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1.
J Neuroinflammation ; 18(1): 255, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34740381

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. Here, we investigated the reactive carbonyl acrolein and (the therapeutic effect of) acrolein quenching by carnosine during neuroinflammation. METHODS: The abundance and localization of acrolein was investigated in inflammatory lesions of MS patients and experimental autoimmune encephalomyelitis (EAE) mice. In addition, we analysed carnosine levels and acrolein quenching by endogenous and exogenous carnosine in EAE. Finally, the therapeutic effect of exogenous carnosine was assessed in vivo (EAE) and in vitro (primary mouse microglia, macrophages, astrocytes). RESULTS: Acrolein was substantially increased in inflammatory lesions of MS patients and EAE mice. Levels of the dipeptide carnosine (ß-alanyl-L-histidine), an endogenous carbonyl quencher particularly reactive towards acrolein, and the carnosine-acrolein adduct (carnosine-propanal) were ~ twofold lower within EAE spinal cord tissue. Oral carnosine treatment augmented spinal cord carnosine levels (up to > tenfold), increased carnosine-acrolein quenching, reduced acrolein-protein adduct formation, suppressed inflammatory activity, and alleviated clinical disease severity in EAE. In vivo and in vitro studies indicate that pro-inflammatory microglia/macrophages generate acrolein, which can be efficiently quenched by increasing carnosine availability, resulting in suppressed inflammatory activity. Other properties of carnosine (antioxidant, nitric oxide scavenging) may also contribute to the therapeutic effects. CONCLUSIONS: Our results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS.

2.
J Autoimmun ; 124: 102723, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34481107

RESUMO

The initiation and progression of autoimmune disorders such as multiple sclerosis (MS) is linked to aberrant cholesterol metabolism and overt inflammation. Liver X receptors (LXR) are nuclear receptors that function at the crossroads of cholesterol metabolism and immunity, and their activation is considered a promising therapeutic strategy to attenuate autoimmunity. However, despite clear functional heterogeneity and cell-specific expression profiles, the impact of the individual LXR isoforms on autoimmunity remains poorly understood. Here, we show that LXRα and LXRß have an opposite impact on immune cell function and disease severity in the experimental autoimmune encephalomyelitis model, an experimental MS model. While Lxrα deficiency aggravated disease pathology and severity, absence of Lxrß was protective. Guided by flow cytometry and by using cell-specific knockout models, reduced disease severity in Lxrß-deficient mice was primarily attributed to changes in peripheral T cell physiology and occurred independent from alterations in microglia function. Collectively, our findings indicate that LXR isoforms play functionally non-redundant roles in autoimmunity, potentially having broad implications for the development of LXR-based therapeutic strategies aimed at dampening autoimmunity and neuroinflammation.

3.
Cell Mol Life Sci ; 78(19-20): 6631-6644, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34482420

RESUMO

The differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes is the prerequisite for remyelination in demyelinated disorders such as multiple sclerosis (MS). Epigenetic mechanisms, such as DNA methylation, have been suggested to control the intricate network of transcription factors involved in OPC differentiation. Yet, the exact mechanism remains undisclosed. Here, we are the first to identify the DNA-binding protein inhibitors, Id2 and Id4, as targets of DNA methylation during OPC differentiation. Using state-of-the-art epigenetic editing via CRISPR/dCas9-DNMT3a, we confirm that targeted methylation of Id2/Id4 drives OPC differentiation. Moreover, we show that in the pathological context of MS, methylation and gene expression levels of both ID2 and ID4 are altered compared to control human brain samples. We conclude that DNA methylation is crucial to suppress ID2 and ID4 during OPC differentiation, a process that appears to be dysregulated during MS. Our data do not only reveal new insights into oligodendrocyte biology, but could also lead to a better understanding of CNS myelin disorders.


Assuntos
Diferenciação Celular/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Proteína 2 Inibidora de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/genética , Fatores de Transcrição/genética , Animais , Células Cultivadas , Epigênese Genética/genética , Camundongos , Bainha de Mielina/genética , Células Precursoras de Oligodendrócitos/fisiologia , Remielinização/genética
4.
Nutrients ; 13(8)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34444774

RESUMO

Multiple health benefits have been ascribed to brown seaweeds that are used traditionally as dietary component mostly in Asia. This systematic review summarizes information on the impact of brown seaweeds or components on inflammation, and inflammation-related pathologies, such as allergies, diabetes mellitus and obesity. We focus on oral supplementation thus intending the use of brown seaweeds as food additives. Despite the great diversity of experimental systems in which distinct species and compounds were tested for their effects on inflammation and immunity, a remarkably homogeneous picture arises. The predominant effects of consumption of brown seaweeds or compounds can be classified into three categories: (1) inhibition of reactive oxygen species, known to be important drivers of inflammation; (2) regulation, i.e., in most cases inhibition of proinflammatory NF-κB signaling; (3) modulation of adaptive immune responses, in particular by interfering with T-helper cell polarization. Over the last decades, several inflammation-related diseases have increased substantially. These include allergies and autoimmune diseases as well as morbidities associated with lifestyle and aging. In this light, further development of brown seaweeds and seaweed compounds as functional foods and nutriceuticals might contribute to combat these challenges.


Assuntos
Suplementos Nutricionais , Hipersensibilidade/dietoterapia , Inflamação/dietoterapia , Alga Marinha , Verduras , Imunidade Adaptativa , Ásia , Bases de Dados Factuais , Dieta , Alimento Funcional , Humanos , Hipersensibilidade/imunologia , Inflamação/imunologia , Obesidade , Espécies Reativas de Oxigênio
5.
Food Res Int ; 147: 110547, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34399524

RESUMO

SCOPE: Dietary advanced glycation endproducts (AGEs) are associated with negative biological effects, possibly due to accumulation in plasma and tissues and through modulation of inflammation and gut microbiota. Whether these biological consequences are reversible by limiting dietary AGE intake is unknown. METHODS AND RESULTS: Young healthy C57BL/6 mice were fed a standard chow (n = 10) or a baked chow high AGE-diet (n = 10) (~1.8-6.9 fold increased protein-bound Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)) for 10 weeks or a switch diet with baked chow for 5 weeks followed by 5 weeks of standard chow (n = 10). We assessed accumulation of AGEs in plasma, kidney, and liver and measured inflammatory markers and gut microbial composition. After 10 weeks of baked chow, a substantial panel of AGEs were increased in plasma, liver, and kidney. These increases were normalized after the switch diet. The inflammatory z-score increased after the baked chow diet. Gut microbial composition differed significantly between groups, with enriched Dubosiella spp. dominating these alterations. CONCLUSION: A high AGE-diet led to an increase of AGEs in plasma, kidney, and liver and to more inflammation and modification of the gut microbiota. These effects were reversed or discontinued by a diet lower in AGEs.


Assuntos
Microbioma Gastrointestinal , Produtos Finais de Glicação Avançada , Animais , Dieta , Inflamação , Camundongos , Camundongos Endogâmicos C57BL
6.
Pharmacol Rev ; 73(3): 1016-1049, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233947

RESUMO

The phosphodiesterase 4 (PDE4) enzyme family plays a pivotal role in regulating levels of the second messenger cAMP. Consequently, PDE4 inhibitors have been investigated as a therapeutic strategy to enhance cAMP signaling in a broad range of diseases, including several types of cancers, as well as in various neurologic, dermatological, and inflammatory diseases. Despite their widespread therapeutic potential, the progression of PDE4 inhibitors into the clinic has been hampered because of their related relatively small therapeutic window, which increases the chance of producing adverse side effects. Interestingly, the PDE4 enzyme family consists of several subtypes and isoforms that can be modified post-translationally or can engage in specific protein-protein interactions to yield a variety of conformational states. Inhibition of specific PDE4 subtypes, isoforms, or conformational states may lead to more precise effects and hence improve the safety profile of PDE4 inhibition. In this review, we provide an overview of the variety of PDE4 isoforms and how their activity and inhibition is influenced by post-translational modifications and interactions with partner proteins. Furthermore, we describe the importance of screening potential PDE4 inhibitors in view of different PDE4 subtypes, isoforms, and conformational states rather than testing compounds directed toward a specific PDE4 catalytic domain. Lastly, potential mechanisms underlying PDE4-mediated adverse effects are outlined. In this review, we illustrate that PDE4 inhibitors retain their therapeutic potential in myriad diseases, but target identification should be more precise to establish selective inhibition of disease-affected PDE4 isoforms while avoiding isoforms involved in adverse effects. SIGNIFICANCE STATEMENT: Although the PDE4 enzyme family is a therapeutic target in an extensive range of disorders, clinical use of PDE4 inhibitors has been hindered because of the adverse side effects. This review elaborately shows that safer and more effective PDE4 targeting is possible by characterizing 1) which PDE4 subtypes and isoforms exist, 2) how PDE4 isoforms can adopt specific conformations upon post-translational modifications and protein-protein interactions, and 3) which PDE4 inhibitors can selectively bind specific PDE4 subtypes, isoforms, and/or conformations.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores da Fosfodiesterase 4 , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Biologia Molecular , Inibidores da Fosfodiesterase 4/farmacologia , Isoformas de Proteínas , Transdução de Sinais
7.
Behav Pharmacol ; 32(6): 459-471, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34320520

RESUMO

Inhibition of phosphodiesterase 4 (PDE4) is a promising pharmacological strategy for the treatment of cerebral ischemic conditions. To increase the relevance and increase the translational value of preclinical studies, it is important to conduct experiments using different animal species and strains, different animal models, and to evaluate long-term functional outcomes after cerebral ischemia. In the present study, the effects of the selective PDE4 inhibitor roflumilast were evaluated in vivo and in vitro. Balb/c mice were subjected to bilateral common carotid artery occlusion (BCCAO) and tested during 21 days in multiple behavioral tasks to investigate the long-term effects of roflumilast on functional recovery. The effects of roflumilast were also investigated on hippocampal cell loss, white matter injury, and expression of neuroinflammatory markers. Roflumilast prevented cognitive and emotional deficits induced by BCCAO in mice. Roflumilast also prevented neurodegeneration and reduced the white matter damage in the brain of ischemic animals. Besides, roflumilast decreased Iba-1 (microglia marker) levels and increased Arginase-1 (Arg-1; microglia M2 phenotype marker) levels in the hippocampus of these mice. Likewise, roflumilast suppressed inducible nitric oxide synthase (microglia M1 phenotype marker) expression and increased Arg-1 levels in a primary mouse microglia culture. These findings support evidence that PDE4 inhibition by roflumilast might be beneficial in cerebral ischemic conditions. The neuroprotective effects of roflumilast appear to be mediated by a decrease in neuroinflammation.

8.
Biomedicines ; 9(7)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206420

RESUMO

Ischemic stroke is caused by a thromboembolic occlusion of a major cerebral artery, with the impaired blood flow triggering neuroinflammation and subsequent neuronal damage. Both the innate immune system (e.g., neutrophils, monocytes/macrophages) in the acute ischemic stroke phase and the adaptive immune system (e.g., T cells, B cells) in the chronic phase contribute to this neuroinflammatory process. Considering that the available therapeutic strategies are insufficiently successful, there is an urgent need for novel treatment options. It has been shown that increasing cAMP levels lowers neuroinflammation. By inhibiting cAMP-specific phosphodiesterases (PDEs), i.e., PDE4, 7, and 8, neuroinflammation can be tempered through elevating cAMP levels and, thereby, this can induce an improved functional recovery. This review discusses recent preclinical findings, clinical implications, and future perspectives of cAMP-specific PDE inhibition as a novel research interest for the treatment of ischemic stroke. In particular, PDE4 inhibition has been extensively studied, and is promising for the treatment of acute neuroinflammation following a stroke, whereas PDE7 and 8 inhibition more target the T cell component. In addition, more targeted PDE4 gene inhibition, or combined PDE4 and PDE7 or 8 inhibition, requires more extensive research.

9.
J Steroid Biochem Mol Biol ; 212: 105942, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34144153

RESUMO

Enhancing the cholesterol turnover in the brain via activation of liver x receptors can restore memory in a mouse model for Alzheimer's disease. The edible Asian brown alga Sargassum fusiforme (Hijiki) contains high amounts of oxysterols such as (3ß, 24ξ)-stigmasta-5, 28-dien-3, 24-diol (24[R, S]-saringosterol) that are a potent liver x receptor agonists. We aimed to find native European seaweed species with contents of 24(R, S)-saringosterol that are comparable to those found in Sargassum fusiforme. Additionally, we hypothesize that seasonal variations modify the amount of 24(R, S)-saringosterol in seaweeds. Sterols and oxysterols were extracted with chloroform/methanol from various seaweed species harvested in the Eastern Scheldt in different seasons between October 2016 and September 2017. Identification and quantification of the lipids was performed by gas chromatography- mass spectrometry and gas chromatography- flame ionization detection. We confirmed that brown algae Undaria pinnatifida harvested in February and Sargassum muticum harvested in October contained the highest amounts of 24(R, S)-saringosterol (32.4 ± 15.25 µg/g, mean ± S.D. and 32.95 ± 2.91 µg/g, respectively) and its precursor fucosterol (1.48 ± 0.11 mg/g), higher than Sargassum fusiforme (20.94 ± 3.00 µg/g, mean ± S.D.), while Ascophyllum nodosum and Fucus vesiculosus and Fucus serratus contained amounts of 24(R, S)-saringosterol (22.09 ± 3.45 µg/g, 18.04 ± 0.52 µg/g and 19.47 ± 9.01 µg/g, mean ± S.D., respectively) comparable to Sargassum fusiforme. In other algae only minor amounts of these sterols were observed. The green algae Ulva lactuca contained only 0.29 mg/g fucosterol and 10.3 µg/g 24 (R, S)-saringosterol, while all investigated red algae did not contain any 24(R, S)-saringosterol or fucosterol. In the Eastern Scheldt algae harvested in September/October delivered the highest yield for 24(R, S)-saringosterol, with the exception of Undaria pinnatifida that showed the highest levels in February. We showed that exposure of lipid extracts of Ulva lactuca to sunlight at room temperature or in the presence of oxygen to UV-C light lead to the quantitative conversion of fucosterol into 24(R, S)-saringosterol. Exposing pure fucosterol to UV-light did not convert any fucosterol into 24(R, S)-saringosterol underscoring the requirement of seaweed constituents in the conversion of fucosterol into 24(R, S)-saringosterol. In conclusion, we showed that brown seaweeds harvested from the Eastern Scheldt contain amounts of 24(R, S)-saringosterol comparable to Sargassum fusiforme, varying per season and showing the highest amounts in spring. In accordance with these observations the amount of 24(R, S)-saringosterol in the brown seaweeds can be modulated by light.


Assuntos
Feófitas/metabolismo , Alga Marinha/metabolismo , Estigmasterol/análogos & derivados , Artefatos , Fatores Biológicos/química , Fatores Biológicos/metabolismo , Clorofila/metabolismo , Isomerismo , Estigmasterol/química , Estigmasterol/metabolismo , Raios Ultravioleta , Ulva/metabolismo
10.
Acta Neuropathol Commun ; 9(1): 108, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103079

RESUMO

Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

11.
Mar Drugs ; 19(4)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801706

RESUMO

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRß-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-ß (Aß) deposition in an Alzheimer's disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aß and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aß plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice independent of effects on Aß load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Cognição/efeitos dos fármacos , Nootrópicos/farmacologia , Estigmasterol/análogos & derivados , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Estigmasterol/farmacologia
12.
Cell Mol Life Sci ; 78(10): 4615-4637, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33751149

RESUMO

Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.


Assuntos
Diferenciação Celular , Doenças do Sistema Nervoso/patologia , Células Precursoras de Oligodendrócitos/patologia , Estresse Oxidativo , Animais , Humanos
13.
Stem Cell Res ; 51: 102169, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33486346

RESUMO

Fibroblasts isolated from a skin biopsy of a healthy 46-year-old female were infected with Sendai virus containing the Yamanaka factors to produce transgene-free human induced pluripotent stem cells (iPSCs). CRISPR/Cas9 was used to generate isogenic cell lines with a gene dose-dependent deficiency of CDH13, a risk gene associated with neurodevelopmental and psychiatric disorders. Thereby, a heterozygous CDH13 knockout (CDH13+/-) and a CDH13 null mutant (CDH13-/-) iPSC line was obtained. All three lines showed expression of pluripotency-associated markers, the ability to differentiate into cells of the three germ layers in vitro, and a normal female karyotype.


Assuntos
Células-Tronco Pluripotentes Induzidas , Transtornos do Neurodesenvolvimento , Sistemas CRISPR-Cas , Caderinas , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética
14.
Theranostics ; 11(5): 2080-2097, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500712

RESUMO

Synapses are the functional units of the brain. They form specific contact points that drive neuronal communication and are highly plastic in their strength, density, and shape. A carefully orchestrated balance between synaptogenesis and synaptic pruning, i.e., the elimination of weak or redundant synapses, ensures adequate synaptic density. An imbalance between these two processes lies at the basis of multiple neuropathologies. Recent evidence has highlighted the importance of glia-neuron interactions in the synaptic unit, emphasized by glial phagocytosis of synapses and local excretion of inflammatory mediators. These findings warrant a closer look into the molecular basis of cell-signaling pathways in the different brain cells that are related to synaptic plasticity. In neurons, intracellular second messengers, such as cyclic guanosine or adenosine monophosphate (cGMP and cAMP, respectively), are known mediators of synaptic homeostasis and plasticity. Increased levels of these second messengers in glial cells slow down inflammation and neurodegenerative processes. These multi-faceted effects provide the opportunity to counteract excessive synapse loss by targeting cGMP and cAMP pathways in multiple cell types. Phosphodiesterases (PDEs) are specialized degraders of these second messengers, rendering them attractive targets to combat the detrimental effects of neurological disorders. Cellular and subcellular compartmentalization of the specific isoforms of PDEs leads to divergent downstream effects for these enzymes in the various central nervous system resident cell types. This review provides a detailed overview on the role of PDEs and their inhibition in the context of glia-neuron interactions in different neuropathologies characterized by synapse loss. In doing so, it provides a framework to support future research towards finding combinational therapy for specific neuropathologies.


Assuntos
Neuroglia/efeitos dos fármacos , Plasticidade Neuronal , Neurônios/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Animais , Humanos , Neuroglia/enzimologia , Neurônios/enzimologia , Transdução de Sinais
15.
Neurobiol Aging ; 97: 56-64, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33157432

RESUMO

Pharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and -D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Expressão Gênica/genética , Estudos de Associação Genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Disfunção Cognitiva/patologia , Estudos de Coortes , Feminino , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino
16.
Plast Reconstr Surg Glob Open ; 8(11): e3246, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33299710

RESUMO

Merely a few reports of late failure (later than the 7th postoperative day) of a digital replantation can be found in the literature. Discussions of the factors that might cause a late failure are concise. To our knowledge, there are no reports of failure in literature as late as the case we are presenting. An 87-year-old white man was diagnosed with acute complications of a digital replantation, 34 years after initial surgery. Ultrasound examination and an arteriography demonstrated occlusion of the arterial anastomosis. The patient's surgical file revealed scars of former replantation surgery of both the index and the middle finger. In the latter, 1 artery and 2 veins were anastomosed. Considering the age and comorbidities of the patient, revascularization of the finger was not performed. Local wound care and analgesic drugs were prescribed. After initial deterioration and ulceration, gradual improvement was noticed. Total wound healing occurred at 3 months after the initial consultation. Compared with free flap surgery in general, finger replantations are at a higher risk of late complications because digital neovascularization is directly correlated to the contact surface area. This contact surface is usually larger in other free flaps. Furthermore, diseases that deteriorate circulation most likely affect the short- and the long-term survival of a digital replantation. From this point of view, performing both volar digital arterial anastomoses, whenever possible, might reduce early as well as late failure in replantation surgery.

17.
Int J Mol Sci ; 21(20)2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33066042

RESUMO

Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes.


Assuntos
Esclerose Múltipla/tratamento farmacológico , Oligodendroglia/metabolismo , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Humanos , Esclerose Múltipla/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico
19.
Hand (N Y) ; : 1558944720930297, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32697106

RESUMO

Background: Trapeziometacarpal arthroplasties are designed to restore an adequate level of mobility, stability, and grip strength. In this article, pain and functional and radiographic outcome of Ivory arthroplasty in male patients are investigated. Methods: Between 2005 and 2012, the Ivory arthroplasty was inserted in 21 male patients with degenerative trapeziometacarpal osteoarthritis, of which 14 patients were found eligible for inclusion. Mobility, grip strength, patient self-assessment (pain; Quick Disabilities of the Arm, Shoulder, and Hand [QuickDASH]), and radiographic outcome were measured. Twenty-two female patients who received an Ivory arthroplasty between 2005 and 2007 were included and underwent the same evaluation. Age at primary surgery, survival rate of the implant, and clinical outcome were compared between the 2 groups. Results: In both groups, QuickDASH score and mean pain sensation improved significantly. The improvement in mobility obtained significance in the female group. In the male group, 7 arthroplasties failed (mean follow-up of 65 months). In the female group, 3 of the 24 arthroplasties failed (mean follow-up of 123 months). Kaplan-Meier survival analysis demonstrated a significant lower implant survival in the male group. Conclusions: Decrease in muscle mass and decline in grip strength that postmenopausal women tend to experience might explain the significant difference in implant survival between sexes. In 4 of the 7 failed arthroplasties in the male group, no surgical revision was required. Trapeziometacarpal arthroplasty, even after radiographic failure, still served as a spacer, avoiding collapse of the thumb base. Nevertheless, the failure rate of the Ivory arthroplasty in male patients is high, and an alternative treatment should be considered.

20.
Proc Natl Acad Sci U S A ; 117(9): 5028-5038, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071226

RESUMO

The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMRß knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMRß KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.


Assuntos
Astrócitos/metabolismo , Oncostatina M/metabolismo , Remielinização/fisiologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Astrócitos/patologia , Axônios , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Bainha de Mielina , Células Precursoras de Oligodendrócitos , Inibidor Tecidual de Metaloproteinase-1/genética
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