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INTRODUCTION: Five to twelve percent of melanomas show aggregation of melanomas or other related tumors within the same family or individual. Genes such as CDKN2A, or BAP1, among others, have been involved in this condition. MATERIAL AND METHODS: Retrospective descriptive study that includes patients from Cruces University Hospital (2016-2023) who met any of the following criteria: presence of two or more melanomas (1), or a melanoma and a pancreatic cancer (2) in the same individual; presence of a melanoma in an individual and one or more first- or second-degree relatives with melanoma or pancreatic cancer (3); first- or second-degree relationship with an individual with a known deleterious variant in genes related to melanoma predisposition (4); or incidental discovery of deleterious variants in genes related to predisposition to melanoma, within hereditary cancer panels carried out for reasons other than melanoma (5). RESULTS: 59 families were included (69 patients; 63.8% women), of which 8.5% (13% of patients) presented pathogenic/likely pathogenic variants (PV/LPV) in CDKN2A (6% of families and patients, excluding criteria 4 and 5), and 1.7% of families (1.4% of patients) presented PV/LPV in BAP1, BRCA2 and TERF2IP. DISCUSSION AND CONCLUSIONS: The frequencies of PV/LPV in CDKN2A are similar to those previously described. This study could contribute to the knowledge of the characteristics of patients who meet genetic study criteria for hereditary melanoma, in a setting of real clinical practice.
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A number of minimally invasive osteotomies have been described for the repair of hallux abducto valgus (HAV) deformities. However, there are no known published studies that evaluate the effects of minimally invasive surgery techniques on the reduction of frontal plane rotation in patients with HAV. The purpose of this study was to assess correction in the transverse and frontal planes in patients undergoing surgical repair of HAV deformity utilizing a modified percutaneous technique. One hundred and five feet in 105 patients with HAV deformity were treated with a third generation minimally invasive technique using a first metatarsal osteotomy that allowed for frontal plane correction in conjunction with an Akin osteotomy. The minimum follow-up time was 12 months. Preoperative and postoperative anteroposterior weightbearing x-ray images were assessed and four measurements were evaluated: hallux abductus angle (HAA), intermetatarsal angle (IMA), tibial sesamoid position and frontal plane rotation of the first metatarsal. There were statistically significant differences for each of the assessments between the preoperative and postoperative radiographs (p < .001). There was a mean reduction in the HAA of 23.5° ± 9.6°, in the IMA, 7.0° ± 3.5°, in the tibial sesamoid position, 2.6 ± 1.3, and an improvement in the assessment of first metatarsal pronation (1.4 ± 0.9). The overall complication rate was 18.1%, with 5.7% of the feet requiring reoperation. The minimally invasive procedure employed by the authors demonstrated suitable outcomes in reducing deformity in both the transverse and frontal planes.
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Hallux Valgus , Procedimentos Cirúrgicos Minimamente Invasivos , Osteotomia , Radiografia , Humanos , Hallux Valgus/cirurgia , Hallux Valgus/diagnóstico por imagem , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Osteotomia/métodos , Estudos Prospectivos , Adulto , Idoso , Resultado do Tratamento , Ossos do Metatarso/cirurgia , Ossos do Metatarso/diagnóstico por imagem , Seguimentos , Adulto JovemRESUMO
Proteostasis mechanisms mediated by macroautophagy/autophagy are altered in neurodegenerative diseases such as Alzheimer disease (AD) and their recovery/enhancement has been proposed as a therapeutic approach. From the two central nodes in the anabolism-catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)_ activation leads to the inhibition of autophagy, whereas adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (Aß) production disturbs the optimal neuronal/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation/degradation of ß-amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced Aß secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on Aß secretion. Conversely, AMPK inhibition did not affect autophagy but reduced Aß secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented Aß secretion. We conclude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that perhaps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy-dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Animais , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Astrócitos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Presenilina-1 , Doença de Alzheimer/metabolismo , Autofagia/fisiologiaRESUMO
Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well-known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post-anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC-MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized ß coefficients = 0.386 and 0.346, R2 = 0.146 and 0.120, respectively). CYP2B6 PMs (n = 10) were significantly related to a higher reduction in pain 30 min after tramadol intake (univariate p = 0.038, multivariate p = 0.016, unstandardized ß coefficient = 0.224, R2 = 0.178), to lower PACU admission time (p = 0.007), and to lower incidence of adverse drug reactions (p = 0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p = 0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response.
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Citocromo P-450 CYP2D6 , Tramadol , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP2B6/genética , Espectrometria de Massas em Tandem , Analgésicos Opioides , Fenótipo , Genótipo , Dor Pós-Operatória , Transportador 1 de Ânion Orgânico Específico do Fígado/genéticaRESUMO
Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including disrupted circadian rhythm. The regulation of circadian rhythm depends on the light information that is projected from the retina to the suprachiasmatic nucleus in the hypothalamus. Studies of AD patients and AD transgenic mice have revealed AD retinal pathology, including amyloid-ß (Aß) accumulation that can directly interfere with the regulation of the circadian cycle. Although the cause of AD pathology is poorly understood, one of the main risk factors for AD is female gender. Here, we found that female APP/PS1 mice at 6- and 12-months old display severe circadian rhythm disturbances and retinal pathological hallmarks, including Aß deposits in retinal layers. Since brain Aß transport is facilitated by aquaporin (AQP)4, the expression of AQPs were also explored in APP/PS1 retina to investigate a potential correlation between retinal Aß deposits and AQPs expression. Important reductions in AQP1, AQP4, and AQP5 were detected in the retinal tissue of these transgenic mice, mainly at 6-months of age. Taken together, our findings suggest that abnormal transport of Aß, mediated by impaired AQPs expression, contributes to the retinal degeneration in the early stages of AD.
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Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Camundongos , Humanos , Feminino , Animais , Lactente , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Retina/metabolismo , Aquaporina 4/genética , Expressão Gênica , Modelos Animais de Doenças , Presenilina-1/genética , Presenilina-1/metabolismo , Placa Amiloide/metabolismoRESUMO
OBJECTIVE: Unexplained changes in regulation of branched chain amino acids (BCAA) during diabetes therapy with metformin have been known for years. Here we have investigated mechanisms underlying this effect. METHODS: We used cellular approaches, including single gene/protein measurements, as well as systems-level proteomics. Findings were then cross-validated with electronic health records and other data from human material. RESULTS: In cell studies, we observed diminished uptake/incorporation of amino acids following metformin treatment of liver cells and cardiac myocytes. Supplementation of media with amino acids attenuated known effects of the drug, including on glucose production, providing a possible explanation for discrepancies between effective doses in vivo and in vitro observed in most studies. Data-Independent Acquisition proteomics identified that SNAT2, which mediates tertiary control of BCAA uptake, was the most strongly suppressed amino acid transporter in liver cells following metformin treatment. Other transporters were affected to a lesser extent. In humans, metformin attenuated increased risk of left ventricular hypertrophy due to the AA allele of KLF15, which is an inducer of BCAA catabolism. In plasma from a double-blind placebo-controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin caused selective accumulation of plasma BCAA and glutamine, consistent with the effects in cells. CONCLUSIONS: Metformin restricts tertiary control of BCAA cellular uptake. We conclude that modulation of amino acid homeostasis contributes to therapeutic actions of the drug.
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Metformina , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Aminoácidos de Cadeia Ramificada/metabolismo , Aminoácidos/metabolismo , Glucose , HomeostaseRESUMO
PURPOSE OF REVIEW: Globalization and the increase in consumption of ultra-processed foods have led to a need for greater knowledge on the health impacts of certain nutrients such as artificial sweeteners. This review aims to analyse the role of artificial sweeteners (nutritive and nonnutritive) and their impact on cardiometabolic and cardiovascular disease (CVD) risk. RECENT FINDINGS: The detrimental effects of a high-calorie, high-sugar diet have been well established. In light of this, health authorities recommend limiting sugar consumption. This has led the food industry to develop different artificial sweeteners with specific properties, such as flavour and stability (nutritive artificial sweeteners: NAS), and others aimed at limiting sugar in the diet (nonnutritive artificial sweeteners: nNAS). Likewise, recent evidence explores the influence of artificial sweeteners (NAS and nNAS) on CVD risk through risk factors such as obesity and type 2 diabetes mellitus, among others. SUMMARY: This review aims to provide an updated overview of the impact of NAS and nNAS on cardiovascular health and provide recommendations regarding their consumption.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Edulcorantes/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Fatores de Risco , Fatores de Risco de Doenças Cardíacas , AçúcaresRESUMO
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a fatal genetic heart disease characterized by cardiac arrhythmias, in which fibrofatty deposition leads to heart failure, with no effective treatments. Plakophilin 2 (PKP2) is the most frequently mutated gene in ARVC, and although altered RNA splicing has been implicated, there are no models to study its effect and therapeutics. Here, we generate a mouse model harboring a PKP2 mutation (IVS10-1G>C) affecting RNA splicing, recapitulating ARVC features and sudden death starting at 4 weeks. Administering AAV-PKP2 gene therapy (adeno-associated viral therapy to drive cardiac expression of PKP2) to neonatal mice restored PKP2 protein levels, completely preventing cardiac desmosomal and pathological deficits associated with ARVC, ensuring 100% survival of mice up to 6 months. Late-stage AAV-PKP2 administration rescued desmosomal protein deficits and reduced pathological deficits including improved cardiac function in adult mice, resulting in 100% survival up to 4 months. We suggest that AAV-PKP2 gene therapy holds promise for circumventing ARVC associated with PKP2 mutations, including splice site mutations.
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Displasia Arritmogênica Ventricular Direita , Terapia Genética , Placofilinas , Animais , Humanos , Masculino , Camundongos , Animais Recém-Nascidos , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/terapia , Dependovirus/genética , Desmossomos/genética , Desmossomos/metabolismo , Modelos Animais de Doenças , Predisposição Genética para Doença , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Camundongos Endogâmicos C57BL , Mutação , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenótipo , Placofilinas/genética , Splicing de RNA/genéticaRESUMO
Instruments for estimating the intake of food components can be useful in the prevention and/or treatment of diseases related to improper diet. There is, at present, no scientifically validated instrument for estimating consumption of trans fatty acids (TFA) in the Mexican population. The objective of this study was to design and validate such an instrument: a questionnaire that can be used to estimate consumption of TFA from food products. The questionnaire was applied to 162 students from the Autonomous University of Querétaro (UAQ). There were two phases to the study: (1) design of a food frequency questionnaire to assess consumption of trans fatty acids (FFQ-TFA) and an eating practices questionnaire (EPQ-TFA); (2) validation of the instrument. Content validity was measured by expert review and by Aiken's V method, obtaining an overall score of 0.895. As final tests for the FFQ-TFA analysis, criterion validity was measured using Spearman's correlation (r = 0.717, p < 0.01) and a linear regression (B = 0.668), considering the results of the 24-h dietary recall (24 HR); and reproducibility or temporal stability was measured using Pearson's correlation (r = 0.406, p < 0.01). Subsequently, a Pearson correlation was applied between TFA consumption estimated by the FFQ-TFA-2 and the global score from the EPQ-TFA-2 (r = 0.351, p < 0.01). A Pearson correlation was applied between the EPQ-TFA-1 and the EPQ-TFA-2 (r = 0.575, p < 0.01). TFA consumption per day was 2.49 ± 1.32 g in the participating population, which was 1.04 ± 0.51% of their total kcal consumption.
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Ácidos Graxos trans , Adulto , Humanos , Reprodutibilidade dos Testes , Registros de Dieta , Dieta , Inquéritos e Questionários , Inquéritos sobre DietasRESUMO
Several studies have demonstrated that the underlying mechanism of insulin resistance (IR) is linked with developing diseases like diabetes mellitus, hypertension, metabolic syndrome, and polycystic ovary syndrome. In turn, the dysfunction of female gonadal hormones (especially 17ß-estradiol) may be related to the development of IR complications since different studies have shown that 17ß-estradiol has a cardioprotector and vasorelaxant effect. This study aimed was to determine the effect of the 17ß-estradiol administration in insulin-resistant rats and its effects on cardiovascular responses in pithed rats. Thus, the vasopressor responses are induced by sympathetic stimulation or i.v. bolus injections of noradrenaline (α1/2), methoxamine (α1), and UK 14,304 (α2) adrenergic agonist were determined in female pithed rats with fructose-induced insulin resistance or control rats treated with: 1) 17ß-estradiol or 2) its vehicle (oil) for 5 weeks. Thus, 17ß-estradiol decreased heart rate, prevented the increase of blood pressure induced by ovariectomy, but with the opposite effect on sham-operated rats; and decreased vasopressor responses induced by i.v. bolus injections of noradrenaline on sham-operated (control and fructose group) and ovariectomized (control) rats, and those induced by i.v. bolus injections of methoxamine (α1 adrenergic agonist). Overall, these results suggest 17ß-estradiol has a cardioprotective effect, and its effect on vasopressor responses could be mediated mainly by the α1 adrenergic receptor. In contrast, IR with ovariectomy 17ß-estradiol decreases or loses its cardioprotector effect, this could suggest a possible link between the adrenergic receptors and the insulin pathway.
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Estradiol , Resistência à Insulina , Sistema Nervoso Simpático , Animais , Feminino , Humanos , Ratos , Agonistas Adrenérgicos/farmacologia , Estradiol/farmacologia , Frutose/farmacologia , Insulina , Resistência à Insulina/fisiologia , Metoxamina/farmacologia , Norepinefrina/farmacologia , Ovariectomia , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Vasoconstritores/farmacologiaRESUMO
The most accepted hypothesis in Alzheimer's disease (AD) is the amyloid cascade which establishes that Aß accumulation may induce the disease development. This accumulation may occur years before the clinical symptoms but it has not been elucidated if this accumulation is the cause or the consequence of AD. It is however, clear that Aß accumulation exerts toxic effects in the cerebral cells. It is important then to investigate all possible associated events that may help to design new therapeutic strategies to defeat or ameliorate the symptoms in AD. Alterations in the mitochondrial physiology have been found in AD but it is not still clear if they could be an early event in the disease progression associated to amyloidosis or other conditions. Using APP/PS1 mice, our results support published evidence and show imbalances in the mitochondrial dynamics in the cerebral cortex and hippocampus of these mice representing very early events in the disease progression. We demonstrate in cellular models that these imbalances are consequence of Aß accumulation that ultimately induce increased mitophagy, a mechanism which selectively removes damaged mitochondria by autophagy. Along with increased mitophagy, we also found that Aß independently increases autophagy in APP/PS1 mice. Therefore, mitochondrial dysfunction could be an early feature in AD, associated with amyloid overload.
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Doença de Alzheimer , Amiloidose , Amiloide , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Autofagia , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Camundongos Transgênicos , Dinâmica Mitocondrial , Modelos TeóricosRESUMO
Senile plaque formation as a consequence of amyloid-ß peptide (Aß) aggregation constitutes one of the main hallmarks of Alzheimer's disease (AD). This pathology is characterized by synaptic alterations and cognitive impairment. In order to either prevent or revert it, different therapeutic approaches have been proposed, and some of them are focused on diet modification. Modification of the ω-6/ω-3 fatty acids (FA) ratio in diets has been proven to affect Aß production and senile plaque formation in the hippocampus and cortex of female transgenic (TG) mice. In these diets, linoleic acid is the main contribution of ω-6 FA, whereas alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) are the contributors of ω-3 FA. In the present work, we have explored the effect of ω-6/ω-3 ratio modifications in the diets of male double-transgenic APPswe/PS1ΔE9 (AD model) and wild-type mice (WT). Amyloid burden in the hippocampus increased in parallel with the increase in dietary ω-6/ω-3 ratio in TG male mice. In addition, there was a modification in the brain lipid profile proportional to the ω-6/ω-3 ratio of the diet. In particular, the higher the ω-6/ω-3 ratio, the lower the ceramides and higher the FAs, particularly docosatetraenoic acid. Modifications to the cortex lipid profile was mostly similar between TG and WT mice, except for gangliosides (higher levels in TG mice) and some ceramide species (lower levels in TG mice).
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Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Ceramidas/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-6/administração & dosagem , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Ácidos Erúcicos/metabolismo , Ácidos Graxos Ômega-3/efeitos adversos , Ácidos Graxos Ômega-6/efeitos adversos , Gangliosídeos/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos TransgênicosRESUMO
The disaccharide trehalose was described as possessing relevant neuroprotective properties as an mTORC1-independent inducer of autophagy, with the ability to protect cellular membranes and denaturation, resulting from desiccation, and preventing the cellular accumulation of protein aggregates. These properties make trehalose an interesting therapeutic candidate against proteinopathies such as Alzheimer's disease (AD), which is characterized by deposits of aggregated amyloid-beta (Aß) and hyperphosphorylated tau. In this study, we observed that trehalose was able to induce autophagy in neurons only in the short-term, whereas long-term treatment with trehalose provoked a relevant anti-amyloidogenic effect in neurons from an AD mouse model that was not mediated by autophagy. Trehalose treatment reduced secreted Aß levels in a manner unrelated to its intracellular accumulation or its elimination through endocytosis or enzymatic degradation. Moreover, the levels of Aß precursor protein (APP) and beta-secretase (BACE1) remained unaltered, as well as the proper acidic condition of the endo-lysosome system. Instead, our results support that the neuroprotective effect of trehalose was mediated by a reduced colocalization of APP and BACE1 in the cell, and, therefore, a lower amyloidogenic processing of APP. This observation illustrates that the determination of the mechanism, or mechanisms, that associate APP and BACE is a relevant therapeutic target to investigate.
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The physiological AKT-MTORC1 and AMPK signaling pathways are considered key nodes in the regulation of anabolism-catabolism, and particularly of macroautophagy/autophagy. Indeed, it is reported that these are altered processes in neurodegenerative proteinopathies such as Alzheimer disease (AD), mainly characterized by deposits of ß-amyloid (Aß) and hyperphosphorylated MAPT. These accumulations disrupt the optimal neuronal proteostasis, and hence, the recovery/enhancement of autophagy has been proposed as a therapeutic approach against these proteinopathies. The purpose of the present study was to characterize the modulation of autophagy by MTORC1 and AMPK signaling pathways in the highly specialized neurons, as well as their repercussions on Aß production. Using a double transgenic mice model of AD, we demonstrated that MTORC1 inhibition, either in vivo or ex vivo (primary neuronal cultures), was able to reduce amyloid secretion through moderate autophagy induction in neurons. The pharmacological prevention of autophagy in neurons augmented the Aß secretion and reversed the effect of rapamycin, confirming the anti-amyloidogenic effects of autophagy in neurons. Inhibition of AMPK with compound C generated the expected decrease in autophagy induction, though surprisingly did not increase the Aß secretion. In contrast, increased activity of AMPK with metformin, AICAR, 2DG, or by gene overexpression did not enhance autophagy but had different effects on Aß secretion: whereas metformin and 2DG diminished the secreted Aß levels, AICAR and PRKAA1/AMPK gene overexpression increased them. We conclude that AMPK has a significantly different role in primary neurons than in other reported cells, lacking a direct effect on autophagy-dependent amyloidosis.Abbreviations: 2DG: 2-deoxy-D-glucose; Aß: ß-amyloid; ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; AD: Alzheimer disease; AICAR: 5-aminoimidazole-4-carboxamide-1-ß-riboside; AKT: AKT kinases group (AKT1 [AKT serine/threonine kinase 1], AKT2 and AKT3); AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; APP: amyloid beta precursor protein; APP/PSEN1: B6.Cg-Tg (APPSwe, PSEN1dE9) 85Dbo/J; ATG: autophagy related; ATP: adenosine triphosphate; BafA1: bafilomycin A1; CA: constitutively active; CGN: cerebellar granule neuron; CoC/compound C: dorsommorphin dihydrochloride; ELISA: enzyme-linked immunosorbent assay; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; Gmax: GlutaMAX™; IN1: PIK3C3/VPS34-IN1; KI: kinase-inactive; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3; MAPT/TAU: microtubule associated protein tau; Metf: metformin; MRT: MRT68921; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PRKAA: 5'-AMP-activated protein kinase catalytic subunit alpha; PtdIns3K: phosphatidylinositol 3-kinase; Rapa: rapamycin; RPS6KB1/S6K: ribosomal protein S6 (RPS6) kinase polypeptide 1; SCR: scramble; SQSTM1/p62: sequestosome 1; ULK1/2: unc-51 like autophagy activating kinase 1/2; WT: wild type.
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Proteínas Quinases Ativadas por AMP/metabolismo , Peptídeos beta-Amiloides/metabolismo , Autofagia/fisiologia , Neurônios/metabolismo , Peptídeos beta-Amiloides/farmacologia , Animais , Autofagia/genética , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Paciente de 59 años quien ingresa al servicio de urgencias con un cuadro de 2 días de evolución de cefalea holocraneana de intensidad moderada 7/10, picos febriles no cuantificados, disnea grado III, adinamia, hiporexia, ageusia y tos no productiva, refiriendo contacto estrecho con hermana confirmada para infección por COVID-19, por lo que se investiga antígeno para COVID-19 con resultado positivo. Se confirma la existencia del síndrome respiratorio agudo grave (SARS-CoV-2) con coinfección por Cryptococus neoformans. El manejo con corticoide sistémico genera un importante inmunocompromiso que predispone al paciente a coinfecciones por gérmenes comunes y oportunistas, como lo es la infección por Cryptococcus neoformans/ Gatti. En este caso la infección por COVID-19 y el desarrollo de SARS-CoV-2 fue la etiología de la infección micótica por cryptococo.
Here, we report a case of a 59-year-old patient with a 2-day history of moderate intensity (7/10) holocranial headache, unquantified febrile peaks, grade III dyspnea, adynamia, hyporexia, ageusia and nonproductive cough admitted to the emergency department. He referred close contact to a sister with confirmed COVID-19. His COVID-19 antigen test results were positive. Severe acute respiratory syndrome (SARS-CoV-2) associated with Cryptococcus neoformans infection was confirmed. The use of systemic corticosteroid therapy leads to immunocompromise and predisposes the patient to common and opportunistic infections such as Cryptococcus neoformans and Cryptococcus gatiii infection. In this case COVID-19 infection and the development of SARS-CoV-2 was the etiology of the Cryptococcus fungal infection.
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Humanos , Masculino , Pessoa de Meia-Idade , Criptococose , COVID-19 , Cefaleia , Síndrome Respiratória Aguda Grave , Relatório de PesquisaRESUMO
The accumulation of extracellular amyloid-beta (Aß), denoted as senile plaques, and intracellular neurofibrillary tangles (formed by hyperphosphorylated Tau protein) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). The current and most accepted hypothesis proposes that the oligomerization of Aß peptides triggers the polymerization and accumulation of amyloid, which leads to the senile plaques. Several strategies have been reported to target Aß oligomerization/polymerization. Since it is thought that Aß levels in the brain and peripheral blood maintain equilibrium, it has been hypothesized that enhancing peripheral clearance (by shifting this equilibrium towards the blood) might reduce Aß levels in the brain, known as the sink effect. This process has been reported to be effective, showing a reduction in Aß burden in the brain as a consequence of the peripheral reduction of Aß levels. Nanoparticles (NPs) may have difficulty crossing the blood-brain barrier (BBB), initially due to their size. It is not clear whether particles in the range of 50-100 nm should be able to cross the BBB without being specifically modified for it. Despite the size limitation of crossing the BBB, several NP derivatives may be proposed as therapeutic tools. The purpose of this review is to summarize some therapeutic approaches based on nanoliposomes using two complementary examples: First, unilamellar nanoliposomes containing Aß generic ligands, such as sphingolipids, gangliosides or curcumin, or some sphingolipid bound to the binding domain of ApoE; and second, nanoliposomes containing monoclonal antibodies against Aß. Following similar rationale NPs of poly(lactide-co-glycolide)-poly (ethylene glycol) conjugated with curcumin-derivate (PLGA-PEG-B6/Cur) were reported to improve the spatial learning and memory capability of APP/PS1 mice, compared with native curcumin treatment. Also, some new nanostructures such as exosomes have been proposed as a putative therapeutic and prevention strategies of AD. Although the unquestionable interest of this issue is beyond the scope of this review article. The potential mechanisms and significance of nanoliposome therapies for AD, which are still are in clinical trials, will be discussed.
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This study assessed the participation of spinal TWIK-related acid-sensitive K+ channels 1 and 3 (TASK-1 and TASK-3) in inflammatory (formalin test) and neuropathic (spinal nerve ligation, SNL) pain in rats. Intrathecal pre-treatment (-10â¯min) with the TASK-1 blocker ML365 or TASK-3 blocker PK-THPP, but not vehicle, enhanced in a dose-dependent manner 1% formalin-induced acute and long-lasting secondary mechanical allodynia and mechanical hyperalgesia in rats. In contrast, intrathecal pre-treatment with terbinafine, an activator of TASK-3, reduced formalin-induced flinching and allodynia/hyperalgesia. Both blockers and terbinafine had similar effects on female and male rats. In addition, intrathecal injection of ML365 or PK-THPP blocked the terbinafine-induced antiallodynic effect in neuropathic rats, but they did not modify baseline withdrawal threshold in naïve or sham-operated rats. TASK-1 and TASK-3 mRNA and protein were expressed in L4 and L5 dorsal root ganglia (DRG) and dorsal and ventral spinal cord of naïve animals. Interestingly, formalin injection increased TASK-1 expression in ipsilateral L5 DRG, but not in the spinal cord. Moreover, formalin injection transiently enhanced TASK-3 expression in ipsilateral L5 DRG and dorsal spinal cord. In contrast, SNL down-regulated TASK-3 expression in the ipsilateral L4 and L5 DRG but not in dorsal or ventral spinal cord, while SNL did not modify TASK-1 expression at any tissue. The pharmacological and molecular results suggest that TASK-1 and TASK-3 have a relevant antinociceptive role in inflammatory and neuropathic pain.