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1.
Artigo em Inglês | MEDLINE | ID: mdl-35553411

RESUMO

Cancer has been a serious threat and impact on the health and life of human. Phototherapy is considered as a promising therapeutic method to replace the traditional treatment in clinic owing to its noninvasive nature and high efficiency. Photoinitiators have long been used in the field of photopolymerization; however, few studies have been carried out on their potential as anticancer agents under light irradiation. In this study, the effect of a photoinitiator, diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide (TPO), on breast cancer is investigated and the related mechanism is elucidated. It is found that TPO has low dark toxicity and significant phototoxicity. TPO can inhibit cell growth and development and promote cell apoptosis through a mitochondrial pathway under light irradiation. Further studies show that cell apoptosis is induced by free radicals produced from the photolysis of TPO to activate JNK phosphorylation. Overall, we identify the antitumor effects of TPO in vitro for the first time, and provides a proof of concept for its application as a novel photolatent therapeutic drug.

2.
FASEB J ; 36 Suppl 12022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35555418

RESUMO

PURPOSE: Foxp3+ T-regulatory (Treg) cells are well established as a crucial component of immune homeostasis and self-tolerance. Histone/protein deacetylase (HDAC) activity within Foxp3+ Tregs plays an important role in regulation of gene expression. HDAC1 and -2 regulate Foxp3 expression and play critical roles in the control of Treg functions and properties. Less understood, are the contributions made by proteins which form large complexes with HDAC1 and -2, such as the paired amphipathic helix protein, Sin3a. METHODS: We sought to evaluate the contributions Sin3a makes to Tregs by undertaking its conditional deletion in Foxp3+ cells. RESULTS: Sin3a-/-Foxp3Cre mice developed severe, systemic autoimmunity, leading to death within 2-3 weeks of birth. These mice had greatly enlarged superficial lymph nodes, massive inflammatory lesions in lungs, skin, livers and kidneys and developed autoantibodies to islet cells, striated muscles, keratin, endomysium and gastric parietal cells. Percentages of Foxp3+ Tregs in the secondary lymphoid organs of Sin3a-/-Foxp3Cre mice were vastly lower than in controls (p values ranging from >0.01 to >0.0001). Further, the amount of Foxp3 mRNA expression (>20-fold) and Foxp3 protein per Treg (>3-fold) were also significantly reduced within Sin3a deficient animals. The ratios of T effectors to Tregs, and follicular T effectors to follicular Tregs were drastically increased within the spleens and superficial lymph nodes (ranging from 87-154% and 152-160%, respectively). Sin3a deficient Tregs produced significant amounts of pro-inflammatory cytokines, including Granzyme B, IFN-γ and IL-2 (ranging from 12-45% of cells). Tregs lacking Sin3a had impaired suppressive function against CD4+ and CD8+ responders (p<0.01 and p<0.05 respectively, compared to WT Tregs) in vitro. In addition, we found that Sin3a was essential for peripheral iTreg conversion since conventional CD4+CD25- cells from Sin3a-/-FoxP3Cre mice completely lacked the ability to convert to Foxp3+ iTregs ex vivo in the presence of IL-2, TGFb, and CD3/CD28 beads. Consistent with impaired Treg function, CD4+ and CD8+ T cells from Sin3a-/-Foxp3Cre mice showed increased activation ex vivo (Ki67+ and CD69+ increased 120% and 230%, respectively) and enhanced production of Granzyme B and cytokines IFN-γ and IL-2 upon stimulation in vitro. To gain a more complete understanding of the regulatory role of Sin3a in Tregs, we are in the process of performing RNAseq. To address the vast reduction of Foxp3+ Tregs within Sin3a-/-FoxP3Cre mice we are investigating methylation of the CNS2 intronic region of Foxp3 by bisulphite conversion and determining the fate of Tregs in vivo by lineage tracing. CONCLUSIONS: These data show that the nuclear co-regulator, Sin3a, functions in modulating Treg gene expression and helps maintain the unique properties of these key immune cells. Our results indicate a potential for therapeutic modulation of Treg functions by pharmacologic targeting of components within the Sin3a complex.

3.
Front Pediatr ; 10: 834268, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35463902

RESUMO

Background: Dyskeratosis congenita (DC) is a rare inheritable disorder characterized by bone marrow failure and mucocutaneous triad (reticular skin pigmentation, nail dystrophy, and oral leukoplakia). Dyskeratosis congenita 1 (DKC1) is responsible for 4.6% of the DC with an X-linked inheritance pattern. Almost 70 DKC1 variations causing DC have been reported in the Human Gene Mutation Database. Results: Here we described a 14-year-old boy in a Chinese family with a phenotype of abnormal skin pigmentation on the neck, oral leukoplakia, and nail dysplasia in his hands and feet. Genetic analysis and sequencing revealed hemizygosity for a recurrent missense mutation c.1156G > A (p.Ala386Thr) in DKC1 gene. The heterozygous mutation (c.1156G > A) from his mother and wild-type sequence from his father were obtained in the same site of DKC1. This mutation was determined as disease causing based on silico software, but the pathological phenotypes of the proband were milder than previously reported at this position (HGMDCM060959). Homology modeling revealed that the altered amino acid was located near the PUA domain, which might affect the affinity for RNA binding. Conclusion: This DKC1 mutation (c.1156G > A, p.Ala386Thr) was first reported in a Chinese family with mucocutaneous triad phenotype. Our study reveals the pathogenesis of DKC1 c.1156G > A mutation to DC with a benign phenotype, which expands the disease variation database, the understanding of genotype-phenotype correlations, and facilitates the clinical diagnosis of DC in China.

4.
Brain Pathol ; : e13070, 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35338543

RESUMO

The M1 polarization of microglia and neuroinflammation restrict the treatment of acute spinal cord injury (ASCI), and long non-coding ribonucleic acid (lncRNA) maternally expressed gene 3 (MEG3) expression is lessened in ASCI. However, the function and mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI are unclear. The expressions of lncRNA MEG3 in ASCI mouse spinal cord tissues and lipopolysaccharide (LPS)-treated primary microglia and BV2 cells were quantified through a quantitative real-time polymerase chain reaction. In-vitro assays were conducted to explore the function of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI. RNA degradation, RNA immunoprecipitation, RNA pull-down, cycloheximide-chase, and ubiquitination analyses were carried out to probe into the mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI. The lncRNA MEG3 expression was lessened in the ASCI mouse spinal cord tissues and LPS-treated primary microglia and BV2 cells, and the overexpression of lncRNA MEG3 restrained the M1 polarization of microglia and the neuroinflammation by regulating the NF-κB signaling pathway. For the investigation of the potential mechanism of such, the overexpression of lncRNA MEG3 restrained the M1 polarization of microglia through the HuR/A20/NF-κB axis and boosted the motor function recovery and neuroinflammation relief in the mice with SCI. The overexpression of lncRNA MEG3 restrained the M1 polarization of microglia through the HuR/A20/NF-κB axis.

5.
Sci Adv ; 8(5): eabl9783, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35108044

RESUMO

eEF-2K has important roles in stress responses and cellular metabolism. We report here a previously unappreciated but critical role of eEF-2K in regulating the fate and cytocidal activity of CD8+ T cells. CD8+ T cells from eEF-2K KO mice were more proliferative but had lower survival than their wild-type counterparts after their activation, followed by occurrence of premature senescence and exhaustion. eEF-2K KO CD8+ T cells were more metabolically active and showed hyperactivation of the Akt-mTOR-S6K pathway. Loss of eEF-2K substantially impaired the activity of CD8+ T cells. Furthermore, the antitumor efficacy and tumor infiltration of the CAR-CD8+ T cells lacking eEF-2K were notably reduced as compared to the control CAR-CD8+ T cells. Thus, eEF-2K is critically required for sustaining the viability and function of cytotoxic CD8+ T cells, and therapeutic augmentation of this kinase may be exploited as a novel approach to reinforcing CAR-T therapy against cancer.


Assuntos
Linfócitos T CD8-Positivos , Quinase do Fator 2 de Elongação/metabolismo , Neoplasias , Animais , Camundongos , Neoplasias/terapia , Fatores de Alongamento de Peptídeos
7.
Environ Pollut ; 294: 118593, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34864100

RESUMO

Periphyton is considered important for removal of organic pollutants from water bodies, but knowledge of the impacts of antibiotics on the community structure and ecological function of waterbodies remains limited. In this study, the effects of oxytetracycline hydrochloride (OTC) on the communities of photoautotrophic epilithon and epipelon and its effect on nitrogen and phosphorus concentrations in the water column were studied in a 12-day mesocosm experiment. The dynamics of nitrogen and phosphorus concentrations in the epipelon and epilithon experiment showed similar patterns. The concentrations of total nitrogen, dissolved total nitrogen, ammonium nitrogen, total phosphorus and dissolved total phosphorus in the water column increased rapidly during the initial days of exposure, after which a downward trend occurred. In the epilithon experiment, we found that the photosynthesis (Fv/Fm) and biomass of epilithon were significantly (P < 0.05) stimulated in the low concentration group. Contrarily, growth and photosynthesis (Fv/Fm) were significantly (P < 0.05) reduced in the medium and high concentration group. We further found that the photosynthetic efficiency of photoautotrophic epilithon was negatively correlated with the concentrations of nitrogen and phosphorus in the water column (P < 0.05). Principal coordinate analysis (PCoA) showed that the communities of epilithic algae in the control group and in the low concentration group were significantly (P < 0.05) different from that of the high concentration group during the initial 4 days. After 8 days' exposure, all groups tended to be similar, indicating that epilithon showed rapid adaptability and/or resilience. Similar results were found for the relative abundance of some epilithic algae. Our findings indicate that the biofilm system has strong tolerance and adaptability to OTC as it recovered fast after an initial suppression, thus showing the important role of periphyton in maintaining the dynamic balance of nutrients with other processes in aquatic ecosystems.


Assuntos
Oxitetraciclina , Perifíton , Poluentes Químicos da Água , Ecossistema , Nitrogênio/análise , Oxitetraciclina/metabolismo , Fósforo/análise , Poluentes Químicos da Água/metabolismo
8.
IEEE Trans Cybern ; 52(1): 333-343, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32149662

RESUMO

Sampled-data state feedback control with stochastic sampling periods for Boolean control networks (BCNs) is investigated in this article. First, based on the algebraic form of BCNs, stochastic sampled-data state feedback control is applied to stabilize the considered system to a fixed point or a given set. Two kinds of distributions of stochastic sampling periods are considered. First, the distribution of sampling periods is assumed to be independent identically distributed (i.i.d.) in the range of any positive integers and the second distribution of sampling periods is assumed to follow an infinite Markov process. A BCN with infinite stochastic sampling periods proves to be equivalent to a finite stochastic switched system, based on which, necessary and sufficient conditions are given to guarantee the stabilization and set stabilization of the BCN with stochastic sampling periods. For the first one, two algorithms are given to guarantee the stabilization and set stabilization of the considered system. For the second one, necessary and sufficient conditions are all presented in the linear programming form. Examples are listed to show the effectiveness of our results.


Assuntos
Algoritmos , Redes Neurais de Computação , Retroalimentação , Cadeias de Markov
9.
IEEE Trans Cybern ; 52(4): 2361-2369, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32886617

RESUMO

In this article, pinning control has been applied to stabilize a kind of stochastic network with finite states called probabilistic logical networks (PLNs). First, the solvability of pinning controllers, including the selection of pinning nodes and the corresponding control design, is addressed to guarantee the stabilization of PLNs. Then, based on the complete matrices set, one necessary and sufficient condition is obtained for PLNs to be stabilized by exact p nodes. In addition, an algorithm is presented for obtaining the minimal number of pinning nodes and how exact they are. As an application, our algorithm is used to calculate the minimal number of pinning nodes for the stabilization of logical networks (LNs). Examples are given to illustrate the process of choosing pinning nodes and show the efficiency of the obtained results.

10.
EBioMedicine ; 74: 103734, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34875457

RESUMO

BACKGROUND: L-kynurenine is a tryptophan-derived immunosuppressive metabolite and precursor to neurotoxic anthranilate and quinolinate. We evaluated the stereoisomer D-kynurenine as an immunosuppressive therapeutic which is hypothesized to produce less neurotoxic metabolites than L-kynurenine. METHODS: L-/D-kynurenine effects on human and murine T cell function were examined in vitro and in vivo (homeostatic proliferation, colitis, cardiac transplant). Kynurenine effects on T cell metabolism were interrogated using [13C] glucose, glutamine and palmitate tracing. Kynurenine was measured in tissues from human and murine tumours and kynurenine-fed mice. FINDINGS: We observed that 1 mM D-kynurenine inhibits T cell proliferation through apoptosis similar to L-kynurenine. Mechanistically, [13C]-tracing revealed that co-stimulated CD4+ T cells exposed to L-/D-kynurenine undergo increased ß-oxidation depleting fatty acids. Replenishing oleate/palmitate restored effector T cell viability. We administered dietary D-kynurenine reaching tissue kynurenine concentrations of 19 µM, which is close to human kidney (6 µM) and head and neck cancer (14 µM) but well below the 1 mM required for apoptosis. D-kynurenine protected Rag1-/- mice from autoimmune colitis in an aryl-hydrocarbon receptor dependent manner but did not attenuate more stringent immunological challenges such as antigen mismatched cardiac allograft rejection. INTERPRETATION: Our dietary kynurenine model achieved tissue concentrations at or above human cancer kynurenine and exhibited only limited immunosuppression. Sub-suppressive kynurenine concentrations in human cancers may limit the responsiveness to indoleamine 2,3-dioxygenase inhibition evaluated in clinical trials. FUNDING: The study was supported by the NIH, the Else Kröner-Fresenius-Foundation, Laffey McHugh foundation, and American Society of Nephrology.


Assuntos
Colite/prevenção & controle , Ácidos Graxos/metabolismo , Proteínas de Homeodomínio/genética , Imunossupressores/administração & dosagem , Cinurenina/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Linfócitos T/citologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colite/genética , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Glucose/metabolismo , Humanos , Imunossupressores/farmacologia , Cinurenina/farmacologia , Masculino , Melanoma Experimental/imunologia , Camundongos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
11.
Materials (Basel) ; 14(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34771958

RESUMO

It has become one of the research directions of intelligent materials for self-healing asphalt pavements to use a bionic microvascular containing oily rejuvenator. The rejuvenator in a microvascular can carry out the healing of asphalt micro-cracks, thus reducing the damage to and prolonging the life of asphalt pavement. The aim of this work was to investigate the smart self-healing capability of an asphalt/microvascular material through its microstructure and mechanical properties. Microstructure observation indicated no interface separation between the microvasculars and bitumen matrix. Micro-CT images showed that microvasculars dispersed in asphalt samples without accumulation or tangles. The phenomenon of microcracks healing without intervention was observed, which proved that the fractured asphalt sample carried out the self-healing process with the help of rejuvenator diffusing out from the broken microvasculars. The self-healing efficiency of asphalt samples was also evaluated through a tensile test considering the factors of microvasculars content, healing time and healing temperature. It was found that the tensile strength of the asphalt samples was greatly enhanced by the addition of microvasculars under a set test condition. Self-healing efficiency was enhanced with more broken microvasculars in the rupture interface of the asphalt sample. During two self-healing cycles, the self-healing efficiency of the asphalt sample with three microvascular per 1 cm2 of a broken interface were able to reach 80% and 86%. This proves that microvasculars containing rejuvenator play a practical role in the self-healing process of asphalt. With an increase in temperature from 0 to 30 °C, the self-healing capability of the asphalt samples increased dramatically. An increase in time increased the self-healing capability of the bitumen samples. At last, a preliminary mathematical model also deduced that the self-healing efficiency was determined by the individual healing steps, including release, penetration and diffusion of the rejuvenator agent.

12.
IEEE Trans Cybern ; PP2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34847051

RESUMO

In this article, the l1-induced performance of the stochastic switched Boolean control network (BCN) is investigated. The switched signal is considered to follow a time-varying probability distribution, the switching of which is considered to have a random dwell time. The asynchronous state feedback control (SFC) is studied to achieve the control objective. This kind of control can avoid the failure of the control due to the inconsistency between the system mode and the control mode, so the results obtained are more general. Using the semitensor product of matrices, the algebraic form of the considered BCN is represented. Under this framework, sufficient conditions are obtained to ensure that the closed-loop system is stochastic stabilized with a prescribed l1-induced performance level ɣ. Parameters can be solved by inequalities. In addition, when the dwell time converges to infinity, the probability distribution of the switched signal becomes fixed. Necessary and sufficient conditions are presented to ensure the stabilization of the closed system under asynchronous SFC as well as the design of the asynchronous SFC. Then, sufficient condition is obtained for the prescribed l1-induced performance level. Examples are presented to show the effectiveness of the obtained results.

13.
Sci Rep ; 11(1): 20430, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650176

RESUMO

Grain filling is the key stage for achieving high grain yield. Subsoiling tillage, as an effective conservation tillage, has been widely used in the maize planting region of China. This study was conducted to explore the effects of subsoiling on the grain filling characteristics of maize varieties of different eras. Five typical maize varieties from different eras (1970s, 1980s, 1990s, 2000s and 2010s) were used as experimental materials with two tillage modalities (rotation tillage and subsoiling tillage). The characteristic parameters (Tmax: the time when the maximum grouting rate was reached, Wmax: the grain weight at the maximum filling rate, Rmax: the maximum grouting rate, P: the active grouting stage, Gmean: the average grouting rate; A: the ultimate growth mass) and rate parameters (T1: the grain filling duration of the gradually increasing stage, V1: the average grain filling rate of the gradually increasing stage, T2: he grain filling duration of the rapidly increasing stage, V2: the average grain filling rate of the rapidly increasing stage, T3: the grain filling duration of the slowly increasing stage, V3: the average grain filling rate of the slowly increasing stage) of grain filling of two tillage modalities were analyzed and compared. The results showed that the filling parameters closely correlated with the 100-kernel weight were significantly different among varieties from different eras, and the grain filling parameters of the 2010s variety were better than those of the other varieties, the P and Tmax prolonged by 4.06-19.25%, 5.88-27.53% respectively, the Rmax and Gmean improved by 5.68-14.81%, 4.76-12.82% and the Wmax increased by 10.14-32.58%. Moreover, the 2010s variety helped the V2 and V3 increase by 6.49-13.89%, 4.55-15.00%. In compared with rotation tillage, the grain yield of maize varieties from different eras increased by 4.28-7.15% under the subsoiling condition, while the 100-kernel weight increased by 3.53-5.06%. Under the same contrast conditions, subsoiling improved the Rmax, Wmax and Gmean by 1.23-4.86%, 4.01-5.96%, 0.25-2.50% respectively, delayed the Tmax by 4.04-5.80% and extended the P by 1.19-4.03%. These differences were major reasons for the significant increases in 100-kernel dry weight under the subsoiling condition. Moreover, subsoiling enhanced the V2 and V3 by 0.70-4.29%, 0.00-2.44%. The duration of each filling stage and filling rate of maize varieties from different eras showed different responses to subsoiling. Under the subsoiling condition, the average filling rate of the 1970-2010s varieties were improved by 1.18%, 0.34%, 0.57%, 1.57% and 2.69%. In the rapidly increasing period, the grain filling rate parameters of the 2010s variety were more sensitive to subsoiling than those of the other varieties. The rapidly increasing and slowly increasing period are the key period of grain filling. Since the 2010s variety and subsoiling all improve the grain filling rate parameters of two periods, we suggest that should select the variety with higher grain filling rate in the rapidly increasing and slowly increasing period, and combine subsoiling measures to improve the grain filling characteristic parameters of maize in production, so as to achieve the purpose of increasing 100 grain weight and yield.

14.
Circulation ; 144(14): 1120-1129, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34510911

RESUMO

BACKGROUND: Vein graft occlusion is deemed a major challenge in coronary artery bypass grafting. Previous studies implied that the no-touch technique for vein graft harvesting could reduce occlusion rate compared with the conventional approach; however, evidence on the clinical benefit and generalizability of the no-touch technique is scare. METHODS: From April 2017 to June 2019, we randomly assigned 2655 patients undergoing coronary artery bypass grafting at 7 hospitals in a 1:1 ratio to receive no-touch technique or conventional approach for vein harvesting. The primary outcome was vein graft occlusion on computed tomography angiography at 3 months and the secondary outcomes included 12-month vein graft occlusion, recurrence of angina, and major adverse cardiac and cerebrovascular events. The generalized estimate equation model was used to account for the cluster effect of grafts from the same patient. RESULTS: During the follow-up, 2533 (96.0%) participants received computed tomography angiography at 3 months after coronary artery bypass grafting and 2434 (92.2%) received it at 12 months. The no-touch group had significantly lower rates of vein graft occlusion than the conventional group both at 3 months (2.8% versus 4.8%; odds ratio, 0.57 [95% CI, 0.41-0.80]; P<0.001) and 12 months (3.7% versus 6.5%; odds ratio, 0.56 [95% CI, 0.41-0.76]; P<0.001). Recurrence of angina was also less common in the no-touch group at 12 months (2.3% versus 4.1%; odds ratio, 0.55 [95% CI, 0.35-0.85]; P<0.01). Rates of major adverse cardiac and cerebrovascular events were of no significant difference between the 2 groups. The no-touch technique was associated with higher rates of leg wound surgical interventions at 3-month follow-up (10.3% versus 4.3%; odds ratio, 2.55 [95% CI, 1.85-3.52]; P<0.001). CONCLUSIONS: Compared with the conventional vein harvesting approach in coronary artery bypass grafting, the no-touch technique significantly reduced the risk of vein graft occlusion and improved patient prognosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03126409.


Assuntos
Ponte de Artéria Coronária/métodos , Procedimentos Cirúrgicos Vasculares/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
15.
Front Mol Biosci ; 8: 727863, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34532346

RESUMO

Eukaryotic Elongation Factor-2 Kinase (eEF2K) acts as a negative regulator of protein synthesis, translation, and cell growth. As a structurally unique member of the alpha-kinase family, eEF2K is essential to cell survival under stressful conditions, as it contributes to both cell viability and proliferation. Known as the modulator of the global rate of protein translation, eEF2K inhibits eEF2 (eukaryotic Elongation Factor 2) and decreases translation elongation when active. eEF2K is regulated by various mechanisms, including phosphorylation through residues and autophosphorylation. Specifically, this protein kinase is downregulated through the phosphorylation of multiple sites via mTOR signaling and upregulated via the AMPK pathway. eEF2K plays important roles in numerous biological systems, including neurology, cardiology, myology, and immunology. This review provides further insights into the current roles of eEF2K and its potential to be explored as a therapeutic target for drug development.

16.
Am J Respir Crit Care Med ; 204(9): 1060-1074, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34346860

RESUMO

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.


Assuntos
Lesão Pulmonar Aguda/etiologia , Interleucina-18/metabolismo , Transplante de Pulmão/efeitos adversos , Obesidade/complicações , Disfunção Primária do Enxerto/etiologia , Traumatismo por Reperfusão/etiologia , Linfócitos T Reguladores/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Obesos , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia
17.
J Am Heart Assoc ; 10(15): e019531, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34320820

RESUMO

Background Coronary computed tomography angiography (CCTA) is a noninvasive, less expensive, low-radiation alternative to invasive coronary angiography (ICA). ICA is recommended for coronary evaluation before heart valvular surgery, and the supporting evidence for CCTA is insufficient. Our study is a single-center, prospective cohort study designed to evaluate the feasibility of CCTA instead of ICA in detection of coronary artery disease before surgery. Methods and Results Heart valvular surgery candidates were consecutively enrolled between April 2017 and December 2018. Nine hundred fifty-eight patients in the CCTA group underwent CCTA primarily, and those with ≥50% coronary stenosis or uncertain diagnosis underwent subsequent ICA. One thousand five hundred twenty-five patients in the ICA group underwent ICA directly before surgery. Coronary artery bypass grafting decision was made by surgeons according to CCTA or ICA results. Most of the patients (78.8%) in the CCTA group avoided invasive angiography. Thirty-day mortality (0.7% versus 0.9%, P=0.821), myocardial infarction (6.4% versus 6.9%, P=0.680 ), and low cardiac output syndrome (4.2% versus 2.8%, P=0.085) were similar in the CCTA and ICA groups. Median duration of follow-up was 19.3 months (interquartile range, 14.2-30.0 months), cumulative rates of mortality (2.6% versus 2.6%, P=0.882) and major adverse cardiac events (9.6% versus 9.0%, P=0.607) showed no difference between the 2 groups. Coronary evaluation expense was lower in the CCTA group ($149.6 versus $636.0, P<0.001). Conclusions The strategy of using CCTA as a doorkeeper in coronary evaluation before heart valvular surgery showed noninferiority in identification of candidates for coronary artery bypass grafting and postoperative safety.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Doenças das Valvas Cardíacas/cirurgia , Cuidados Pré-Operatórios , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Tomada de Decisão Clínica , Estudos de Coortes , Ponte de Artéria Coronária , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/cirurgia , Estudos de Viabilidade , Feminino , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Resultado do Tratamento
18.
Front Immunol ; 12: 703632, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290714

RESUMO

The Mads/Mef2 (Mef2a/b/c/d) family of transcription factors (TFs) regulates differentiation of muscle cells, neurons and hematopoietic cells. By functioning in physiological feedback loops, Mef2 TFs promote the transcription of their repressor, Hdac9, thereby providing temporal control of Mef2-driven differentiation. Disruption of this feedback is associated with the development of various pathologic states, including cancer. Beside their direct involvement in oncogenesis, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg (eTreg) phenotype and for the activation of an epigenetic program that suppresses the anti-tumor immune responses of conventional T and B cells. We now report that as with Mef2d, the deletion of Mef2c in Tregs switches off the expression of Il10 and Icos and leads to enhanced antitumor immunity in syngeneic models of lung cancer. Mechanistically, Mef2c does not directly bind the regulatory elements of Icos and Il10, but its loss-of-function in Tregs induces the expression of the transcriptional repressor, Hdac9. As a consequence, Mef2d, the more abundant member of the Mef2 family, is converted by Hdac9 into a transcriptional repressor on these loci. This leads to the impairment of Treg suppressive properties in vivo and to enhanced anti-cancer immunity. These data further highlight the central role played by the Mef2/Hdac9 axis in the regulation of CD4+Foxp3+ Treg function and adds a new level of complexity to the analysis and study of Treg biology.


Assuntos
Histona Desacetilases/imunologia , Tolerância Imunológica , Neoplasias Pulmonares/imunologia , Neoplasias Experimentais/imunologia , Proteínas Repressoras/imunologia , Linfócitos T Reguladores/imunologia , Animais , Histona Desacetilases/genética , Imunidade Celular , Neoplasias Pulmonares/genética , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias Experimentais/genética , Proteínas Repressoras/genética
19.
Environ Pollut ; 287: 117604, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34171729

RESUMO

In the past decades, research on water pollution microplastics (MPs) has intensified tremendously. However, the relationship between MPs and environmental factors in urban river networks is under researched. Our study selected 65 sampling sites from a sophisticated urban river network system in Shanghai Municipality, China. Here, the combined influence of land-use types, river width, and water quality parameters to explore MPs distribution patterns. We found that MPs abundance ranged from 0.7 to 24.3 items/L, and the spatial difference in abundance was significant at a limited number of sampling sites. Fibrous MPs were the most abundant MPs in the river system. 72.7% of MPs <3 mm. Of the ten polymers detected, polypropylene and polyethylene terephthalate were predominant. In addition, cotton fiber was the main non-plastic component found in the samples. Moreover, land-use types showed no significant impact on MPs in the buffer zone of the sampling sites. However, point source pollution may cause an abnormal increase in MPs abundance. Through redundant analysis, we found that the phytoplankton abundance (e.g., chlorophyll-a) was influenced by MPs shape, while the river width influence MPs size. Construction activities were identified as the leading point source of pollution for the abnormal increase in local MPs pollution. Our results will inform on MPs distribution patterns in the super-metropolis river system.


Assuntos
Microplásticos , Poluentes Químicos da Água , China , Monitoramento Ambiental , Plásticos , Rios , Poluentes Químicos da Água/análise , Qualidade da Água
20.
Artigo em Inglês | MEDLINE | ID: mdl-33994002

RESUMO

OBJECTIVE: Acute kidney injury is a common complication after on-pump coronary artery bypass grafting. Prediction of acute kidney injury remains a challenge. Our study aims to identify a panel of urine metabolites for preoperative warning of acute kidney injury after on-pump coronary artery bypass grafting. METHODS: A total of 159 patients undergoing isolated on-pump coronary artery bypass grafting were enrolled from July 7, 2017, to May 17, 2019. Preoperative urine samples were analyzed with the approach of liquid chromatography-mass spectrometry-based urine metabolomics. The study end point was the episode of acute kidney injury within 48 hours postoperatively. The predictive performance was determined by the area under the curve and calibration curve. The results were validated using bootstrap resampling. RESULTS: The acute kidney injury (n = 55) and nonacute kidney injury (n = 104) groups showed significant different metabolic profiling. A total of 28 metabolites showed significant differences between the acute kidney injury and nonacute kidney injury groups. A metabolite panel of 5 metabolites (tyrosyl-gamma-glutamate, deoxycholic acid glycine conjugate, 5-acetylamino-6-amino-3-methyluracil, arginyl-arginine, and L-methionine) was discovered to have a good predicting performance (area under the curve, 0.89; 95% confidence interval, 0.82-0.93), which is higher than the clinical factor-based model (area under the curve, 0.63; 95% confidence interval, 0.53-0.72). Internal validation by bootstrap resampling showed an adjusted area under the curve of 0.88, and the calibration curve demonstrated good agreement between prediction and observation in the probability of postoperative acute kidney injury. Decision curve analysis revealed a superior net benefit of the metabolite model over the traditional clinical factor-based model. CONCLUSIONS: We present 5 urine metabolites related to acute kidney injury after coronary artery bypass grafting. This metabolite model may serve as a preoperative warning of acute kidney injury after on-pump coronary artery bypass grafting.

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