal system and upregulates ß3 adrenergic receptor (ß3 AR). However, the effect of selective ß3 AR agonist mirabegron in CIH-induced atherosclerosis remains unknown. METHODS: We generated a CIH-induced atherosclerosis model through exposing ApoE-/- mice to CIH (8 h per day, cyclic inspiratory oxygen fraction 5-21%, 60-s cycle) for 6 weeks after 4-week high-fat dieting and investigated the effects of mirabegron, a selective ß3 AR agonist, on CIH-induced atherosclerosis. The coronary endarterectomy (CE) specimens from coronary artery disease patients with OSA and without OSA were collected. RESULTS: The expression of ß3 AR was significantly elevated in CIH-induced atherosclerosis model. Furthermore, treatment with mirabegron (10mg/kg per day by oral administration for 6 weeks) ameliorated atherosclerosis in ApoE-/- mice in CIH but not in normoxia. Mechanistically, mirabegron activated ß3 AR and ameliorated intraplaque oxidative stress by suppressing p22phox expression and reactive oxygen species (ROS) level. In addition, in human CE specimens, ß3 AR was also upregulated associated with increased p22phox expression and ROS level both in the lumen and in the plaque of coronary artery in OSA subjects. CONCLUSION: This study first demonstrated that mirabegron impeded the progression of CIH-induced atherosclerosis, at least in part, via ß3 AR-mediated oxidative stress, suggesting a promising therapeutic strategy for protecting against atherosclerosis induced by CIH.

9.
Ther Adv Musculoskelet Dis ; 13: 1759720X211006964, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959198

RESUMO

Introduction: To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX). Methods: This was a 52-week, randomized, double-blind, placebo controlled, phase III study in patients with RA who had an inadequate response to MTX. Patients (n = 290) receiving stable background MTX were randomly assigned (1:1) to receive placebo or baricitinib 4 mg once daily with a primary endpoint at week 12. PROs assessed included Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity, patient's assessment of pain, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), European Quality of Life-5 Dimensions-5 Level index scores and visual analogue scale, and measures collected in electronic patient daily diaries: duration of morning joint stiffness, Worst Tiredness, and Worst Joint Pain. Treatment comparisons were made with logistic regression and analysis of covariance models for categorical and continuous variables, respectively. Results: Statistically significant (p ⩽ 0.05) improvements in all PROs were observed in the baricitinib 4 mg group compared to placebo as early as week 1 to week 4; and were sustained to week 24. These improvements were maintained until week 52 for the baricitinib group. A significantly larger proportion of patients met or exceeded the minimum clinically important difference for HAQ-DI (⩾0.22) and FACIT-F (3.56) profiles in the baricitinib group. Conclusion: Baricitinib provided significant improvements in PROs compared to placebo to 52 weeks of treatment in patients with RA who had an inadequate response to MTX.Clinicaltrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT02265705; NCT02265705; RA-BALANCE. Registered 13 October 2014.

10.
Clin Rheumatol ; 40(10): 3989-4005, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33990888

RESUMO

OBJECTIVES: To assess the efficacy and safety of jakinibs for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response or intolerance to conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library. Randomized placebo-controlled trials (RCTs) of jakinibs in RA patients were eligible. The effective outcome was RA improvement to reach an American College of Rheumatology 20%/50%/70% (ACR20/50/70) response rate at weeks 12 and 24 after treatment. The safety outcomes included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events, infections, and serious infections. RESULTS: Twenty-eight randomized, double-blind, controlled trials including 14,500 patients were included. At both weeks 12 and 24, the pooled analysis suggested effective treatment with jakinibs, represented as an increased clinical response of ACR20, ACR50, and ACR70. Subgroup analysis based on different types of jakinibs demonstrated that only peficitinib treatment had no impact on the clinical response of ACR50 or ACR70 at week 12. Jakinibs were associated with an increased incidence of infections at week 12 and TEAEs and infections at week 24. No increase in the risk of SAEs, discontinuations due to adverse events, or serious infections was observed in comparisons between treatment with jakinibs and treatment with placebo in these patients. CONCLUSIONS: Jakinibs are efficacious and well tolerated in RA patients up to 24 weeks, although they are associated with an increased risk of infectious complications. Key Points • ACR20/50/70 in patients treated with jakinibs was significantly higher than those in patients treated with placebo. • No difference in ACR50/70 was observed in patients with RA treated with peficitinib and placebo. • Jakinibs are beneficial and well tolerated in RA treatment.


Assuntos
Antirreumáticos , Artrite Reumatoide , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Método Duplo-Cego , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
11.
BMC Cardiovasc Disord ; 21(1): 200, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882833

RESUMO

BACKGROUND: Myocardial ischemia-reperfusion (IR) injury is a damage due to an initial reduction in blood flow to the heart, preventing it from receiving enough oxygen, and subsequent restoration of blood flow through the opening of an occluded coronary artery producing paradoxical harmful effects. The finding of new therapies to prevent IR is of utmost importance. Allicin is a compound isolated from garlic having the ability to prevent and cure different diseases, and a protective effect on the myocardium was also demonstrated. Therefore, the aim of this study was to evaluate the in vitro protective effect of Allicin against myocardial IR injury on cardiomyocytes. METHODS: We established an in vitro hypoxia-reoxygenation (HR) model of primary porcine cardiomyocytes to simulate myocardial IR injury. Primary porcine cardiomyocytes were extracted from Mini-musk swines (1 day old). After a period of adaptation of at least 2-3 days, cardiomyocytes in good condition were selected and randomly divided into control group (normal oxygen for 5 h), HR group (2 h of hypoxia/3 h of reoxygenation), and HR + Allicin group (hypoxia/reoxygenation + Allicin treatment). RESULTS: After the induction of hypoxia/reoxygenation, Allicin treatment enhanced the cell viability. Moreover, Allicin treatment resulted in a reduction of apoptosis from 13.5 ± 1.2% to 6.11 ± 0.15% compared with the HR group (p < 0.05), and the apoptosis related proteins were regulated as well, with a decreased expression of Bax, cleaved caspase-3 and cytosolic cytochrome C and an increase in Bcl-2 expression in the HR + Allicin group (all p < 0.01). Pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor alpha were down-regulated by the treatment with Allicin (both p < 0.01). In addition, it significantly decreased intracellular reactive oxygen species generation (p < 0.01) and reduced the loss of mitochondrial membrane potential (p < 0.01). Furthermore, the expression of PPARγ coactivator-1α and endothelial nitric oxide synthase was up-regulated (both p < 0.01), while the expression of Endothelin-1, hypoxia inducing factor-1α and transforming growth factor beta was down-regulated (all p < 0.01) by Allicin treatment. CONCLUSIONS: These results suggested that Allicin protected the cardiomyocytes against HR damage by reducing apoptosis, inflammation and mitochondrial injury, thus providing a basis for its potential use in the treatment of myocardial IR.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Dissulfetos/farmacologia , Mediadores da Inflamação/metabolismo , Inflamação/prevenção & controle , Mitocôndrias Cardíacas/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Ácidos Sulfínicos/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Hipóxia Celular , Células Cultivadas , Citocinas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Suínos , Porco Miniatura
12.
Front Psychol ; 12: 638320, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33643169

RESUMO

The perception of the relationship between humans and nature is important for promoting not only pro-environmental behaviors but also psychological well-being. The present research explored how people's self-construal would moderate the relationship between the need to belong, the desire for social acceptance and connectedness and perceived nature relatedness. Two studies using community samples with diverse demographic characteristics in two different cultures (Study 1: the United States; Study 2: Singapore) obtained consistent findings. The results showed that independent self-construal, which emphasizes separateness from others in the social contexts, moderated the relationship between the need to belong and nature relatedness. Specifically, the need to belong was negatively associated with nature relatedness among people with a stronger independent self-construal, while this pattern was not significant among those with a weaker independent self-construal. No evidence for the moderating role of interdependent self-construal was found in the two studies. These findings highlighted the importance of non-nature experience in understanding people's perception of human-nature relationships.

13.
Autophagy ; 17(8): 1934-1946, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32722981

RESUMO

Mitophagy, the elimination of damaged mitochondria through autophagy, promotes neuronal survival in cerebral ischemia. Previous studies found deficient mitophagy in ischemic neurons, but the mechanisms are still largely unknown. We determined that BNIP3L/NIX, a mitophagy receptor, was degraded by proteasomes, which led to mitophagy deficiency in both ischemic neurons and brains. BNIP3L exists as a monomer and homodimer in mammalian cells, but the effects of homodimer and monomer on mitophagy are unclear. Site-specific mutations in the transmembrane domain of BNIP3L (S195A and G203A) only formed the BNIP3L monomer and failed to induce mitophagy. Moreover, overexpression of wild-type BNIP3L, in contrast to the monomeric BNIP3L, rescued the mitophagy deficiency and protected against cerebral ischemic injury. The macroautophagy/autophagy inhibitor 3-MA and the proteasome inhibitor MG132 were used in cerebral ischemic brains to identify how BNIP3L was reduced. We found that MG132 blocked the loss of BNIP3L and subsequently promoted mitophagy in ischemic brains. In addition, the dimeric form of BNIP3L was more prone to be degraded than its monomeric form. Carfilzomib, a drug for multiple myeloma therapy that inhibits proteasomes, reversed the BNIP3L degradation and restored mitophagy in ischemic brains. This treatment protected against either acute or chronic ischemic brain injury. Remarkably, these effects of carfilzomib were abolished in bnip3l-/- mice. Taken together, the present study linked BNIP3L degradation by proteasomes with mitophagy deficiency in cerebral ischemia. We propose carfilzomib as a novel therapy to rescue ischemic brain injury by preventing BNIP3L degradation.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ATG7: autophagy related 7; BCL2L13: BCL2-like 13 (apoptosis facilitator); BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CFZ: carfilzomib; COX4I1: cytochrome c oxidase subunit 4I1; CQ: chloroquine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; I-R: ischemia-reperfusion; MAP1LC3A/LC3A: microtube-associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtube-associated protein 1 light chain 3 beta; O-R: oxygen and glucose deprivation-reperfusion; OGD: oxygen and glucose deprivation; PHB2: prohibitin 2; pMCAO: permanent middle cerebral artery occlusion; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; PT: photothrombosis; SQSTM1: sequestosome 1; tMCAO: transient middle cerebral artery occlusion; TOMM20: translocase of outer mitochondrial membrane 20; TTC: 2,3,5-triphenyltetrazolium hydrochloride.

14.
Adv Ther ; 38(1): 772-781, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33237533

RESUMO

INTRODUCTION: Baricitinib is an oral, selective inhibitor of Janus kinase which demonstrates clinical efficacy in patients with rheumatoid arthritis (RA). This report aims to analyze the onset time of baricitinib in Chinese patients with moderately to severely active RA who had an inadequate response to methotrexate. METHODS: This post hoc analysis evaluated clinical improvements of Chinese patients treated with baricitinib 4 mg once daily compared with placebo, based on data from a phase 3 study RA-BALANCE. Efficacy measures including American College of Rheumatology 20% (ACR20) response, ACR core set values, Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28) using high-sensitivity C-reactive protein (hsCRP), DAS28-erythrocyte sedimentation rate, Simplified Disease Activity Index, Clinical Disease Activity Index, DAS28-hsCRP ≤ 3.2 response (low disease activity), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated at weeks 1, 2, 4, 8, 12, 14, 16, 20, and 24 (except for FACIT-F evaluated every 4 weeks). A logistic regression model and an analysis of covariance model were used to analyze treatment comparisons of categorical and continuous measures, respectively. RESULTS: Statistically significant (p ≤ 0.05) improvements were observed as early as week 1 or 2 for the baricitinib group compared to placebo in almost all main efficacy measures. For other outcomes including 66 swollen joint count, 68 tender joint count, FACIT-F, and DAS28-hsCRP ≤ 3.2 response rate, differences were evident (p ≤ 0.05) by week 4 in the baricitinib group compared with placebo. Significant improvements in all efficacy measures were sustained through 24 weeks. CONCLUSIONS: Baricitinib demonstrated a rapid onset of efficacy on ACR20 response, ACR core set values, disease activity, and patient-reported outcome improvements in Chinese patients from RA-BALANCE. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02265705.


Assuntos
Antirreumáticos , Artrite Reumatoide , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Azetidinas , China , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Metotrexato/uso terapêutico , Purinas , Pirazóis , Índice de Gravidade de Doença , Sulfonamidas , Resultado do Tratamento
15.
Arthritis Rheumatol ; 73(6): 1033-1043, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33381895

RESUMO

OBJECTIVE: Adult-onset Still's disease (AOSD) is a severe autoinflammatory disease. Neutrophil activation with enhanced neutrophil extracellular trap (NET) formation is involved in the pathogenesis of AOSD. Functional leukocyte immunoglobulin-like receptor A3 (LIR-A3; gene name LILRA3) has been reported to be associated with many autoimmune diseases. We aimed to investigate the association of LILRA3 with disease susceptibility and neutrophil activation in AOSD. METHODS: The LILRA3 deletion polymorphism and its tagging single-nucleotide polymorphism rs103294 were genotyped in 164 patients with AOSD and 305 healthy controls. The impact of LILRA3 on clinical features and messenger RNA expression was evaluated. Plasma levels of LIR-A3 were detected using enzyme-linked immunosorbent assay (ELISA), and the correlation between LIR-A3 plasma levels and disease activity and levels of circulating NET-DNA was investigated. LIR-A3-induced NETs were determined using PicoGreen double-stranded DNA dye and immunofluorescence analysis in human neutrophils and a neutrophil-like differentiated NB4 cell line transfected with LIR-B2 small interfering RNA. RESULTS: The findings from genotyping demonstrated that functional LILRA3 was a risk factor for AOSD (11% in AOSD patients versus 5.6% in healthy controls; odds ratio 2.089 [95% confidence interval 1.030-4.291], P = 0.034), and associated with leukocytosis (P = 0.039) and increased levels of circulating neutrophils (P = 0.027). Functional LILRA3 messenger RNA expression was higher in the peripheral blood mononuclear cells (P < 0.0001) and neutrophils (P < 0.001) of LILRA3+/+ patients. Plasma levels of LIR-A3 were elevated in patients with AOSD (P < 0.0001) and correlated with disease activity indicators and levels of circulating NET-DNA complexes. Finally, enhanced NET formation was identified in neutrophils from healthy controls and patients with inactive AOSD after stimulation of the neutrophils with LIR-A3. Moreover, NET formation was impaired in NB4 cells after knockdown of LILRB2 gene expression. CONCLUSION: Our study provides the first evidence that functional LILRA3 is a novel genetic risk factor for the development of AOSD and that functional LIR-A3 may play a pathogenic role by inducing formation of NETs.


Assuntos
Armadilhas Extracelulares/genética , Ativação de Neutrófilo/genética , Receptores Imunológicos/genética , Doença de Still de Início Tardio/genética , Adulto , Estudos de Casos e Controles , Armadilhas Extracelulares/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Leucocitose , Masculino , Neutrófilos , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Receptores Imunológicos/metabolismo , Doença de Still de Início Tardio/metabolismo
16.
Clin Interv Aging ; 15: 2277-2289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33304098

RESUMO

Contrast-induced encephalopathy (CIE) is a rare complication following percutaneous carotid and coronary interventions, and important diagnostic radiological signs include brain edema and cortical enhancement. In this report, we detail a case of probable CIE in an 84-year-old woman following a normal diagnostic coronary angiography (CAG) that involved 20 mL of the low-osmolar, non-ionic monomeric, iodine-based contrast agent iopromide (Ultravist 370). The patient was unconscious and presented with hemiparesis, hemianopia, recurrent seizures, and cardiac and respiratory arrest within minutes to hours following the procedure. Non-contrast computed tomography (CT) of the head showed increased subarachnoid density, cortical enhancement, and brain edema in the right hemisphere. Three days of rehydration, reduction in cranial pressure, and treatment with an anticonvulsant and dexamethasone resulted in a gradual recovery with no neurological deficits. This case highlights that severe neurotoxic symptoms may occur in response to low doses of low-osmolar, non-ionic, monomeric contrast agents. This finding is of importance to interventional cardiologists for diagnostic considerations and development of treatment plans.


Assuntos
Encefalopatias/induzido quimicamente , Meios de Contraste/efeitos adversos , Angiografia Coronária/efeitos adversos , Iohexol/análogos & derivados , Idoso de 80 Anos ou mais , Encefalopatias/diagnóstico , Encefalopatias/terapia , Artérias Carótidas/efeitos dos fármacos , Meios de Contraste/administração & dosagem , Feminino , Humanos , Iodo/efeitos adversos , Iohexol/administração & dosagem , Iohexol/efeitos adversos , Resultado do Tratamento
17.
Int J Biol Macromol ; 165(Pt B): 2387-2394, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33132128

RESUMO

Effects of xanthan gum (XG) addition and oil contents on the structural and rheological properties of Pickering emulsion stabilized by xanthan gum/Lysozyme nanoparticles (XG/Ly NPs) were analyzed by microstructure, creaming index, and rheological analysis. The results showed that XG addition reduced the droplet size of the emulsion, and a denser three-dimensional network structure was formed between droplets in the continuous phase. Thus, the migration of droplets slowed down, and the stability of Pickering emulsion increased. Rheological studies indicated that the network structure of Pickering emulsion depends on XG addition and oil content. The critical strain (γco) displayed three regimes. For low oil content (20%), γco decreased with the increase of XG concentration. For Pickering emulsion with medium oil content (40%, v/v), γco increased with increasing addition of XG. When high oil content (60-80%) was provided, γco was almost independent of XG addition. The results showed that the microstructure, stability and rheological properties of Pickering emulsion stabilized by XG/Ly NPs could be regulated by XG addition and oil content. This attempt provided theoretical support for regulating Pickering emulsion properties by polysaccharides addition, and established Pickering emulsions with various demands.


Assuntos
Emulsões/química , Muramidase/metabolismo , Nanopartículas/química , Polissacarídeos Bacterianos/química , Reologia , Nanopartículas/ultraestrutura , Tamanho da Partícula , Viscosidade
18.
Chemosphere ; 261: 127929, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33113658

RESUMO

To elucidate the effects of extracellular polymeric substance (EPS) on the sludge dewaterability, this study comparatively investigated the changes in EPS composition and spatial distribution, together with the sludge dewaterability after lysozyme (LZM) conditioning. The protein concentration in the tightly bound EPS (TB-EPS) increased from 3.47 mg g-1 DS to 4.99 mg g-1 DS within the first 2 min, then gradually decreased, which could be described by a piecewise linear function. Unlike TB-EPS, the protein content variation trend in both soluble EPS (S-EPS) and loosely bound EPS (LB-EPS) followed the typical first-order kinetics. Additionally, the extended DLVO theory was employed in combination with viscoelastic acoustic response analysis to further explore the impact of EPS composition on water adhesion and microbial cell. After the extraction of S-EPS from the conditioned sludge, the adsorption free energy (ΔGadh) of EPS ascended to -61.05 mJ m-2, indicating the weakened microbial hydrophobicity. By contrast, the ΔGadh value declined after the subsequent extraction of LB-EPS and TB-EPS. Meanwhile, the adsorption potential energy between S-EPS and microbial cells showed an increasing trend, whereas the repulsion potential energy between TB-EPS and microbial cells fell to 1.40 × 104 kT, signifying a weakened adsorption capacity to water. Accordingly, the viscosity and shear modulus of each EPS layer were reduced after conditioning, which contributed to the transformation of bound water into free water. These changes reasonably explained the results that the water content in the dewatered sludge after conditioning was reduced to 58.54%, and the bound water content decreased by 15.06%.


Assuntos
Matriz Extracelular de Substâncias Poliméricas/química , Muramidase/química , Proteínas/análise , Esgotos/química , Eliminação de Resíduos Líquidos/métodos , Água/análise , Acústica , Adsorção , Cinética , Esgotos/análise , Viscosidade
20.
J Chromatogr A ; 1628: 461449, 2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32822988

RESUMO

This paper reported a new method for the determination of the water distribution in sludge. It was based on a multiple headspace extraction (MHE) procedure to step-wise remove the water vapor from a closed vial containing a sludge sample, followed by a gas chromatographic measurement (GC). By plotting the GC signal of water vapor vs. the headspace extraction number, three different trend lines from the profile can be observed. From which two transition points can be determined and thus the stages for the free water, capillary water, and adsorption water release can be divided. Based on the sum of GC peak areas ate each stage, the content of these water types in the sludge can be calculated through a method calibration. The results showed that the MHE-GC method has a better measurement repeatability (RSD < 18.6%) and sensitivity (limit of quantitation = 0.028%) than the thermal drying method (used as a reference method). There was also a good agreement between the MHE-GC and the reference method on the free water and capillary water analysis. Moreover, the results on the adsorption water and bound water testing by the present method is more justifiable than the reference method.


Assuntos
Cromatografia Gasosa/métodos , Esgotos/análise , Água/análise , Calibragem , Dessecação , Pressão , Reprodutibilidade dos Testes , Temperatura , Fatores de Tempo
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