RESUMO
Appearance of plaques on a bacterial lawn is a sign of successive rounds of bacteriophage infection. Yet, mechanisms evolved by bacteria to limit plaque spread have been hardly explored. Here, we investigated the dynamics of plaque development by lytic phages infecting the bacterium Bacillus subtilis. We report that plaque expansion is followed by a constriction phase owing to bacterial growth into the plaque zone. This phenomenon exposed an adaptive process, herein termed "phage tolerance response", elicited by non-infected bacteria upon sensing infection of their neighbors. The temporary phage tolerance is executed by the stress-response RNA polymerase sigma factor σX (SigX). Artificial expression of SigX prior to phage attack largely eliminates infection. SigX tolerance is primarily conferred by activation of the dlt operon, encoding enzymes that catalyze D-alanylation of cell wall teichoic acid polymers, the major attachment sites for phages infecting Gram-positive bacteria. D-alanylation impedes phage binding and hence infection, thus enabling the uninfected bacteria to form a protective shield opposing phage spread.
Assuntos
Bacillus subtilis/virologia , Bacteriófagos/patogenicidade , Interações Hospedeiro-Patógeno , Bacillus subtilis/metabolismo , Óperon , Fator sigma/metabolismoRESUMO
BACKGROUND: Macrophage-derived extracellular vesicle (macrophage-EV) is highly studied for its regulatory role in atherosclerosis (AS). Our current study tried to elucidate the possible role of macrophage-EV loaded with small interfering RNA against high-mobility group box 1 (siHMGB1) affecting atherosclerotic plaque formation. METHODS: In silico analysis was performed to find critical factors in mouse atherosclerotic plaque formation. EVs secreted by RAW 264.7 cells were collected by ultracentrifugation and characterized, followed by the preparation of macrophage-EV-loaded siHMGB1 (macrophage-EV/siHMGB1). ApoE-/- mice were used to construct an AS mouse model by a high-fat diet, followed by injection of macrophage-EV/siHMGB1 to assess the in vivo effect of macrophage-EV/siHMGB1 on AS mice. RAW264.7 cells were subjected to ox-LDL, LPS or macrophage-EV/siHMGB1 for analyzing the in vitro effect of macrophage-EV/siHMGB1 on macrophage pyrophosis and inflammation. RESULTS: In silico analysis found that HMGB1 was closely related to the development of AS. Macrophage-EV/siHMGB could inhibit the release of HMGB1 from macrophages to outside cells, and the reduced HMGB1 release could inhibit foam cell formation. Besides, macrophage-EV/siHMGB also inhibited the LPS-induced Caspase-11 activation, thus inhibiting macrophage pyroptosis and preventing atherosclerotic plaque formation. CONCLUSION: Our results proved that macrophage-EV/siHMGB could inhibit foam cell formation and suppress macrophage pyroptosis, finally preventing atherosclerotic plaque formation in AS mice.
Assuntos
Aterosclerose , Vesículas Extracelulares , Proteína HMGB1 , Placa Aterosclerótica , Animais , Camundongos , Apolipoproteínas E/genética , Aterosclerose/genética , Caspases , Regulação para Baixo , Proteína HMGB1/genética , Lipopolissacarídeos/farmacologia , Macrófagos , PiroptoseRESUMO
Atherosclerosis is characterized by the development of intimal plaque, thrombosis, and stenosis of the vessel lumen causing decreased blood flow and hypoxia precipitating angina. Chronic inflammation in the stable plaque renders it unstable and rupture of unstable plaques results in the formation of emboli leading to hypoxia/ischemia to the organs by occluding the terminal branches and precipitate myocardial infarction and stroke. Such delibitating events could be controlled by the strategies that prevent plaque development or plaque stabilization. Despite the use of statins to stabilize plaques, there is a need for novel targets due to continuously increasing cases of cardiovascular events. Sirtuins (SIRTs), a family of signaling proteins, are involved in sustaining genome integrity, DNA damage response and repair, modulating oxidative stress, aging, inflammation, and energy metabolism. SIRTs play a critical role in modulating inflammation and involves in the development and progression of atherosclerosis. The role of SIRTs in relation to atherosclerosis and plaque vulnerability is scarcely discussed in the literature. Since SIRTs regulate oxidative stress, inflammation, and aging, they may also regulate plaque progression and vulnerability as these molecular mechanisms underlie the pathogenesis of plaque development, progression, and vulnerability. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture, focusing on the highlights in genomics, molecular pathways, and cell types involved in the underlying pathophysiology.
Assuntos
Aterosclerose , Placa Aterosclerótica , Sirtuínas , Humanos , Aterosclerose/patologia , Placa Aterosclerótica/patologia , Inflamação , HipóxiaRESUMO
BACKGROUND: Herpes simplex virus type 1 (HSV-1) infection is a common viral disease that mainly causes oral lesions, but can also cause genital lesions in some instances. Current treatments with nucleoside analogs are limited by the emergence of drug resistance. Therefore, novel anti-HSV-1 drugs are urgently needed. METHODS: In this study, we screened a library of 2080 compounds for anti-HSV-1 activity using a plaque formation assay. We selected 11 potential inhibitors of HSV-1 and further evaluated their antiviral effects by plaque reduction assay and real-time polymerase chain reaction (qPCR). RESULTS: Five compounds, namely ginsenoside Rd, brassinolide, rosamultin, 3'-hydroxy puerarin, and clinafloxacin HCl, showed potent anti-HSV-1 activity and completely suppressed plaque formation at a concentration of 10 µM. Among them, clinafloxacin HCl, a fluoroquinolone antibiotic, exhibited a high selectivity index for HSV-1. CONCLUSIONS: Our findings suggest that these five compounds have potential antiviral properties against HSV-1 and may have different mechanisms of action. Further studies are warranted to elucidate the antiviral mechanisms of these compounds and to explore their therapeutic potential for HSV-1 infection.
Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Chlorocebus aethiops , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Herpesvirus Humano 2 , Herpes Simples/tratamento farmacológico , Ensaio de Placa Viral , Células VeroRESUMO
Amyloid-ß (Aß) is a peptide formed by 39-43 amino acids, heterogenous by the length of its C-terminus. Aß constitutes a subnanomolar monomeric component of human biological fluids; however, in sporadic variants of Alzheimer's disease (AD), it forms soluble neurotoxic oligomers and accumulates as insoluble extracellular polymeric aggregates (amyloid plaques) in the brain tissues. The plaque formation is controlled by zinc ions; therefore, abnormal interactions between the ions and Aß seem to take part in the triggering of sporadic AD. The amyloid plaques contain various Aß isoforms, among which the most common is Aß with an isoaspartate in position 7 (isoD7). The spontaneous conversion of D7 to isoD7 is associated with Aß aging. Aß molecules with isoD7 (isoD7-Aß) easily undergo zinc-dependent oligomerization, and upon administration to transgenic animals (mice, nematodes) used for AD modeling, act as zinc-dependent seeds of the pathological aggregation of Aß. The formation of zinc-bound homo- and hetero-oligomers with the participation of isoD7-Aß is based on the rigidly structured segment 11-EVHH-14, located in the Aß metal binding domain (Aß16). Some hereditary variants of AD are associated with familial mutations within the domain. Among these, the most susceptible to zinc-dependent oligomerization is Aß with Taiwan (D7H) mutation (D7H-Aß). In this study, the D7H-Aß metal binding domain (D7H-Aß16) has been used as a model to establish the molecular mechanism of zinc-induced D7H-Aß oligomerization through turbidimetry, dynamic light scattering, isothermal titration calorimetry, mass spectrometry, and computer modelling. Additionally, the modeling data showed that a molecule of D7H-Aß, as well as isoD7-Aß in combination with two Aß molecules, renders a stable zinc-induced heterotrimer. The trimers are held together by intermolecular interfaces via zinc ions, with the primary interfaces formed by 11-EVHH-14 sites of the interacting trimer subunits. In summary, the obtained results confirm the role of the 11-EVHH-14 region as a structure and function determinant for the zinc-dependent oligomerization of all known Aß species (including various chemically modified isoforms and AD-associated mutants) and point at this region as a potent target for drugs aimed to stop amyloid plaque formation in both sporadic and hereditary variants of AD.
Assuntos
Doença de Alzheimer , Humanos , Animais , Camundongos , Doença de Alzheimer/metabolismo , Zinco/metabolismo , Taiwan , Placa Amiloide , Peptídeos beta-Amiloides/metabolismo , Isoformas de Proteínas/genética , Mutação , ÍonsRESUMO
OBJECTIVE: Atherosclerosis (AS) is an inflammatory disease and the formation of atherosclerotic plaque plays a critical role in AS progression. We aimed to investigate the effect of long non-coding RNA (lncRNA) activated by DNA damage (NORAD)/microRNA-495-3p (miR-495-3p)/Krüppel-like factor 5 (KLF5) axis on atherosclerotic plaque formation. METHODS: The ApoE-/- mice were fed a high-fat diet to construct AS mouse models and the modeled mice were treated with altered NORAD, miR-495-3p or KLF5. NORAD, miR-495-3p and KLF5 expression in mouse aorta tissues were evaluated, and the levels of inflammatory factors, oxidative stress factors, endothelial function indices and blood lipid in mice were all determined. The atherosclerotic plaque area, lipid deposition area, collagen fibers and CD68 expression in mouse aorta tissues were assessed. The regulatory relation between NORAD and miR-495-3p, and the target relation between miR-495-3p and KLF5 were confirmed. RESULTS: NORAD and KLF5 were increased whereas miR-495-3p was decreased in atherosclerotic mouse aortas. Inhibited NORAD or elevated miR-495-3p suppressed inflammation, oxidative stress, endothelial dysfunction, blood lipid level, atherosclerotic plaque area, collagen fibers and CD68 expression in atherosclerotic mouse aortas. Effects of elevated miR-495-3p on atherosclerotic mice could be reversed by up-regulation of KLF5. NORAD served as a sponge of miR-495-3p and miR-495-3p directly targeted KLF5. CONCLUSION: Silenced NORAD elevated miR-495-3p to suppress atherosclerotic plaque formation via reducing KLF5. Findings in our research may be helpful for exploring molecular mechanisms of AS.
Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Fatores de Transcrição Kruppel-Like/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Aterosclerose/patologia , Dano ao DNA/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Inflamação/genética , Inflamação/patologia , Camundongos , Camundongos Knockout , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologiaRESUMO
Amyloid beta (Aß) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer's disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aß peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aß experiments, as it allows to explore the binding mechanism between metal ions and Aß oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aß peptides. Aß oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aß binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aß. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aß dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.
Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Ansiolíticos/uso terapêutico , Gabapentina/uso terapêutico , Hidroxiquinolinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , HumanosRESUMO
Toxicity testing and regulation of advanced materials at the nanoscale, i.e. nanosafety, is challenged by the growing number of nanomaterials and their property variants requiring assessment for potential human health impacts. The existing animal-reliant toxicity testing tools are onerous in terms of time and resources and are less and less in line with the international effort to reduce animal experiments. Thus, there is a need for faster, cheaper, sensitive and effective animal alternatives that are supported by mechanistic evidence. More importantly, there is an urgency for developing alternative testing strategies that help justify the strategic prioritization of testing or targeting the most apparent adverse outcomes, selection of specific endpoints and assays and identifying nanomaterials of high concern. The Adverse Outcome Pathway (AOP) framework is a systematic process that uses the available mechanistic information concerning a toxicological response and describes causal or mechanistic linkages between a molecular initiating event, a series of intermediate key events and the adverse outcome. The AOP framework provides pragmatic insights to promote the development of alternative testing strategies. This review will detail a brief overview of the AOP framework and its application to nanotoxicology, tools for developing AOPs and the role of toxicogenomics, and summarize various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development. The review also presents a network of AOPs derived from connecting all AOPs, which shows that several adverse outcomes induced by nanomaterials originate from a molecular initiating event that describes the interaction of nanomaterials with lung cells and involve similar intermediate key events. Finally, using the example of an established AOP for lung fibrosis, the review will discuss various in vitro tests available for assessing lung fibrosis and how the information can be used to support a tiered testing strategy for lung fibrosis. The AOPs and AOP network enable deeper understanding of mechanisms involved in inhalation toxicity of nanomaterials and provide a strategy for the development of alternative test methods for hazard and risk assessment of nanomaterials.
Assuntos
Rotas de Resultados Adversos , Alternativas aos Testes com Animais , Nanoestruturas/toxicidade , Projetos de Pesquisa , Testes de Toxicidade/métodos , Animais , HumanosRESUMO
BACE1 is the rate-limiting protease in the production of synaptotoxic ß-amyloid (Aß) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early ß-amyloid pathology. The longitudinal approach allowed to assess the kinetics of individual plaques and associated presynaptic pathology, before and throughout treatment. BACE1 inhibition could not halt but slow down progressive ß-amyloid deposition and associated synaptic pathology. Notably, the data revealed that the initial process of plaque formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. This finding of particular susceptibility of plaque formation has profound implications to achieve optimal therapeutic efficacy for the prospective treatment of AD.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Ácidos Picolínicos/farmacologia , Tiazinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Masculino , Camundongos Transgênicos , Placa Amiloide/tratamento farmacológico , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/genética , Proteína Vesicular 1 de Transporte de Glutamato/metabolismoRESUMO
BACKGROUND: The effect of the redox state of human serum albumin (HSA) on the antioxidant properties of the entire body has been a focus of recent research. The usefulness of HSA redox state as a biomarker for reducing oxidative stress has been investigated in clinical settings; however, evidence for its significance as a health index in non-clinical settings is yet to be established. This study aimed to examine the associations between HSA redox state and the atherosclerotic indices of carotid intima-media thickness (IMT) and plaque formation in a rural Japanese population. METHODS: We conducted a cross-sectional study as part of a health check-up program in the rural area of Hokkaido, Japan, at the end of August 2013. A total of 281 residents (124 men and 157 women) were included in the final analysis. Lifestyle-related data were obtained through a self-reported questionnaire, and ultrasound examinations were performed to measure IMT and determine plaque formation. The high-performance liquid chromatography postcolumn bromocresol green method was used to separate HSA into human nonmercaptalbumin and human mercaptalbumin (HMA). RESULTS: We found a significant negative relationship between the fraction of HMA [f(HMA)] and IMT (standardized ß = - 0.132, p = 0.03). Moreover, f(HMA) was significantly associated with plaque formation (p < 0.01) with an odds ratio of 0.89 (95% confidence interval, 0.81-0.97) for every 10% increment in f(HMA). CONCLUSIONS: We found that the HSA redox state, as determined by f(HMA), was associated with atherosclerotic indices in Japanese subjects. These results suggest that the HSA redox state indicates the risk of developing atherosclerosis.
Assuntos
Aterosclerose/epidemiologia , Espessura Intima-Media Carotídea/estatística & dados numéricos , Albumina Sérica Humana/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/etiologia , Biomarcadores , Estudos Transversais , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Oxirredução , Fatores de Risco , Albumina Sérica/metabolismoRESUMO
In this paper, a model is developed for the evolution of plaques in arteries, which is one of the main causes for the blockage of blood flow. Plaque rupture and spread of torn-off material may cause closures in the down-stream vessel system and lead to ischemic brain or myocardial infarctions. The model covers the flow of blood and its interaction with the vessel wall. It is based on the assumption that the penetration of monocytes from the blood flow into the vessel wall, and the accumulation of foam cells increasing the volume, are main factors for the growth of plaques. The dynamics of the vessel wall is governed by a deformation gradient, which is given as composition of a purely elastic tensor, and a tensor modeling the biologically caused volume growth. An equation for the evolution of the metric is derived quantifying the changing geometry of the vessel wall. To calculate numerically the solutions of the arising free boundary problem, the model system of partial differential equations is transformed to an ALE (Arbitrary Lagrangian-Eulerian) formulation, where all equations are given in fixed domains. The numerical calculations are using newly developed algorithms for ALE systems. The results of the simulations, obtained for realistic system parameters, are in good qualitative agreement with observations. They demonstrate that the basic modeling assumption can be justified. The increase of stresses in the vessel wall can be computed. Medical treatment tries to prevent critical stress values, which may cause plaque rupture and its consequences.
Assuntos
Modelos Cardiovasculares , Placa Aterosclerótica/etiologia , Algoritmos , Artérias/fisiopatologia , Fenômenos Biomecânicos , Velocidade do Fluxo Sanguíneo , Simulação por Computador , Hemorreologia , Humanos , Hidrodinâmica , Conceitos Matemáticos , Placa Aterosclerótica/fisiopatologiaRESUMO
UNLABELLED: In the 19th century, the mouthwash Listerine® was formulated from four essential oils. Later, the oils were replaced by their marker substances. To keep them in solution, 24-27% ethanol was added as a vehicle. This is an update of our previous review on the efficacy and safety of Listerine®. METHOD: PubMed was searched for clinical studies on the therapeutic benefits and safety of Listerine® from the end of 2011 to the end of October 2015. RESULTS: Sixteen studies were found and extracted. Three of the four 6-month studies were of sound confirmatory design. Two of these investigated Listerine® and one Listerine Zero®. The evidence of effectiveness for Listerine®, based on the bulk of three confirmatory studies and numerous exploratory studies carried out so far, is strong, but only moderate for Listerine® Zero and poor for Listerine® Cool Blue. In the three safety studies identified, we found methodological flaws that biased the results. CONCLUSIONS: Evidence is accumulating that Listerine® is effective in improving oral health, but the absence of systematic toxicological studies means that an accurate safety assessment cannot be made.
Assuntos
Placa Dentária/tratamento farmacológico , Gengivite/tratamento farmacológico , Antissépticos Bucais/uso terapêutico , Óleos Voláteis/uso terapêutico , Saúde Bucal , Salicilatos/uso terapêutico , Terpenos/uso terapêutico , Combinação de Medicamentos , Humanos , Salicilatos/química , Terpenos/químicaRESUMO
We investigated the association of depressive symptoms with carotid intima-media thickness (IMT) and plaques in the general Korean population. A total of 7,554 Korean males and females aged 45-74 yr who were free from cardiovascular diseases were included in the analyses. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D). Subjects with a score of ≥16 were classified as having clinically significant depressive symptoms. Carotid ultrasonography was used to measure mean carotid IMT (C-IMT) and to determine the presence of plaques. A significant association between depressive symptoms and C-IMT was observed only in females. After adjustment for established cardiovascular risk factors, females with depressive symptoms had significantly greater C-IMT than females without depressive symptoms (mean difference 0.011±0.004 mm; 95% confidence interval, 0.003-0.019 mm). Compared with controls, the fully adjusted risk of females with depressive symptoms for abnormal C-IMT (≥1.0 mm) was significant (odds ratio, 1.63; 95% confidence interval, 1.16-2.30). No significant association between depressive symptoms and carotid plaques was observed in either gender. This study shows a significant association between depressive symptoms and C-IMT in middle-aged and older females.
Assuntos
Doenças das Artérias Carótidas/diagnóstico , Depressão/diagnóstico , Idoso , Consumo de Bebidas Alcoólicas , Povo Asiático , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Estudos Transversais , Depressão/etiologia , Depressão/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Escalas de Graduação Psiquiátrica , República da Coreia , Fatores de Risco , Fatores Sexuais , Fumar , Inquéritos e QuestionáriosRESUMO
Effective oral care is important for maintaining a high quality of life. Therefore, plaque control can prevent the development and recurrence of periodontitis. Brushing with a toothbrush and toothpaste is a common way to remove plaque; however, excessive brushing or brushing with abrasive toothpaste can cause wear and tear on the dental crown. Hence, we aimed to quantitatively compare the plaque-removal efficiency and tooth wear of toothbrushes using the bioelectric effect (BE) with those of electric-mechanical toothbrushes. To generate the BE signal, an electronic circuit was developed and embedded in a toothbrush. Further, typodonts were coated with cultured artificial plaques and placed in a brushing simulator. A toothpaste slurry was applied, and the typodonts were eluted with tap water after brushing. The plaques of the typodonts were captured, and the images were quantified. For the tooth wear experiment, polymethyl methacrylate disk resin blocks were brushed twice a day, and the thickness of the samples was measured. Subsequently, statistical differences between the experimental toothbrushes and typical toothbrushes were analyzed. The BE toothbrush had a higher plaque-removal efficiency and could minimize tooth wear. This study suggests that the application of BE may be a new solution for oral care.
RESUMO
Atherosclerosis (AS) is a chronic inflammatory disease characterized by the formation of atherosclerotic plaques that consist of numerous cells including smooth muscle cells, endothelial cells, immune cells, and foam cells. The most abundant innate and adaptive immune cells, including neutrophils, monocytes, macrophages, B cells, and T cells, play a pivotal role in the inflammatory response, lipoprotein metabolism, and foam cell formation to accelerate atherosclerotic plaque formation. In this review, we have discussed the underlying mechanisms of activated immune cells in promoting AS and reviewed published clinical trials for the treatment of AS by suppressing immune cell activation. We have also presented some crucial shortcomings of current clinical trials. Lastly, we have discussed the therapeutic potential of novel compounds, including herbal medicine and dietary food, in alleviating AS in animals. Despite these limitations, further clinical trials and experimental studies will enhance our understanding of the mechanisms modulated by immune cells and promote widespread drug use to treat AS by suppressing immune system-induced inflammation.
RESUMO
OBJECTIVE: Chlorhexidine (CHX) is considered the gold standard against gram-negative microorganisms. Little has been written about the simultaneous influence that both time and concentration could have on antiplaque formation effectiveness of CHX. The aim of this study is to compare the clinical and microbiological effectiveness of two different CHX concentrations and time applications in a 4-day plaque regrowth study model. MATERIAL AND METHODS: Twenty volunteers were enrolled in a randomized double-blind crossover study comparing the effectiveness of CHX 0.3% and CHX 0.2% mouth rinses applied for 15 and 30 s, respectively. Plaque index (PII), total bacterial counts and the detection of specific periopathogens were measured at the 5th day of each mouth rinse application. Taste acceptance was evaluated using a questionnaire. RESULTS: Chlorhexidine 0.3% resulted in a statistically greater reductions (10%) in PIl and periopathogens compared to CHX 0.2%. Furthermore, patients reported comparable taste acceptance in both groups. CONCLUSION: Chlorhexidine is an effective oral antiseptic. The CHX 0.3% mouth rinse formulation used for 15 s resulted in superior clinical and microbiological outcomes compared to the CHX 0.2% formulation, used for 30 s.
Assuntos
Anti-Infecciosos Locais/administração & dosagem , Clorexidina/administração & dosagem , Placa Dentária/prevenção & controle , Antissépticos Bucais/administração & dosagem , Análise de Variância , Contagem de Colônia Microbiana , Estudos Cross-Over , Índice de Placa Dentária , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Estatísticas não Paramétricas , Inquéritos e Questionários , PaladarRESUMO
Vascular calcification (VC) is concomitant with atherosclerosis, yet it remains uncertain why rupture-prone high-risk plaques do not typically show extensive calcification. Intraplaque hemorrhage (IPH) deposits erythrocyte-derived cholesterol, enlarging the necrotic core and promoting high-risk plaque development. Pro-atherogenic CD163+ alternative macrophages engulf hemoglobin:haptoglobin (HH) complexes at IPH sites. However, their role in VC has never been examined to our knowledge. Here we show, in human arteries, the distribution of CD163+ macrophages correlated inversely with VC. In vitro experiments using vascular smooth muscle cells (VSMCs) cultured with HH-exposed human macrophage - M(Hb) - supernatant reduced calcification, while arteries from ApoE-/- CD163-/- mice showed greater VC. M(Hb) supernatant-exposed VSMCs showed activated NF-κB, while blocking NF-κB attenuated the anticalcific effect of M(Hb) on VSMCs. CD163+ macrophages altered VC through NF-κB-induced transcription of hyaluronan synthase (HAS), an enzyme that catalyzes the formation of the extracellular matrix glycosaminoglycan, hyaluronan, within VSMCs. M(Hb) supernatants enhanced HAS production in VSMCs, while knocking down HAS attenuated its anticalcific effect. NF-κB blockade in ApoE-/- mice reduced hyaluronan and increased VC. In human arteries, hyaluronan and HAS were increased in areas of CD163+ macrophage presence. Our findings highlight an important mechanism by which CD163+ macrophages inhibit VC through NF-κB-induced HAS augmentation and thus promote the high-risk plaque development.
Assuntos
Aterosclerose , Placa Aterosclerótica , Calcificação Vascular , Camundongos , Humanos , Animais , NF-kappa B , Ácido Hialurônico , Camundongos Knockout para ApoE , Macrófagos , Aterosclerose/complicações , Apolipoproteínas E/genéticaRESUMO
Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis, consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress, and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis showed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.
Assuntos
Aterosclerose , Doença da Artéria Coronariana , Hiperlipoproteinemia Tipo II , Placa Aterosclerótica , Camundongos , Humanos , Animais , Suínos , Fator de Crescimento Insulin-Like I/metabolismo , Aterosclerose/patologia , Placa Aterosclerótica/patologiaRESUMO
According to the WHO, the entire global population is exposed to air pollution levels higher than recommended for health preservation. Air pollution is a complex mixture of nano- to micro-sized particles and gaseous components that poses a major global threat to public health. Among the most important air pollutants, causal associations have been established between particulate matter (PM), mainly < 2.5 µm, and cardiovascular diseases (CVD), i.e., hypertension, coronary artery disease, ischemic stroke, congestive heart failure, arrhythmias as well as total cardiovascular mortality. Aim of this narrative review is to describe and critically discuss the proatherogenic effects of PM2.5 that have been attributed to many direct or indirect effects comprising endothelial dysfunction, a chronic low-grade inflammatory state, increased production of reactive oxygen species, mitochondrial dysfunction and activation of metalloproteases, all leading to unstable arterial plaques. Higher concentrations of air pollutants are associated with the presence of vulnerable plaques and plaque ruptures witnessing coronary artery instability. Air pollution is often disregarded as a CVD risk factor, in spite of the fact that it is one of the main modifiable factors relevant for prevention and management of CVD. Thus, not only structural actions should be taken in order to mitigate emissions, but health professionals should also take care to counsel patients on the risks of air pollution.