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1.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638933

RESUMO

Lung cancer is the leading cause of cancer-related mortality worldwide, and its tumorigenesis involves the accumulation of genetic and epigenetic events in the respiratory epithelium. Epigenetic modifications, such as DNA methylation, RNA modification, and histone modifications, have been widely reported to play an important role in lung cancer development and in other pulmonary diseases. Whereas the functionality of DNA and chromatin modifications referred to as epigenetics is widely characterized, various modifications of RNA nucleotides have recently come into prominence as functionally important. N6-methyladosine (m6A) is the most prevalent internal modification in mRNAs, and its machinery of writers, erasers, and readers is well-characterized. However, several other nucleotide modifications of mRNAs and various noncoding RNAs have also been shown to play an important role in the regulation of biological processes and pathology. Such epitranscriptomic modifications play an important role in regulating various aspects of RNA metabolism, including transcription, translation, splicing, and stability. The dysregulation of epitranscriptomic machinery has been implicated in the pathological processes associated with carcinogenesis including uncontrolled cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In recent years, with the advancement of RNA sequencing technology, high-resolution maps of different modifications in various tissues, organs, or disease models are being constantly reported at a dramatic speed. This facilitates further understanding of the relationship between disease development and epitranscriptomics, shedding light on new therapeutic possibilities. In this review, we summarize the basic information on RNA modifications, including m6A, m1A, m5C, m7G, pseudouridine, and A-to-I editing. We then demonstrate their relation to different kinds of lung diseases, especially lung cancer. By comparing the different roles RNA modifications play in the development processes of different diseases, this review may provide some new insights and offer a better understanding of RNA epigenetics and its involvement in pulmonary diseases.

2.
Expert Rev Neurother ; 21(10): 1101-1123, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34551653

RESUMO

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein IgG antibody-associated disorders (MOGAD) comprise two groups of rare neuroinflammatory diseases that cause attack-related damage to the central nervous system (CNS). Clinical attacks are often characterized by optic neuritis, transverse myelitis, and to a lesser extent, brainstem encephalitis/area postrema syndrome. Retinal optical coherence tomography (OCT) is a non-invasive technique that allows for in vivo thickness quantification of the retinal layers. Apart from OCT, magnetic resonance imaging (MRI) plays an increasingly important role in NMOSD and MOGAD diagnosis based on the current international diagnostic criteria. Retinal OCT and brain/spinal cord/optic nerve MRI can help to distinguish NMOSD and MOGAD from other neuroinflammatory diseases, particularly from multiple sclerosis, and to monitor disease-associated CNS-damage. AREAS COVERED: This article summarizes the current status of imaging research in NMOSD and MOGAD, and reviews the clinical relevance of OCT, MRI and other relevant imaging techniques for differential diagnosis, screening and monitoring of the disease course. EXPERT OPINION: Retinal OCT and MRI can visualize and quantify CNS damage in vivo, improving our understanding of NMOSD and MOGAD pathology. Further efforts on the standardization of these imaging techniques are essential for implementation into clinical practice and as outcome parameters in clinical trials.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34348969

RESUMO

OBJECTIVE: To investigate the association of combined serum neurofilament light chain (sNfL) and retinal optical coherence tomography (OCT) measurements with future disease activity in patients with early multiple sclerosis (MS). METHODS: We analyzed sNfL by single molecule array technology and performed OCT measurements in a prospective cohort of 78 patients with clinically isolated syndrome and early relapsing-remitting MS with a median (interquartile range) follow-up of 23.9 (23.3-24.7) months. Patients were grouped into those with abnormal or normal sNfL levels, defined as sNfL ≥/<80th percentile of age-corrected reference values. Likewise, patients were grouped by a median split into those with thin or thick ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer, and inner nuclear layer in nonoptic neuritis eyes. Outcome parameters were violation of no evidence of disease activity (NEDA-3) criteria or its components. RESULTS: Patients with abnormal baseline sNfL had a higher risk of violating NEDA-3 (hazard ratio [HR] 2.28, 95% CI 1.27-4.09, p = 0.006) and developing a new brain lesion (HR 2.47, 95% CI 1.30-4.69, p = 0.006), but not for a new relapse (HR 2.21, 95% CI 0.97-5.03, p = 0.058). Patients with both abnormal sNfL and thin GCIP had an even higher risk for NEDA-3 violation (HR 3.61, 95% CI 1.77-7.36, p = 4.2e-4), new brain lesion (HR 3.19, 95% CI 1.51-6.76, p = 0.002), and new relapse (HR 5.38, 95% CI 1.61-17.98, p = 0.006) than patients with abnormal sNfL alone. CONCLUSIONS: In patients with early MS, the presence of both abnormal sNfL and thin GCIP is a stronger risk factor for future disease activity than the presence of each parameter alone.

4.
J Chin Med Assoc ; 84(9): 827-832, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34292208

RESUMO

The Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented disruption to the normal operation of the healthcare system. On a worldwide scale, hospitals suspended nonurgent surgeries and outpatient visits to downsize clinical loadings to redistribute manpower to counteract the pandemic's impact. So far, there is no evidence-based guideline defining a clear line between urgent and nonurgent indications of intravitreal injections (IVI). Herein, we aimed to summarize IVI algorithm modifications and discuss the patient prioritization according to medical needs in the hostile environment in the COVID crisis. Assessing current literature, we found that neovascular age-related macular degeneration is considered the utmost priority among conditions that require IVI. Other conditions assigned with a high priority include monocular or quasi-monocular patients (only one eye > 20/40), neovascular glaucoma, and new patients with significant vision loss. Although patients with central retinal vein occlusion and proliferative diabetic retinopathy are not advised to delay treatments, we found no consistent evidence that correlated with a worse outcome. Diabetic macular edema and branch retinal vein occlusion patients undertaking treatment delay should be regularly followed up every 2 to 3 months. Serving as the principle of management behind the algorithm modifications, the reduction of both patient visit and IVI therapy counts should be reckoned together with the risk of permanent visual loss and COVID infection.


Assuntos
COVID-19/epidemiologia , Injeções Intravítreas/métodos , SARS-CoV-2 , Algoritmos , Humanos , Higiene , Segurança do Paciente
5.
Medicine (Baltimore) ; 100(22): e26227, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087903

RESUMO

RATIONALE: Retinopathy of prematurity (ROP) is one of the major leading causes of childhood visual morbidity worldwide. Retinal break and traction develop in regressed ROP can further result in rhegmatogenous or tractional retinal detachment years or even decades later. PATIENT CONCERNS: Here, we reported a case of bilateral ROP related late complication in a 36-year-old male with a chief complaint of increased floaters in his left eye. DIAGNOSES: The fundus examination showed demarcation lines over temporal side in both eyes with tractional retinal detachment and retinal breaks anterior to the lines. A diagnosis of ROP-related late complication of combined tractional and rhegmatogenous retinal detachment was made. INTERVENTIONS: Peripheral laser photocoagulation along the demarcation lines for confining the detachment area in both eyes was performed with a stable condition during follow up. OUTCOMES: After laser retinopexy, the patient was followed up at one week and four months later with stable laser scars and without progression of the retinal detachments. CONCLUSION: Regressed ROP-associated retinal detachment can occur at any time during life. Special care and follow-up may be necessary for these patients.


Assuntos
Fotocoagulação a Laser/métodos , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/terapia , Adulto , Assistência ao Convalescente , Fundo de Olho , Humanos , Fotocoagulação a Laser/efeitos adversos , Masculino , Descolamento Retiniano/etiologia , Perfurações Retinianas/complicações , Retinopatia da Prematuridade/complicações , Retinopatia da Prematuridade/epidemiologia , Resultado do Tratamento , Acuidade Visual/fisiologia
6.
Small ; 17(28): e2100546, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34105245

RESUMO

The clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) is an efficient and precise gene-editing technology that offers a versatile solution for establishing treatments directed at genetic diseases. Currently, CRISPR/Cas9 delivery into cells relies primarily on viral vectors, which suffer from limitations in packaging capacity and safety concerns. These issues with a nonviral delivery strategy are addressed, where Cas9•sgRNA ribonucleoprotein (RNP) complexes can be encapsulated into supramolecular nanoparticles (SMNP) to form RNP⊂SMNPs, which can then be delivered into targeted cells via supramolecular nanosubstrate-mediated delivery. Utilizing the U87 glioblastoma cell line as a model system, a variety of parameters for cellular-uptake of the RNP-laden nanoparticles are examined. Dose- and time-dependent CRISPR/Cas9-mediated gene disruption is further examined in a green fluorescent protein (GFP)-expressing U87 cell line (GFP-U87). The utility of an optimized SMNP formulation in co-delivering Cas9 protein and two sgRNAs that target deletion of exons 45-55 (708 kb) of the dystrophin gene is demonstrated. Mutations in this region lead to Duchenne muscular dystrophy, a severe genetic muscle wasting disease. Efficient delivery of these gene deletion cargoes is observed in a human cardiomyocyte cell line (AC16), induced pluripotent stem cells, and mesenchymal stem cells.


Assuntos
Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Proteína 9 Associada à CRISPR , Edição de Genes , Vetores Genéticos , Humanos
7.
World J Gastroenterol ; 27(22): 2979-2993, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34168402

RESUMO

The landscape of gastrointestinal endoscopy continues to evolve as new technologies and techniques become available. The advent of image-enhanced and magnifying endoscopies has highlighted the step toward perfecting endoscopic screening and diagnosis of gastric lesions. Simultaneously, with the development of convolutional neural network, artificial intelligence (AI) has made unprecedented breakthroughs in medical imaging, including the ongoing trials of computer-aided detection of colorectal polyps and gastrointestinal bleeding. In the past demi-decade, applications of AI systems in gastric cancer have also emerged. With AI's efficient computational power and learning capacities, endoscopists can improve their diagnostic accuracies and avoid the missing or mischaracterization of gastric neoplastic changes. So far, several AI systems that incorporated both traditional and novel endoscopy technologies have been developed for various purposes, with most systems achieving an accuracy of more than 80%. However, their feasibility, effectiveness, and safety in clinical practice remain to be seen as there have been no clinical trials yet. Nonetheless, AI-assisted endoscopies shed light on more accurate and sensitive ways for early detection, treatment guidance and prognosis prediction of gastric lesions. This review summarizes the current status of various AI applications in gastric cancer and pinpoints directions for future research and clinical practice implementation from a clinical perspective.


Assuntos
Inteligência Artificial , Neoplasias Gástricas , Detecção Precoce de Câncer , Endoscopia Gastrointestinal , Humanos , Redes Neurais de Computação , Neoplasias Gástricas/diagnóstico por imagem
8.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070492

RESUMO

Inherited retinal dystrophies (IRDs) are rare but highly heterogeneous genetic disorders that affect individuals and families worldwide. However, given its wide variability, its analysis of the driver genes for over 50% of the cases remains unexplored. The present study aims to identify novel driver genes, disease-causing variants, and retinitis pigmentosa (RP)-associated pathways. Using family-based whole-exome sequencing (WES) to identify putative RP-causing rare variants, we identified a total of five potentially pathogenic variants located in genes OR56A5, OR52L1, CTSD, PRF1, KBTBD13, and ATP2B4. Of the variants present in all affected individuals, genes OR56A5, OR52L1, CTSD, KBTBD13, and ATP2B4 present as missense mutations, while PRF1 and CTSD present as frameshift variants. Sanger sequencing confirmed the presence of the novel pathogenic variant PRF1 (c.124_128del) that has not been reported previously. More causal-effect or evidence-based studies will be required to elucidate the precise roles of these SNPs in the RP pathogenesis. Taken together, our findings may allow us to explore the risk variants based on the sequencing data and upgrade the existing variant annotation database in Taiwan. It may help detect specific eye diseases such as retinitis pigmentosa in East Asia.


Assuntos
Catepsina D/genética , Predisposição Genética para Doença , Distrofias Retinianas/genética , Adulto , Idoso , Catepsina D/sangue , Feminino , Mutação da Fase de Leitura , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Linhagem , Perforina/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas , Distrofias Retinianas/congênito , Distrofias Retinianas/patologia , Retinite Pigmentosa/congênito , Retinite Pigmentosa/diagnóstico por imagem , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Fatores de Risco , Tomografia de Coerência Óptica , Sequenciamento Completo do Exoma
9.
Medicine (Baltimore) ; 100(20): e25898, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011056

RESUMO

BACKGROUND: Although tranexamic acid (TXA), a readily accessible antifibrinolytic agent, is widely adopted in hemorrhage scenarios, its role on mortality in patients with hemoptysis remains uncertain. New evidence is yet to be generated to evaluate the risk of mortality after using TXA in patients with hemoptysis. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases were searched from inception to May 2020. Randomized controlled trials and observational studies that evaluated the effect of TXA on patients with hemoptysis were included. Data were independently extracted by 2 reviewers and synthesized using a random-effects model. MAIN RESULTS: Five studies with a total of 20,047 patients were analyzed. When compared with the control, administration of TXA was associated with a reduction in short-term mortality (risk ratio = 0.78, 95% confidence interval [CI] 0.72-0.85; I2 = 0), shorter bleeding time (mean difference = - 24.61 hours, 95% CI - 35.96 to -13.26, I2 = 0), shorter length of hospital stay (mean difference = -1.94 days, 95% CI -2.48 to -1.40, I2 = 0), and lower need for intervention (risk ratio = 0.38, 95% CI 0.16-0.87, I2 = 0) in patients with hemoptysis. Compared with control, administration of TXA did not cause increased major or minor adverse effects. CONCLUSIONS: TXA provided benefits in terms of a lower short-term mortality rate, less bleeding time, shorter length of hospital stays, and less need for intervention in patients with hemoptysis. Use of TXA was not associated with increased adverse effects.


Assuntos
Antifibrinolíticos/administração & dosagem , Hemoptise/tratamento farmacológico , Mortalidade Hospitalar , Ácido Tranexâmico/administração & dosagem , Antifibrinolíticos/efeitos adversos , Tempo de Sangramento , Hemoptise/mortalidade , Humanos , Tempo de Internação/estatística & dados numéricos , Metanálise como Assunto , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto , Ácido Tranexâmico/efeitos adversos , Resultado do Tratamento
10.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926102

RESUMO

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye's accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.


Assuntos
Amaurose Congênita de Leber/genética , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , Dependovirus/genética , Proteínas do Olho/genética , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos , Humanos , Amaurose Congênita de Leber/terapia , Mutação , RNA , Retina/efeitos dos fármacos , Retina/metabolismo , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/metabolismo
11.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33810164

RESUMO

The ductus arteriosus (DA) is a physiologic vessel crucial for fetal circulation. As a major regulating factor, the prostaglandin pathway has long been the target for DA patency maintenance or closure. However, the adverse effect of prostaglandins and their inhibitors has been a major unsolved clinical problem. Furthermore, a significant portion of patients with patent DA fail to respond to cyclooxygenase inhibitors that target the prostaglandin pathway. These unresponsive medical patients ultimately require surgical intervention and highlight the importance of exploring pathways independent from this well-recognized prostaglandin pathway. The clinical limitations of prostaglandin-targeting therapeutics prompted us to investigate molecules beyond the prostaglandin pathway. Thus, this article introduces molecules independent from the prostaglandin pathway based on their correlating mechanisms contributing to vascular remodeling. These molecules may serve as potential targets for future DA patency clinical management.


Assuntos
Canal Arterial/metabolismo , Canal Arterial/patologia , Remodelação Vascular , Animais , Biomarcadores , Movimento Celular , Proliferação de Células , Canal Arterial/embriologia , Permeabilidade do Canal Arterial/etiologia , Permeabilidade do Canal Arterial/metabolismo , Matriz Extracelular , Humanos , Miócitos de Músculo Liso/metabolismo , Prostaglandinas/metabolismo , Transdução de Sinais , Remodelação Vascular/genética
12.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339321

RESUMO

Neuromuscular diseases (NMDs) belong to a class of functional impairments that cause dysfunctions of the motor neuron-muscle functional axis components. Inherited monogenic neuromuscular disorders encompass both muscular dystrophies and motor neuron diseases. Understanding of their causative genetic defects and pathological genetic mechanisms has led to the unprecedented clinical translation of genetic therapies. Challenged by a broad range of gene defect types, researchers have developed different approaches to tackle mutations by hijacking the cellular gene expression machinery to minimize the mutational damage and produce the functional target proteins. Such manipulations may be directed to any point of the gene expression axis, such as classical gene augmentation, modulating premature termination codon ribosomal bypass, splicing modification of pre-mRNA, etc. With the soar of the CRISPR-based gene editing systems, researchers now gravitate toward genome surgery in tackling NMDs by directly correcting the mutational defects at the genome level and expanding the scope of targetable NMDs. In this article, we will review the current development of gene therapy and focus on NMDs that are available in published reports, including Duchenne Muscular Dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked myotubular myopathy (XLMTM), Spinal Muscular Atrophy (SMA), and Limb-girdle muscular dystrophy Type 2C (LGMD2C).


Assuntos
Edição de Genes/métodos , Terapia Genética/métodos , Doenças Neuromusculares/genética , Animais , Sistemas CRISPR-Cas , Ensaios Clínicos como Assunto , Humanos , Doenças Neuromusculares/terapia
13.
Medicine (Baltimore) ; 99(46): e23279, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181719

RESUMO

BACKGROUND: Magnesium sulfate (MgSO4) is widely used in analgesia for different conditions. Recent randomized controlled trials (RCTs) have evaluated the effects of MgSO4 on renal colic; however, this new evidence has not been synthesized. Thus, we conducted a systematic review and meta-analysis to assess the efficacy and safety of MgSO4 in comparison with control for renal colic. METHODS: PubMed, EMBASE, and Scopus databases were searched from inception to February 2020. We included RCTs that evaluated MgSO4 vs control for patients with renal colic. Data were independently extracted by 2 reviewers and synthesized using a random-effects model. RESULTS: Four studies with a total of 373 patients were analyzed. Intravenous MgSO4 15 to 50 mg/kg did not significantly reduce renal colic pain severity at 15 minutes (mean difference [MD] = 0.35, 95% confidence interval [CI] -0.51 to 1.21; 2 RCTs), 30 minutes (MD = 0.19, 95% CI -0.74 to 1.13; 4 RCTs), and 60 minutes (MD = -0.28, 95% CI -0.72 to 0.16; 3 RCTs) in comparison with controls. In patients who failed to respond to initial analgesics, intravenous MgSO4 15 mg/kg or 2 ml of 50% solution provided similar pain relief to ketorolac or morphine at 30 minutes (P = .90) and 60 minutes (P = .57). No significant hemodynamic changes were observed with short-term use of MgSO4 in these studies. CONCLUSION: MgSO4 provides no superior therapeutic benefits in comparison with control treatments. MgSO4 may be used as a rescue medication in patients not responding to initial analgesics. The short-term use of MgSO4 did not affect hemodynamic values.


Assuntos
Sulfato de Magnésio/normas , Manejo da Dor/normas , Cólica Renal/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/normas , Analgésicos/uso terapêutico , Humanos , Sulfato de Magnésio/farmacologia , Sulfato de Magnésio/uso terapêutico , Manejo da Dor/métodos , Manejo da Dor/estatística & dados numéricos
14.
Int J Mol Sci ; 21(13)2020 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-32635482

RESUMO

The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during the fetal period that is essential for the normal development of the fetus. Complete closure usually occurs after birth but the vessel might remain open in certain infants, as patent ductus arteriosus (PDA), causing morbidity or mortality. The mechanism of DA closure is a complex process involving an orchestration of cell-matrix interaction between smooth muscle cells (SMC), endothelial cells, and extracellular matrix (ECM). ECM is defined as the noncellular component secreted by cells that consists of macromolecules such as elastin, collagens, proteoglycan, hyaluronan, and noncollagenous glycoproteins. In addition to its role as a physical scaffold, ECM mediates diverse signaling that is critical in development, maintenance, and repair in the cardiovascular system. In this review, we aim to outline the current understandings of ECM and its role in the pathophysiology of PDA, with emphasis on DA remodeling and highlight future outlooks. The molecular diversity and plasticity of ECM present a rich array of potential therapeutic targets for the management of PDA.


Assuntos
Permeabilidade do Canal Arterial/patologia , Matriz Extracelular/patologia , Remodelação Vascular/fisiologia , Animais , Células Endoteliais/patologia , Humanos , Miócitos de Músculo Liso/patologia
15.
Front Immunol ; 11: 610492, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33613533

RESUMO

In response to a variety of stresses, mammalian cells activate the inflammasome for targeted caspase-dependent pyroptosis. The research community has recently begun to deduce that the activation of inflammasome is instigated by several known oncogenic stresses and metabolic perturbations; nevertheless, the role of inflammasomes in the context of cancer biology is less understood. In manipulating the expression of inflammasome, researchers have found that NLRP3 serves as a deterministic player in conducting tumor fate decisions. Understanding the mechanistic underpinning of pro-tumorigenic and anti-tumorigenic pathways might elucidate novel therapeutic onco-targets, thereby providing new opportunities to manipulate inflammasome in augmenting the anti-tumorigenic activity to prevent tumor expansion and achieve metastatic control. Accordingly, this review aims to decode the complexity of NLRP3, whereby summarizing and clustering findings into cancer hallmarks and tissue contexts may expedite consensus and underscore the potential of the inflammasome in drug translation.


Assuntos
Biomarcadores Tumorais/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Morte Celular , Proliferação de Células , Metabolismo Energético , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Transdução de Sinais , Evasão Tumoral , Microambiente Tumoral
16.
ACS Appl Mater Interfaces ; 11(43): 40909-40915, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31573187

RESUMO

Electron beam (e-beam) has been developed for nanomaterial observation and moreover to induce structural evolutions in atomic scale. In this work, we demonstrate the deoxidation of cuprous oxide (Cu2O) and the formation of an atomically flat surface on a Cu nanowire by e-beam irradiation. To develop e-beam irradiation applications, the relation between e-beam radiation and the atomic surface is significant. Through the density functional theory simulation of atomic sputtering, an obvious disparity in the sputtering threshold has been found under different structural conditions, which leads to different structural evolutions. Both surface deoxidation and atomic surface flattening reactions have been identified as self-limiting and irreversible processes via in situ transmission electron microscope observation. Under e-beam irradiation, the dynamic mechanism of atomic surface flattening is driven by the convergence of total surface energy and confirmed by climbing-image nudged elastic band (ci-NEB) calculations. With precise control, e-beam irradiation reveals enormous potentials in atomic surface engineering.

17.
Int J Mol Sci ; 20(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934882

RESUMO

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.


Assuntos
Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Células Th1/imunologia , Células Th17/imunologia , Animais , Quimiotaxia/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Imunização , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/farmacologia , Subpopulações de Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos
18.
Cell Physiol Biochem ; 52(3): 408-420, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845380

RESUMO

BACKGROUND/AIMS: The adipocyte-secreting adipokine, resistin, may play a critical role in the modulation of inflammatory diseases. Migration and infiltration of mononuclear cells into inflammatory sites are critical events during the development of osteoarthritis (OA). Monocyte chemoattractant protein-1 (MCP-1), also known as chemokine ligand 2 (CCL2), plays a critical role in the regulation of monocyte migration and infiltration. In this study, we show how resistin promotes MCP-1 expression in OA synovial fibroblasts and monocyte migration. METHODS: We used qPCR to detect MCP-1 and miRNA expression. THP-1 migration was investigated by Transwell assay. The Western blotting was used to examine the resistinmediated signaling pathways. RESULTS: Resistin activated the phosphatidylinositol-3-kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) signaling pathways, while PI3K, Akt and mTOR inhibitors or small interfering RNAs diminished resistin-induced MCP-1 expression and monocyte migration. We also demonstrate that resistin stimulates MCP-1mediated monocyte migration by suppressing microRNA (miR)-33a and miR-33b via the PI3K, Akt and mTOR signaling pathways. CONCLUSION: These results provide new insights into the mechanisms of resistin action that may have therapeutic implications for patients with OA.


Assuntos
Quimiocina CCL2/metabolismo , Expressão Gênica/efeitos dos fármacos , Resistina/farmacologia , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/química , Quimiocina CCL2/genética , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Resistina/genética , Resistina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/citologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-30691187

RESUMO

Research has shown that long-term exposure to lead harms the hematological system. The homeostatic iron regulator HFE (hemochromatosis) mutation, which has been shown to affect iron absorption and iron overload, is hypothesized to be related to lead intoxication in vulnerable individuals. The aim of our study was to investigate whether the HFE genotype modifies the blood lead levels that affect the distributions of serum iron and other red blood cell indices. Overall, 121 lead workers and 117 unexposed age-matched subjects were recruited for the study. The collected data included the blood lead levels, complete blood count, serum iron, total iron binding capacity, transferrin, and ferritin, which were measured during regular physical examinations. All subjects filled out questionnaires that included demographic information, medical history, and alcohol and tobacco consumption. HFE genotyping for C282Y and H63D was determined using polymerase chain reaction and restriction fragment length polymorphism (PCR/RFLP). The mean blood lead level in lead workers was 19.75 µg/dL and was 2.86 µg/dL in unexposed subjects. Of 238 subjects, 221 (92.9%) subjects were wild-type (CCHH) for HFE C282Y and H63D, and 17 (7.1%) subjects were heterozygous for a H63D mutation (CCHD). Multiple linear regression analysis showed that blood lead was significantly negatively associated with hemoglobin (Hb), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular volume (MCV), whereas the HFE variant was associated negatively with MCV and positively with ferritin. An interactive influence on MCV was identified between blood lead and HFE variants. Our research found a significant modifying effect of the HFE variant, which possibly affected MCV. The HFE H63D heterozygous (CCHD) variant seemed to provide a protective factor against lead toxicity. Future studies should focus on competing binding proteins between iron and lead influenced by gene variation.


Assuntos
Proteína da Hemocromatose/genética , Ferro/sangue , Chumbo/sangue , Adulto , Índices de Eritrócitos , Eritrócitos/metabolismo , Feminino , Ferritinas/sangue , Genótipo , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Reação em Cadeia da Polimerase , Transferrina/metabolismo
20.
Chem Commun (Camb) ; 54(71): 9941-9944, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30116815

RESUMO

We utilized in situ transmission electron microscopy to observe phase transformation in CVD-grown MoS2. Significantly, the reaction was performed under electron irradiation through appropriate control of the electron dose and exposure time. Moreover, we proposed a new route between the 2H and 1T phases that involved the higher energy states TS1/TS2.

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