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Many of the survivors of the novel coronavirus disease (COVID-19) are suffering from persistent symptoms, causing significant morbidity and decreasing their quality of life, termed "post-COVID-19 syndrome" or "long COVID". Understanding the mechanisms surrounding PCS is vital to developing the diagnosis, biomarkers, and possible treatments. Here, we describe the prevalence and manifestations of PCS, and similarities with previous SARS epidemics. Furthermore, we look at the molecular mechanisms behind the neurological features of PCS, where we highlight important neural mechanisms that may potentially be involved and pharmacologically targeted, such as glutamate reuptake in astrocytes, the role of NMDA receptors and transporters (EAAT2), ROS signaling, astrogliosis triggered by NF-κB signaling, KNDy neurons, and hypothalamic networks involving Kiss1 (a ligand for the G-protein-coupled receptor 54 (GPR54)), among others. We highlight the possible role of reactive gliosis following SARS-CoV-2 CNS injury, as well as the potential role of the hypothalamus network in PCS manifestations.
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COVID-19 , SARS-CoV-2 , COVID-19/complicações , Gliose , Humanos , Qualidade de Vida , Síndrome de COVID-19 Pós-AgudaRESUMO
The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.
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Antineoplásicos , Infecções por HIV , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , HumanosRESUMO
The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population-based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES-D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES-D score, occurrence of a major depressive episode (MDE) during follow-up and regular antidepressant treatment during the 6 months preceding follow-up assessment as outcomes. The GRS was associated with MDE occurrence (p = .02) and ln CES-D score (p = .001). The HTR1A rs878567 variant was associated with ln CES-D after adjustment for demographic and clinical variables [p = .02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six-fold higher likelihood of regular AD therapy at follow-up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p = .03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs.
Assuntos
Antidepressivos/uso terapêutico , Citocromo P-450 CYP2C19/genética , Transtorno Depressivo Maior/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1A de Serotonina/genética , Adulto , Idoso , Transtorno Depressivo Maior/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Estudos Prospectivos , Índice de Gravidade de Doença , Suíça , Resultado do TratamentoRESUMO
BACKGROUND: An infection-immune association of periodontal disease with rheumatoid arthritis has been suggested. This study aimed to investigate the effect of pre-existing periodontitis on the development and the immune/inflammatory response of pristane-induced arthritis. METHODS: We investigated the effect of periodontitis induced by ligature placement and Porphyromonas gingivalis (P. gingivalis) infection, in combination with Fusobacterium nucleatum to promote its colonization, on the development of pristane-induced arthritis (PIA) in rats (Dark Agouti). Disease progression and severity of periodontitis and arthritis was monitored using clinical assessment, micro-computed tomography (micro-CT)/intraoral radiographs, antibody response, the inflammatory markers such as α-1-acid glycoprotein (α-1-AGP) and c-reactive protein (CRP) as well as cytokine multiplex profiling at different time intervals after induction. RESULTS: Experimentally induced periodontitis manifested clinically (P < 0.05) prior to pristane injection and progressed steadily until the end of experiments (15 weeks), as compared to the non-ligated arthritis group. Injection of pristane 8 weeks after periodontitis-induction led to severe arthritis in all rats demonstrating that the severity of arthritis was not affected by the pre-existence of periodontitis. Endpoint analysis showed that 89% of the periodontitis-affected animals were positive for antibodies against arginine gingipain B and furthermore, the plasma antibody levels to a citrullinated P. gingivalis peptidylarginine deiminase (PPAD) peptide (denoted CPP3) were significantly (P < 0.05) higher in periodontitis rats with PIA. Additionally, there was a trend towards increased pro-inflammatory and anti-inflammatory cytokine levels, and increased α-1-AGP levels in plasma from periodontitis-challenged PIA rats. CONCLUSIONS: Pre-existence of periodontitis induced antibodies against citrullinated peptide derived from PPAD in rats with PIA. However, there were no differences in the development or severity of PIA between periodontitis challenged and periodontitis free rats.
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Artrite Experimental/complicações , Periodontite/induzido quimicamente , Periodontite/complicações , Adesinas Bacterianas/sangue , Adesinas Bacterianas/imunologia , Animais , Formação de Anticorpos/imunologia , Artrite Experimental/diagnóstico por imagem , Peso Corporal , Proteína C-Reativa/metabolismo , Quimiocinas/metabolismo , Cisteína Endopeptidases/sangue , Cisteína Endopeptidases/imunologia , Cisteína Endopeptidases Gingipaínas , Hidrolases/sangue , Hidrolases/imunologia , Masculino , Orosomucoide/metabolismo , Periodontite/diagnóstico por imagem , Periodontite/microbiologia , Porphyromonas gingivalis/fisiologia , Proteína-Arginina Desiminase do Tipo 3 , Ratos , Terpenos , Microtomografia por Raio-XRESUMO
The potent inflammatory mediator prostaglandin E2 (PGE2) is implicated in the pathogenesis of several chronic inflammatory conditions, including periodontitis. The inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1), catalyzing the terminal step of PGE2 biosynthesis, is an attractive target for selective PGE2 inhibition. To identify mPGES-1 inhibitors, we investigated the effect of aminothiazoles on inflammation-induced PGE2 synthesis in vitro, using human gingival fibroblasts stimulated with the cytokine IL-1ß and a cell-free mPGES-1 activity assay, as well as on inflammation-induced bone resorption in vivo, using ligature-induced experimental periodontitis in Sprague-Dawley rats. Aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) and 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644) reduced IL-1ß-induced PGE2 production in fibroblasts (IC50 1.1 and 1.5 µM, respectively) as well as recombinant mPGES-1 activity, without affecting activity or expression of the upstream enzyme cyclooxygenase-2. In ligature-induced experimental periodontitis, alveolar bone loss, assessed by X-ray imaging, was reduced by 46% by local treatment with TH-848, compared to vehicle, without any systemic effects on PGE2, 6-keto PGF1α, LTB4 or cytokine levels. In summary, these results demonstrate that the aminothiazoles represent novel mPGES-1 inhibitors for inhibition of PGE2 production and reduction of bone resorption in experimental periodontitis, and may be used as potential anti-inflammatory drugs for treatment of chronic inflammatory diseases, including periodontitis.
Assuntos
Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/biossíntese , Periodontite/tratamento farmacológico , Antagonistas de Prostaglandina/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Tiazóis/farmacologia , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Periodontite/enzimologia , Periodontite/metabolismo , Prostaglandina-E Sintases , Ratos , Ratos Sprague-DawleyRESUMO
Introduction: Depression is a major global burden with unclear pathophysiology and poor treatment outcomes. Diagnosis of depression continues to rely primarily on behavioral rather than biological methods. Investigating tools that might aid in diagnosing and treating early-onset depression is essential for improving the prognosis of the disease course. While there is increasing evidence of possible biomarkers in adult depression, studies investigating this subject in adolescents are lacking. Methods: In the current study, we analyzed protein levels in 461 adolescents assessed for depression using the Development and Well-Being Assessment (DAWBA) questionnaire as part of the domestic Psychiatric Health in Adolescent Study conducted in Uppsala, Sweden. We used the Proseek Multiplex Neuro Exploratory panel with Proximity Extension Assay technology provided by Olink Bioscience, followed by transcriptome analyses for the genes corresponding to the significant proteins, using four publicly available cohorts. Results: We identified a total of seven proteins showing different levels between DAWBA risk groups at nominal significance, including RBKS, CRADD, ASGR1, HMOX2, PPP3R1, CD63, and PMVK. Transcriptomic analyses for these genes showed nominally significant replication of PPP3R1 in two of four cohorts including whole blood and prefrontal cortex, while ASGR1 and CD63 were replicated in only one cohort. Discussion: Our study on adolescent depression revealed protein-level and transcriptomic differences, particularly in PPP3R1, pointing to the involvement of the calcineurin pathway in depression. Our findings regarding PPP3R1 also support the role of the prefrontal cortex in depression and reinforce the significance of investigating prefrontal cortex-related mechanisms in depression.
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Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.
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The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer's disease, Parkinson's disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors' will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development.
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There is a growing awareness that the large number of environmental pollutants we are exposed to on a daily basis are causing major health problems. Compared to traditional studies that focus on individual pollutants, there are relatively few studies on how pollutants mixtures interact. Several studies have reported a relationship between environmental pollutants and the development of cancer, even when pollutant levels are below toxicity reference values. The possibility of synergistic interactions between different pollutants could explain how even low concentrations can cause major health problems. These intricate that molecular interactions can occur through a wide variety of mechanisms, and our understanding of the physiological effects of mixtures is still limited. The purpose of this paper is to discuss recent reports that address possible synergistic interactions between different types of environmental pollutants that could promote cancer development. Our literature studies suggest that key biological pathways are frequently implicated in such processes. These include increased production of reactive oxygen species, activation by cytochrome P450, and aryl hydrocarbon receptor signaling, among others. We discuss the need to understand individual pathological vulnerability not only in relation to basic genetics and gene expression, but also in terms of measurable exposure to contaminants. We also mention the need for significant improvements in future studies using a multitude of disciplines, such as the development of high-throughput study models, better tools for quantifying pollutants in cancer patients, innovative pharmacological and toxicological studies, and high-efficiency computer analysis, which allow us to analyze the molecular mechanisms of mixtures.
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Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future.
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Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Citocinas/antagonistas & inibidores , Descoberta de Drogas , Inflamação/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/química , Neoplasias/tratamento farmacológico , Preparações Farmacêuticas/metabolismo , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Citocinas/metabolismo , Desenho de Fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ligantes , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
BACKGROUND: Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. RESULTS: We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (total n = 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (padj. < 0.05) with meQTL effect. Lower DNAm at cg02098413 located in the HACE1 promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (praw = 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated with HACE1 mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lower HACE1 mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p = 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2) (padj. = 0.015, mRNA difference = 5.2%). Gene ontology analysis of the miRNA target genes highlighted implication in neuronal processes. CONCLUSIONS: Collectively, our findings from a multi-tissue (blood and brain) and multi-layered (genetic, epigenetic, transcriptomic) approach suggest that genetic factors may influence depression by modulating DNAm and miRNA levels. Alterations at HACE1 and SHANK2 loci imply potential mechanisms, such as oxidative stress in the brain, underlying depression. Our results deepened the knowledge of molecular mechanisms in depression and suggest new epigenetic targets that should be further evaluated.
Assuntos
Encéfalo/metabolismo , Depressão/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Alelos , Autopsia , Encéfalo/patologia , Estudos de Casos e Controles , Metilação de DNA , Depressão/sangue , Depressão/diagnóstico , Transtorno Depressivo Maior/genética , Epigenômica/métodos , Feminino , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , MicroRNAs/metabolismo , Neurônios/patologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , RNA não Traduzido/metabolismoRESUMO
INTRODUCTION: The G protein-coupled receptors (GPCR) superfamily is among the most widely exploited targets for therapeutics, with drugs mainly targeting the Rhodopsin, Glutamate and Secretin family receptors. The receptors of the Adhesion family, however, remain comparatively unexplored in this aspect. This review aims to discuss the druggability of Adhesion GPCRs (aGPCR), highlighting the relevant opportunities and challenges. AREAS COVERED: In this review, the authors provide a disease-oriented summary of aGPCR involvement in humans and discuss the current status of characterizing therapeutic agents with a focus on new opportunities using low molecular weight substances. EXPERT OPINION: The small molecule antagonist dihydromunduletone and partial agonist 3-α-acetoxydihydrodeoxygedunin, along with the endogenous natural ligand synaptamide currently comprise some of the most important discoveries made in an attempt to characterize aGPCR druggability. The small molecule modulators provide important insights regarding the structure-activity relationship and suggest that targeting the tethered peptide agonist results in a nonselective pharmacological action, while synaptamide may be considered a potentially attractive tool to achieve a higher degree of selectivity.
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Desenvolvimento de Medicamentos , Descoberta de Drogas , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Animais , Humanos , Ligantes , Terapia de Alvo Molecular , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
Unrecognized depression during adolescence can result in adult suicidal behaviour. The aim of this study was to identify, replicate and characterize DNA methylation (DNAm) shifts in depression aetiology, using a longitudinal, multi-tissue (blood and brain) and multi-layered (genetics, epigenetics, transcriptomics) approach. We measured genome-wide blood DNAm data at baseline and one-year follow-up, and imputed genetic variants, in 59 healthy adolescents comprising the discovery cohort. Depression and suicidal symptoms were determined using the Development and Well-Being Assessment (DAWBA) depression band, Montgomery-Åsberg Depression Rating Scale-Self (MADRS-S) and SUicide Assessment Scale (SUAS). DNAm levels at follow-up were regressed against depression scores, adjusting for sex, age and the DNAm residuals at baseline. Higher methylation levels of 5% and 13% at cg24627299 within the MET gene were associated with higher depression scores (praw<1e-4) and susceptibility for suicidal symptoms (padj.<0.005). The nearby rs39748 was discovered to be a methylation and expression quantitative trait locus in blood cells. mRNA levels of hepatocyte growth factor (HGF) expression, known to strongly interact with MET, were inversely associated with methylation levels at cg24627299, in an independent cohort of 1180 CD14+ samples. In an open-access dataset of brain tissue, lower methylation at cg24627299 was found in 45 adults diagnosed with major depressive disorder compared with matched controls (padj.<0.05). Furthermore, lower MET expression was identified in the hippocampus of depressed individuals compared with controls in a fourth, independent cohort. Our findings reveal methylation changes at MET in the pathology of depression, possibly involved in downregulation of HGF/c-MET signalling the hippocampal region.
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Metilação de DNA , Depressão/genética , Proteínas Proto-Oncogênicas c-met/genética , Adolescente , Feminino , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Transcriptoma , Adulto JovemRESUMO
OBJECTIVE: To investigate implant stability using resonance frequency measurements of topographically changed and/or surface chemistry-modified implants in rabbit bone. MATERIAL AND METHODS: Six groups of microstructured, screw-shaped titanium implants: two oxidized, cation-incorporated experimental implants [Mg implants and MgMp implants with micropatterned thread flanges (80-150 microm wide and 60-70 microm deep)] and four commercially available clinical implants (TiUnite((R)), Osseotite((R)), SLA((R)), and TiOblast((R))) were installed in 10 rabbit tibia for 6 weeks. The surface properties of the implants were characterized in detail using several analytical techniques. Implant stability was measured using a resonance frequency analyzer (Osstell(TM)). RESULTS: Surface characterization of the implants revealed microstructured, moderately rough implant surfaces varying 0.7-1.4 mum in S(a) (mean height deviation), but with clear differences in surface chemistry. After 6 weeks, all implants showed statistically significantly higher increases in implant stability. When compared with one another, MgMp implants showed the most significant mean implant stability quotient (ISQ) value relative to the others (PAssuntos
Densidade Óssea/fisiologia
, Implantes Dentários
, Retenção em Prótese Dentária
, Osseointegração/fisiologia
, Animais
, Ligas Dentárias
, Implantação Dentária Endóssea/métodos
, Planejamento de Prótese Dentária
, Falha de Restauração Dentária
, Análise do Estresse Dentário/instrumentação
, Análise do Estresse Dentário/métodos
, Implantes Experimentais
, Magnésio
, Coelhos
, Estresse Mecânico
, Propriedades de Superfície
, Tíbia/cirurgia
, Titânio
, Vibração
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PURPOSE: The aim of the present study was to investigate perceived oral health in patients with Crohn's disease (CD) in comparison with a control group without CD. MATERIALS AND METHODS: The study population comprised 1943 patients with CD recruited from the Swedish National Patients Organisation of inflammatory bowel disease and 1000 randomly selected controls. All participants received a questionnaire with questions concerning socioeconomic variables, education, civil status, income, dental care habits, oral health and tobacco use. RESULTS: Eighty-eight per cent of the patients and 75% of the controls answered the questionnaire. Patients with CD perceived their oral health to be worse than controls. The odds ratio (OR) for the patients to estimate their oral health as much worse than others in the same age group was 9.7 (95% CI, 5.8 to 16.4) after adjustment for age, smoking habit, gender and education. The patients also reported a significantly greater need for dental treatment than the controls, with an OR of 5.7 (95% CI, 4.2 to 7.9) after taking into account the age, smoking habit, gender and education. Furthermore, the patients with CD reported significantly more mouth-related problems than controls (OR 3.2), such as significantly more caries and more gingival bleeding. Of note, there were significantly more smokers in the patient group. CONCLUSIONS: The results of the present study show that patients with CD perceived their oral health to be worse and have a greater need for dental treatment compared with the control group.
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Atitude Frente a Saúde , Doença de Crohn/psicologia , Nível de Saúde , Doenças da Boca/complicações , Saúde Bucal , Adulto , Idoso , Estudos de Casos e Controles , Doença de Crohn/complicações , Feminino , Humanos , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Doenças da Boca/psicologia , Razão de Chances , Valores de Referência , AutoexameRESUMO
Mast cells act as sensors in innate immunity and as effector cells in adaptive immune reactions. Here we demonstrate that SLC10A4, also referred to as the vesicular aminergic-associated transporter, VAAT, modifies mast cell degranulation. Strikingly, Slc10a4 -/- bone marrow-derived mast cells (BMMCs) had a significant reduction in the release of granule-associated mediators in response to IgE/antigen-mediated activation, whereas the in vitro development of mast cells, the storage of the granule-associated enzyme mouse mast cell protease 6 (mMCP-6), and the release of prostaglandin D2 and IL-6 were normal. Slc10a4-deficient mice had a strongly reduced passive cutaneous anaphylaxis reaction and a less intense itching behaviour in response to the mast cell degranulator 48/80. Live imaging of the IgE/antigen-mediated activation showed decreased degranulation and that ATP was retained to a higher degree in mast cell granules lacking SLC10A4. Furthermore, ATP was reduced by two thirds in Slc10a4 -/- BMMCs supernatants in response to IgE/antigen. We speculate that SLC10A4 affects the amount of granule-associated ATP upon IgE/antigen-induced mast cell activation, which affect the release of granule-associated mast cell mediators. In summary, SLC10A4 acts as a regulator of degranulation in vitro and of mast cell-related reactions in vivo.
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Degranulação Celular , Imunoglobulina E/metabolismo , Fatores Imunológicos/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Anafilaxia Cutânea Passiva , Simportadores , Proteínas de Transporte Vesicular/deficiênciaRESUMO
Sorption processes involving secondary iron minerals may significantly contribute to immobilisation of metals in soils and surface waters. In the present work the effect of dissolved organic matter (DOM) from a concentrated bog-water on the adsorption of Cu(II) onto schwertmannite (Fe8O8(OH)6SO4) and goethite (alpha-FeOOH) has been studied. The acid/ base behaviour of DOM up to pH 6 was explained by assuming a diprotic acid with a density of carboxylate groups of 6.90 microeq (mg C)(-1). The resulting acidity constants, recalculated to zero ionic strength were pK(0)a1 = 3.61 and pK(0)a2 = 5.34. The uptake of DOM to schwertmannite and goethite was highest at low pH although adsorption was significant also under mildly alkaline conditions. Adsorption to the two minerals was similar although at high pH more DOM was adsorbed to schwertmannite than to goethite. DOM enhanced the adsorption of Cu(II) at moderately low pH in the goethite system but there was no effect of DOM in the case of schwertmannite. The presence of Cu(II) resulted in a decreased adsorption of DOM to goethite at weakly acidic pH and increased adsorption at high pH. In the case of schwertmannite, Cu(II) did not affect DOM uptake.
Assuntos
Cobre/química , Compostos de Ferro/química , Compostos Orgânicos/química , Adsorção , Concentração de Íons de Hidrogênio , Minerais , Eliminação de Resíduos Líquidos , Água/químicaRESUMO
The striatum serves as the main input to the basal ganglia, and is key for the regulation of motor behaviors, compulsion, addiction, and various cognitive and emotional states. Its deterioration is associated with degenerative disorders such as Huntington's disease. Despite its apparent anatomical uniformity, it consists of intermingled cell populations, which have precluded straightforward anatomical sub-classifications adhering to functional dissections. Approximately 95% of the striatal neurons are inhibitory projection neurons termed medium spiny neurons (MSNs). They are commonly classified according to their expression of either dopamine receptor D1 or D2, which also determines their axonal projection patterns constituting the direct and indirect pathway in the basal ganglia. Immunohistochemical patterns have further indicated compartmentalization of the striatum to the striosomes and the surrounding matrix, which integrate MSNs of both the D1 and D2 type. Here, we present a transgenic mouse line, Gpr101-Cre, with Cre recombinase activity localized to matrix D1 and D2 MSNs. Using two Gpr101-Cre founder lines with different degrees of expression in the striatum, we conditionally deleted the vesicular inhibitory amino acid transporter (VIAAT), responsible for storage of GABA and glycine in synaptic vesicles. Partial ablation of VIAAT (in ~36% of MSNs) resulted in elevated locomotor activity compared to control mice, when provoked with the monoamine reuptake inhibitor cocaine. Near complete targeting of matrix MSNs led to profoundly changed motor behaviors, which increased in severity as the mice aged. Moreover, these mice had exaggerated muscle rigidity, retarded growth, increased rate of spontaneous deaths, and defective memory. Therefore, our data provide a link between dysfunctional GABA signaling of matrix MSNs to specific behavioral alterations, which are similar to the symptoms of Huntington's disease.
RESUMO
The role of organic acids in buffering pH in surface waters has been studied using a small brownwater stream (26mg L(-1) TOC) draining a forested catchment in Northern Sweden. Under the conditions of elevated pressure of CO2 stream field pH was changed between 3.5 and 6.1 during the acidification and alkalinization experiment. Acid-base characteristics of the natural organic matter were also determined using a high precision potentiometric method for a concentrated sample from the same stream. We compared the predictions from the Windermere Humic Aqueous Model (WHAM Model V), a model derived from the potentiometric titration (diprotic/monoprotic acid model) and a previously derived triprotic acid model which only uses alkalinity and TOC as input variables. The predicted buffering characteristics of all three models are very similar in the pH range 4.5-7 which suggests that during routine analysis alkalinity and TOC are sufficient to give a good estimate of organic acid anion charge contribution in a large range of surface waters. A slightly adjusted version of WHAM V successfully describes the organic charge contribution in a large number of sampled surface water lakes, which were previously used to calibrate the triprotic model.