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1.
Genes (Basel) ; 12(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356070

RESUMO

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin-angiotensin-aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Asma/diagnóstico , Teste para COVID-19 , COVID-19/enzimologia , Hipertensão Pulmonar/diagnóstico , Pulmão/enzimologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Asma/enzimologia , Asma/genética , COVID-19/genética , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Inflamação/diagnóstico , Inflamação/enzimologia , Inflamação/genética , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/genética , Sistema Renina-Angiotensina
2.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299198

RESUMO

An inflammasome is an intracellular protein complex that is activated in response to a pathogenic infection and cellular damage. It triggers inflammatory responses by promoting inflammatory cell death (called pyroptosis) and the secretion of pro-inflammatory cytokines, interleukin (IL)-1ß and IL-18. Many types of inflammasomes have been identified and demonstrated to play a central role in inducing inflammatory responses, leading to the onset and progression of numerous inflammatory diseases. Methylation is a biological process by which methyl groups are transferred from methyl donors to proteins, nucleic acids, and other cellular molecules. Methylation plays critical roles in various biological functions by modulating gene expression, protein activity, protein localization, and molecular stability, and aberrant regulation of methylation causes deleterious outcomes in various human diseases. Methylation is a key determinant of inflammatory responses and diseases. This review highlights the current understanding of the functional relationship between inflammasome regulation and methylation of cellular molecules in inflammatory responses and diseases.


Assuntos
Metilação de DNA , Inflamassomos/metabolismo , Inflamação/metabolismo , Metiltransferases/metabolismo , Animais , Humanos , Inflamação/enzimologia , Inflamação/genética , Inflamação/patologia , Piroptose
3.
Invest Ophthalmol Vis Sci ; 62(7): 25, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34160563

RESUMO

Purpose: The ocular surface is considered an important route for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. The expression level of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is vital for viral infection. However, the regulation of ACE2 expression on the ocular surface is still unknown. We aimed to determine the change in ACE2 expression in inflamed corneal epithelium and explore potential drugs to reduce the expression of ACE2 on the ocular surface. Methods: The expression of the SARS-CoV-2 receptors ACE2 and TMPRSS2 in human corneal epithelial cells (HCECs) was examined by qPCR and Western blotting. The altered expression of ACE2 in inflammatory corneal epithelium was evaluated in TNFα- and IL-1ß-stimulated HCECs and inflamed mouse corneal epithelium, and the effect of resveratrol on ACE2 expression in HCECs was detected by immunofluorescence and Western blot analysis. Results: ACE2 and TMPRSS2 are expressed on the human corneal epithelial cells. ACE2 expression is upregulated in HCECs by stimulation with TNFα and IL-1ß and inflamed mouse corneas, including dry eye and alkali-burned corneas. In addition, resveratrol attenuates the increased expression of ACE2 induced by TNFα in HCECs. Conclusions: This study demonstrates that ACE2 is highly expressed in HCECs and can be upregulated by stimulation with inflammatory cytokines and inflamed mouse corneal epithelium. Resveratrol may be able to reduce the increased expression of ACE2 on the inflammatory ocular surface. Our work suggests that patients with an inflammatory ocular surface may display higher ACE2 expression, which increases the risk of SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Inibidores Enzimáticos/farmacologia , Epitélio Corneano/enzimologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Ceratite/enzimologia , Resveratrol/farmacologia , SARS-CoV-2/fisiologia , Adulto , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Western Blotting , Células Cultivadas , Epitélio Corneano/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Interleucina-1beta/farmacologia , Ceratite/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima
4.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073678

RESUMO

The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases.


Assuntos
Heme Oxigenase-1/metabolismo , Heme/metabolismo , Inflamação/metabolismo , Pneumonia/metabolismo , Animais , Humanos , Inflamação/enzimologia , Inflamação/etiologia , Pneumonia/enzimologia , Pneumonia/etiologia , Sepse/etiologia , Sepse/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo
5.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067027

RESUMO

Diabetes mellitus is a metabolic disease that causes a hyperglycemic status which leads, over time, to serious damage to the heart, blood vessels, eyes, kidneys and nerves. The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes. As the aging population is exposed to polypharmacy along with inflammatory comorbidities, consideration of phenoconversion related to drug metabolizing enzymes is of importance when applying pharmacogenomic results and establishing personalized and more precise drug regimens.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Inflamação/enzimologia , Inflamação/patologia , Animais , Doença Crônica , Humanos , Insulina/metabolismo , Modelos Biológicos
6.
Expert Opin Ther Pat ; 31(9): 809-836, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33896339

RESUMO

Introduction: Glutaminyl cyclase (QC) enzymes catalyze the post-translational processing of several substrates with N-terminal glutamine or glutamate to form pyroglutamate (pE) residue. In addition to physiological functions, emerging evidence demonstrates that human QCs play a part in pathological processes in diverse diseases such as Alzheimer's disease (AD), inflammatory and cancer diseases.Areas covered: In recent years, efforts to effectively develop QC small-molecule inhibitors have been made and different chemical classes have been disclosed. This review summarizes the patents/applications regarding QC inhibitors released from 2004 (first patent) to now. The patents are mostly described in terms of chemical structures, biochemical/pharmacological activities, and potential clinical applications.Expert opinion: For more than 15 years of research, the knowledge on the QC activity domain has considerably increased and therapeutic potential of QC inhibitors has been explored. An important number of studies and patents have been published to expand the use of QC inhibitors. QC enzymes are pharmacologically interesting targets to be used as an AD-modifying therapy, or for other QC-associated disorder. Distinct classes of chemical scaffolds and potential clinical uses have been claimed by various organizations. For the coming years, there is much to experience in the QC field.


Assuntos
Doença de Alzheimer , Aminoaciltransferases/antagonistas & inibidores , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Aminoaciltransferases/metabolismo , Animais , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Patentes como Assunto
7.
J Immunol ; 206(9): 1983-1990, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33879578

RESUMO

Nucleoside triphosphate diphosphohydrolases (NTPDases) are a family of enzymes that hydrolyze nucleotides such as ATP, UTP, ADP, and UDP to monophosphates derivates such as AMP and UMP. The NTPDase family consists of eight enzymes, of which NTPDases 1, 2, 3, and 8 are expressed on cell membranes thereby hydrolyzing extracellular nucleotides. Cell membrane NTPDases are expressed in all tissues, in which they regulate essential physiological tissue functions such as development, blood flow, hormone secretion, and neurotransmitter release. They do so by modulating nucleotide-mediated purinergic signaling through P2 purinergic receptors. NTPDases 1, 2, 3, and 8 also play a key role during infection, inflammation, injury, and cancer. Under these conditions, NTPDases can contribute and control the pathophysiology of infectious, inflammatory diseases and cancer. In this review, we discuss the role of NTPDases, focusing on the less understood NTPDases 2-8, in regulating inflammation and immunity during infectious, inflammatory diseases, and cancer.


Assuntos
Adenosina Trifosfatases/genética , Regulação Enzimológica da Expressão Gênica , Imunidade/genética , Inflamação/genética , Família Multigênica , Neoplasias/genética , Adenosina Trifosfatases/metabolismo , Animais , Humanos , Inflamação/enzimologia , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias/enzimologia , Nucleotídeos/metabolismo
9.
Cell ; 184(10): 2618-2632.e17, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33836156

RESUMO

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.


Assuntos
COVID-19/tratamento farmacológico , DNA Topoisomerases Tipo I/metabolismo , SARS-CoV-2/metabolismo , Inibidores da Topoisomerase I/farmacologia , Topotecan/farmacologia , Animais , COVID-19/enzimologia , COVID-19/patologia , Chlorocebus aethiops , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/patologia , Inflamação/virologia , Mesocricetus , Camundongos , Camundongos Transgênicos , Células THP-1 , Células Vero
10.
Biomolecules ; 11(3)2021 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800947

RESUMO

Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.


Assuntos
COVID-19/metabolismo , Pulmão/fisiopatologia , Metaloproteinases da Matriz/metabolismo , Proteínas Quinases/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , COVID-19/enzimologia , COVID-19/fisiopatologia , COVID-19/virologia , Comorbidade , Citocinas/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/metabolismo , Inflamação/patologia , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/virologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Síndrome do Desconforto Respiratório/enzimologia , Síndrome do Desconforto Respiratório/fisiopatologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
11.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802197

RESUMO

Dysregulation of the proteolytic balance is often associated with diseases. Serine proteases and matrix metalloproteases are involved in a multitude of biological processes and notably in the inflammatory response. Within the framework of digestive inflammation, several studies have stressed the role of serine proteases and matrix metalloproteases (MMPs) as key actors in its pathogenesis and pointed to the unbalance between these proteases and their respective inhibitors. Substantial efforts have been made in developing new inhibitors, some of which have reached clinical trial phases, notwithstanding that unwanted side effects remain a major issue. However, studies on the proteolytic imbalance and inhibitors conception are directed toward host serine/MMPs proteases revealing a hitherto overlooked factor, the potential contribution of their bacterial counterpart. In this review, we highlight the role of proteolytic imbalance in human digestive inflammation focusing on serine proteases and MMPs and their respective inhibitors considering both host and bacterial origin.


Assuntos
Doenças Inflamatórias Intestinais/enzimologia , Metaloproteinases da Matriz/metabolismo , Proteólise , Serina Proteases/metabolismo , Animais , Humanos , Inflamação/enzimologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia
12.
Toxicol Appl Pharmacol ; 418: 115494, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722668

RESUMO

Tumor progression locus 2 (Tpl2, gene name MAP3K8), a mitogen-activated protein kinase, is widely expressed in immune and non-immune cells to integrate tumor necrosis factor (TNF), toll-like receptors (TLRs), and interleukin-1 (IL1) receptor signaling to regulate inflammatory response. Given its central role in inflammatory response, Tpl2 is an attractive small molecule drug target. However, the role of Tpl2 as an oncogene or tumor suppressor gene remains controversial, and its function outside immune cells is not understood. We therefore utilized a Tpl2 kinase dead (Tpl2-KD) mouse model in an 18-month aging study to further elucidate Tpl2 effects on lifespan and chronic disease. Histopathological studies revealed the incidence and severity of spontaneous tumors and non-neoplastic lesions were comparable between wild type and Tpl2-KD mice. The only finding was that male Tpl2-KD mice had higher bodyweight and an increased incidence of liver steatosis, suggesting a sex-specific role for Tpl2 in hepatic lipid metabolism. In conclusion, loss of Tpl2 kinase activity did not lead to increased tumorigenesis over aging in mice but affected likely alterations in lipid metabolism in male animals.


Assuntos
Fígado Gorduroso/enzimologia , Inflamação/enzimologia , Fígado/enzimologia , MAP Quinase Quinase Quinases/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fatores Etários , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Genótipo , Inflamação/genética , Metabolismo dos Lipídeos , Fígado/patologia , MAP Quinase Quinase Quinases/deficiência , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/genética , Neoplasias/patologia , Fenótipo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Fatores Sexuais
13.
Am J Respir Cell Mol Biol ; 64(6): 709-721, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33662229

RESUMO

Obesity is a risk factor for the development of asthma and represents a difficult-to-treat disease phenotype. Aerobic glycolysis is emerging as a key feature of asthma, and changes in glucose metabolism are linked to leukocyte activation and adaptation to oxidative stress. Dysregulation of PKM2 (pyruvate kinase M2), the enzyme that catalyzes the last step of glycolysis, contributes to house dust mite (HDM)-induced airway inflammation and remodeling in lean mice. It remains unclear whether glycolytic reprogramming and dysregulation of PKM2 also contribute to obese asthma. The goal of the present study was to elucidate the functional role of PKM2 in a murine model of obese allergic asthma. We evaluated the small molecule activator of PKM2, TEPP46, and assessed the role of PKM2 using conditional ablation of the Pkm2 allele from airway epithelial cells. In obese C57BL/6NJ mice, parameters indicative of glycolytic reprogramming remained unchanged in the absence of stimulation with HDM. Obese mice that were subjected to HDM showed evidence of glycolytic reprogramming, and treatment with TEPP46 diminished airway inflammation, whereas parameters of airway remodeling were unaffected. Epithelial ablation of Pkm2 decreased central airway resistance in both lean and obese allergic mice in addition to decreasing inflammatory cytokines in the lung tissue. Lastly, we highlight a novel role for PKM2 in the regulation of glutathione-dependent protein oxidation in the lung tissue of obese allergic mice via a putative IFN-γ-glutaredoxin1 pathway. Overall, targeting metabolism and protein oxidation may be a novel treatment strategy for obese allergic asthma.


Assuntos
Asma/enzimologia , Asma/patologia , Hipersensibilidade/enzimologia , Hipersensibilidade/patologia , Inflamação/enzimologia , Inflamação/patologia , Piruvato Quinase/metabolismo , Animais , Asma/complicações , Asma/parasitologia , Hiper-Reatividade Brônquica/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glutationa/metabolismo , Glicólise , Homeostase/efeitos dos fármacos , Hipersensibilidade/complicações , Hipersensibilidade/parasitologia , Mediadores da Inflamação/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Biológicos , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Pyroglyphidae , Pirróis/administração & dosagem , Pirróis/farmacologia
14.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672962

RESUMO

Sepsis results in lethal organ malfunction due to dysregulated host response to infection, which is a condition with increasing prevalence worldwide. Transglutaminase 2 (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. TG2 plays important roles in diverse cellular processes, including extracellular matrix stabilization, cytoskeletal function, cell motility, adhesion, signal transduction, apoptosis, and cell survival. We have shown that the co-culture of Candida albicans and hepatocytes activates and induces the translocation of TG2 into the nucleus. In addition, the expression and activation of TG2 in liver macrophages was dramatically induced in the lipopolysaccharide-injected and cecal ligation puncture-operated mouse models of sepsis. Based on these findings and recently published research, we have reviewed the current understanding of the relationship between TG2 and sepsis. Following the genetic and pharmacological inhibition of TG2, we also assessed the evidence regarding the use of TG2 as a potential marker and therapeutic target in inflammation and sepsis.


Assuntos
Biomarcadores/metabolismo , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/metabolismo , Inflamação/enzimologia , Sepse/enzimologia , Transglutaminases/metabolismo , Animais , Apoptose , Sobrevivência Celular , Proteínas de Ligação ao GTP/genética , Humanos , Inflamação/diagnóstico , Inflamação/terapia , Camundongos , Sepse/diagnóstico , Sepse/terapia , Transglutaminases/genética
15.
Obes Rev ; 22(5): e13225, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33660398

RESUMO

Angiotensin-converting enzyme 2 (ACE2) has been an increasingly prevalent target for investigation since its discovery 20 years ago. The finding that it serves a counterregulatory function within the traditional renin-angiotensin system, implicating it in cardiometabolic health, has increased its clinical relevance. Focus on ACE2's role in cardiometabolic health has largely centered on its apparent functions in the context of obesity. Interest in ACE2 has become even greater with the discovery that it serves as the cell receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), opening up numerous mechanisms for deleterious effects of infection. The proliferation of ACE2 within the literature coupled with its dual role in SARS-CoV-2 infection and obesity necessitates review of the current understanding of ACE2's physiological, pathophysiological, and potential therapeutic functions. This review highlights the roles of ACE2 in cardiac dysfunction and obesity, with focus on epicardial adipose tissue, to reconcile the data in the context of SARS-CoV-2 infection.


Assuntos
Tecido Adiposo/enzimologia , Enzima de Conversão de Angiotensina 2/fisiologia , COVID-19/enzimologia , Obesidade/enzimologia , Pericárdio/enzimologia , SARS-CoV-2 , COVID-19/epidemiologia , Doenças Cardiovasculares/enzimologia , Comorbidade , Humanos , Inflamação/enzimologia , Inflamação/virologia , Obesidade/epidemiologia , Proteínas Recombinantes , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2/metabolismo
16.
Mol Cell Endocrinol ; 529: 111260, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33781838

RESUMO

Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system (RAS), has been identified as the receptor for the SARS-CoV-2. Several RAS components including ACE2 and its substrate Ang II are present in both eye and skin, two stratified squamous epithelial tissues that isolate organisms from external environment. Our recent findings in cornea and others in both skin and eye suggest contribution of this system, and specifically of ACE2 in variety of physiological and pathological responses of these organ systems. This review will focus on the role RAS system plays in both skin and cornea, and will specifically discuss our recent findings on ACE2 in corneal epithelial inflammation, as well as potential implications of ACE2 in patients with COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Epitélio Corneano/enzimologia , Receptores de Coronavírus/metabolismo , Pele/enzimologia , Autofagia , COVID-19/enzimologia , COVID-19/virologia , Humanos , Inflamação/enzimologia , Sistema Renina-Angiotensina/fisiologia , Cicatrização
17.
Oxid Med Cell Longev ; 2021: 6612796, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628365

RESUMO

Aromatase is a key enzyme in the transformation of androgen into estrogen. Its high expression will destroy the hormonal balance in the male body, and the excessive transformation of androgen into estrogen in the body will further damage the spermatogenic function of the testis, affect the normal development of the sperm, and cause spermatogenic disturbance. Adipose tissue has a high expression of aromatase and shows high enzymatic activity and ability to convert estrogen. Adipose tissue is the most estrogen-producing nongonadal tissue in the body because of its large size, accounting for about 20% of the body mass in healthy adults. PPARγ is recognized as the key adipose differentiation in the transcriptional regulation of the transcription factor. In the process of adipocyte differentiation, PPARγ regulate the expression of aromatase. The increase of aromatase is associated with the inflammatory response in adipose tissue caused by obesity. After obesity, the increase of proinflammatory factors in adipocytes will lead to enhanced transcription of the CYP19 gene encoding aromatase in adipocytes, which in turn will lead to increased expression of aromatase in adipocytes. This article reviews the regulation of male sterility from the angle of the "obesity-inflammation-aromatase" axis.


Assuntos
Aromatase/metabolismo , Pesquisa Biomédica , Infertilidade Masculina/enzimologia , Infertilidade Masculina/patologia , Inflamação/complicações , Inflamação/enzimologia , Obesidade/complicações , Obesidade/enzimologia , Animais , Humanos , Inflamação/patologia , Masculino , Modelos Biológicos , Obesidade/patologia
18.
Eur J Pharmacol ; 897: 173945, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33596416

RESUMO

The objective of study was to investigate the inhibitory effect of sinomenine on neuropathic pain on dorsal root ganglia (DRG). The DRG cell line and spinal nerve ligation (SNL) model were used in this study. The effect of sinomenine on the cell viability was examined by MTT assay. The expression of p38 MAPK, NF-κB, c-fos, SP and TNF-α was detected by using immunofluorescence and immunohistochemistry assay. We also assessed the level of p-CaMKII, COX-2, p-CREB, IL-17A, TLR4 and IL-1ß via western blotting and RT-qPCR. Compared to the controls, sinomenine showed a protective effect on TNF-α-induced apoptosis on DRG cells in a dose-dependent manner, with an increase of cell viability and a decrease of reactive oxygen species level as well as LDH release. Parallelly, sinomenine treatment significantly reduced the expression of various factors related to stress and inflammation, including p38 MAPK, NF-κB, c-fos, p-CAMKII, COX-2, p-CREB, TLR4 and IL-17A in DRG cells in vitro. Furthermore, we found that administration of sinomenine significantly reduced mechanical withdrawal threshold and thermal withdrawal latency and inhibited the inflammation and activation of p38 signaling in SNL rats. It is noting that combined therapy of sinomenine and pulsed radiofrequency exhibited higher efficacy of dorsal root ganglia inflammation than single treatment as well as the combination of oxycodone and pulsed radiofrequency. Sinomenine inhibited the apoptosis of DRG cell by regulating p38 MAPK/CREB signalling pathway, which provides evidence to alleviate neuropathic pain in clinic.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Gânglios Espinais/efeitos dos fármacos , Inflamação/prevenção & controle , Morfinanos/farmacologia , Neuralgia/prevenção & controle , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Analgésicos Opioides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Terapia Combinada , Modelos Animais de Doenças , Gânglios Espinais/enzimologia , Gânglios Espinais/patologia , Gânglios Espinais/fisiopatologia , Inflamação/enzimologia , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Masculino , Neuralgia/enzimologia , Neuralgia/patologia , Neuralgia/fisiopatologia , Oxicodona/farmacologia , Limiar da Dor/efeitos dos fármacos , Tratamento por Radiofrequência Pulsada , Ratos Sprague-Dawley , Transdução de Sinais
19.
Toxicol Appl Pharmacol ; 415: 115449, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33577919

RESUMO

Cadmium (Cd) was a serious heavy metal pollutant. Cd exposure will cause damage to reproductive organs. It was largely unknown whether Cd exposure caused inflammation and apoptosis in epididymis. In this study, we established models of Cd exposure in swine, and the apoptotic level of epididymis was detected by in situ TUNEL fluorescence staining assay, the results showed that Cd exposure significantly increased TUNEL-apoptosis index. Furthermore, the results of qRT-PCR and Western blot showed that Cd activated the proto-oncogenic serine/threonine kinase-1 (RAF1)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signal pathway (RAF1/MEK/ERK) and led to the subsequent up-regulation of the nuclear factor-κB (NF-κB), tumor necrosis factor α (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), caused inflammation in epididymis. NF-κB inflammation pathway also mediated the tumor protein P53 (P53) and indirectly activated the Cytochrome c (Cytc), B-cell lymphoma-2 (Bcl-2), Bcl-2-Associated X protein (Bax), Caspase 3, Caspase 9. In summary, we believed that the RAF1/MEK/ERK pathway came into play in the apoptosis of epididymal tissues exposed to Cd by activating the NF-κB Inflammation pathway, followed by activation of the mitochondrial apoptotic pathway. This study provides more abundant data for exploring the reproductive toxicity of Cd.


Assuntos
Apoptose/efeitos dos fármacos , Cloreto de Cádmio/toxicidade , Epididimo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular , Inflamação/induzido quimicamente , Mitocôndrias/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Epididimo/enzimologia , Epididimo/patologia , Proteínas de Choque Térmico/metabolismo , Inflamação/enzimologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Transdução de Sinais , Sus scrofa
20.
Clin Sci (Lond) ; 135(1): 19-34, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33399849

RESUMO

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic ß-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild-type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1ß protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1ß secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, up-regulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D.


Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Adulto , Animais , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/enzimologia , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/enzimologia , Macrófagos Peritoneais/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Gravidez , Transdução de Sinais , Estreptozocina
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