Alterations of mRNAs and Non-coding RNAs Associated with Neuroinflammation in Alzheimer's Disease.

Alzheimer's disease is a neurodegenerative pathology whose pathognomonic hallmarks are increased generation of ß-amyloid (Aß) peptide, production of hyperphosphorylated (pTau), and neuroinflammation. The last is an alteration closely related to the progression of AD and although it is present in multiple neurodegenerative diseases, the pathophysiological events that characterize neuroinflammatory processes vary depending on the disease. In this article, we focus on mRNA and non-coding RNA alterations as part of the pathophysiological events characteristic of neuroinflammation in AD and the influence of these alterations on the course of the disease through interaction with multiple RNAs related to the generation of Aß, pTau, and neuroinflammation itself.

The impact of subchronic hypercaloric and restriction diets on sexual behavior, serum testosterone, and prostate histology in rats.

The role of diet in health is crucial, with calorie intake playing a significant role. Hypercaloric diets (HD) often lead to adipose tissue accumulation and increased risk of chronic diseases, including reproductive impairments. By contrast, restriction diets (RD) help with weight loss, improve cardiovascular function, and ameliorate reproduction. Herein we sought to investigate the impact of subchronic HD and RD on body weight, sexual behavior, serum testosterone and prostate histology in rats. Hence, 10-week old male rats gained sexual experience during five trials with ovariectomized, hormone-primed females. Then at postnatal week PW15 the males were organized in three groups, depending on the feeding they received until PW18: HD, RD and standard diet (SD). During PW19-22 they were tested for sexual behavior, and at PW23 were euthanized for prostate histology (hematoxylin & eosin stain) and hormone analysis. Results indicated that HD males increased their body weight (16-23%) compared to SD and RD. Furthermore, HD males showed 65% less testosterone than RD males. The prostate of HD males revealed histological alterations, including a notable increase in epithelium height and other abnormal features, while no changes were observed in the performance of sexual behavior between HD and RD, although HD appeared to facilitate ejaculation when compared to SD. The histological features of RD males were comparable to SD males. Accordingly, we argue that subchronic modifications in calorie intake can alter body weight (in HD), serum testosterone levels (HD and RD in opposite directions), and prostate histology (in HD), while having no immediate effect on male sexual behavior.

Potential drugs for the treatment of Alzheimer's disease.

It is well known that amyloid precursor protein (APP), the enzyme ß-secretase 1 (BACE1), cyclooxygenase 2 (COX-2), nicastrin (NCT), and hyperphosphorylated tau protein (p-tau) are closely related to the development of Alzheimer's disease (AD). In addition, recent evidence shows that neuroinflammation also contributes to the pathogenesis of AD. Although the mechanism is not clearly known, such inflammation could alter the activity of the aforementioned molecules. Therefore, the use of anti-inflammatory agents could slow the progression of the disease. Nimesulide, resveratrol, and citalopram are three anti-inflammatory agents that could contribute to a decrease in neuroinflammation and consequently to a decrease in the overexpression of APP, BACE1, COX-2, NCT, and p-Tau, as they possess anti-inflammatory effects that could regulate the expression of APP, BACE1, COX-2, NCT, and p-Tau of potent pro-inflammatory markers indirectly involved in the expression of APP, BACE1, NCT, COX-2, and p-Tau; therefore, their use could be beneficial as preventive treatment as well as in the early stages of AD.

Involvement of the PRL-PAK1 Pathway in Cancer Cell Migration.

Prolactin (PRL) is a polypeptide hormone synthesized in the lactotrophs of the adenohypophysis and in extrahypophyseal glands (such as the prostate and breasts) where it promotes their development. PRL is also involved in cancer development in these glands. It has been shown to stimulate cancer cell migration, suggesting its possible involvement in metastasis, in which cell migration plays an essential role. However, the role of PRL in cell migration is still unclear. Moreover, the intracellular mechanisms activated by PRL to carry out cell migration are less well understood. PRL exerts its effects via the PRL receptor (PRLR), which leads intracellularly to phosphorylation of Janus protein kinase 2 (JAK2), which in turn phosphorylates p21-activated protein kinase (PAK1), leading to an increase in cell migration. Although several studies have described the involvement of the PRL-PAK1 pathway in breast cancer cell migration, the molecular mechanisms have not been fully elucidated and there is no integration of these into signaling pathways. This study was conducted based on literature search of review articles and original research in the PubMed database, using the following keywords: PRL, cell migration, PRL and cell migration, PAK1 and signaling pathways. The aim of this review article was to describe the major signaling pathways controlled by PRL-PAK1 and propose a comprehensive model of the signaling pathways associated with PRL-PAK1.

Structure-Based Virtual Screening of Sterols and Triterpenoids Isolated from Ganoderma (Agaricomycetes) Medicinal Mushrooms Shows Differences in Their Affinity for Human Glucocorticoid and Mineralocorticoid Receptors.

An extensive database of sterols and triterpenoids isolated from Ganoderma mushrooms was evaluated by in silico structure-based virtual screening to determine their respective ligand affinities for the glucocorticoid or mineralocorticoid receptor (GCR or MNR). The main ligands for GCR in our database were ergosta-7,22-dien-3-one (compound 1) and ganodermaside B (compound 2), while the best ligands for MNR were 2ß,3α,9α-trihydroxyergosta-7,22-diene (compound 8) and 5α-ergosta-7,22-dien-3ß-ol (compound 3). The binding free energy (BFE) values calculated for such metabolites were similar to those of the natural ligands for each receptor (i.e., dexamethasone for GCR and aldosterone for MNR). Moreover, the differences between mean BFE values calculated for both receptors suggest that ergosta-7,22-dien-3-one (compound 1), ganodermaside B (compound 2), fungisterol (compound 5), ganoderic acid Ma (compound 9), and cerevisterol (compound 10) might be used as specific ligands for GCR, with a significantly lower affinity for MNR. Finally, it is worth noting that even though this work is exclusively theoretical, the reported bioactivities (either pro- or anti-inflammatory) for those metabolites that were previously studied are consistent with our findings, suggesting that the well-known immunomodulatory effect of Ganoderma triterpenoids and sterols might be attributed, at least partially, to their ability to act as specific GCR ligands.

Ergosterol exerts a differential effect on AR-dependent LNCaP and AR-independent DU-145 cancer cells.

Androgen-dependent LNCaP and androgen-independent DU-145 cells, were treated with different concentrations of ergosterol (15 µM and 25 µM) and its respective cell viability was measured by MTT bioassay. While ergosterol showed an antiproliferative effect on LNCaP, on DU-145 promoted cell proliferation. This differential effect suggests that the effect of ergosterol might be related to its ability to act as an Androgen Receptor ligand. In silico Molecular Dynamics simulations were performed to analyze the interaction mechanism between androgen receptor and ergosterol, in comparison with natural ligands, 5α-dihydrotestosterone and testosterone. Our model suggests that the binding of androgen receptor with ergosterol is thermodinamically feasible, which is concordant with our experimental results.

Razor scrape assay, an alternative variation to wound and healing assays.

Cell migration is the process by which cells move through tissues, and it is crucial to carry out a wide variety of physiological and pathological processes. The study methods to evaluate cell migration are very useful tools for biomedical research. Among these methods, the wound and healing assay is one of the simplest, most economical and is widely used in research. However, one of its disadvantages is that the width and shape of the wound can vary among experimental samples since the scraping is carried out manually, representing a difficult variable to control. In the present article a variant of the razor scrape assay is addressed, which eliminates this variation in the width of the wound, thus facilitating the measurement and comparison using the total area of cell migration.•A method that can be carried out under standard culture conditions.•Avoids the disadvantage of variation in width and shape of the wound.•It constitutes a simple, cheap option and multiple advantages over the traditional method.

Observational study of people infected with SARS-Cov-2, treated with amantadine.

BACKGROUND: We conducted an observational study of 15 patients from a Southeastern area of Mexico with symptoms compatible with SARS-Cov-2, which were treated with the antiviral amantadine. METHODOLOGY: In this study, data were collected from 15 individuals with clinical symptoms of COVID-19 infection, which were treated on an ambulatory basis with 100 mg of amantadine for a period of 14 days. RESULTS: This drug demonstrated its effectiveness, as patients recovered successfully with this treatment without the necessity of attending a hospital to use mechanical ventilation. All patients developed IgG antibodies to SARS-Cov-2. CONCLUSION: Amantadine can be used as a viable and cost-effective alternative for treating people with severe acute respiratory syndrome (SARS-Cov-2) on an ambulatory basis, while the vaccine is not available.

Quantification of neural and hormonal receptors at the prostate of long-term sexual behaving male rats after lesion of pelvic and hypogastric nerves.

Prostate function is regulated by androgens and a neural control via the pelvic and hypogastric nerves. As such, this sexual gland contains receptors for acetylcholine and noradrenaline, although it is unknown whether the expression of these receptors is affected by sexual behavior and even less by denervation of the gland. Thus, the purpose of this work was to evaluate the effect of repeated sexual behavior on the expression of noradrenaline, acetylcholine, and androgen receptors at the prostate, and how they are affected by denervation. To achieve this, we used sexually experienced males denervated at the pelvic or hypogastric nerves, or both. The messenger (mRNA) and protein for androgen, noradrenergic, and cholinergic receptors were evaluated. The weight of the gland and the levels of serum testosterone were also measured. We found that: (1) sexual behavior was not affected by denervation; (2) blood testosterone levels increased due to sexual behavior but such increase is prevented by denervation; (3) the weight of the ventral prostate increased with sexual behavior but was not affected by denervation; (4) AR messenger levels increased with sexual behavior but were not altered by denervation; (5) the messenger for noradrenergic and cholinergic receptors decreased after denervation, and those for muscarinic receptors increased, and (6) only AR protein decreased after denervation of both nerves, while those for other receptors remained unchanged. In summary, we show that the three receptors have different regulatory mechanisms, and that only androgen receptors are regulated by both autonomic systems.

Molecular Dynamics and Virtual Screening Analysis of Lanosterol Derivatives from Ganoderma Medicinal Mushrooms (Agaricomycetes) as Selective Ligands of Human Androgen Receptor.

Male sex hormones such as testosterone and dihydrotestosterone play important roles in several physiological and pathological processes. The biological activities of the aforementioned metabolites are mediated by the multidomain androgen receptor (AR), which is therefore a well-studied drug target. Ganoderma mushroom lanostanoid extracts have previously been shown to exert antiandrogenic activity; therefore, this work aims to identify which lanostane derivatives might act as selective ligands for AR. Because protein flexibility is of paramount importance for ligand binding, different conformations of AR were sampled to account for binding modes within a ligand binding site, then subjected to virtual screening against a metabolite library. Fifteen Ganoderma lanostanoids were selected as AR ligands, according to their calculated binding affinity to this nuclear receptor. The results show the relevance of certain structural and chemical aspects of our ligands, such as the presence of a ketonic group on C-3, which influences the process through which they bind to AR.

Abeta(1-42) induces abnormal alternative splicing of tau exons 2/3 in NGF-induced PC12 cells.

Protein tau plays a pivotal role in the pathophysiology of Alzheimer's disease, where its hyperphos-phorylation promotes aggregation and microtubule destabilization. Tau undergoes alternative splicing which generates six isoforms in the human brain, due to inclusion/exclusion of exons 2, 3 and 10. Dysregulation of the splicing process of tau exon 10 is sufficient to cause tauopathy and has shown to be influenced by beta-amyloid peptides, but splicing of other exons is less studied. We studied the effects of beta-amyloid(42) in the alternative splicing of tau exons 2/3 and 6, using untreated and Nerve Growth Factor-induced PC12 cells. Beta-amyloid exposure caused formed cell processes to retract in differentiated cells and altered the expression of exons 2/3 in both undifferentiated and differentiated cells. Expression of exon 6 was repressed in undifferentiated cells only. Our results suggest that beta-amyloid interferes with the splicing process of exons 2/3, favoring their exclusion and thus the expression of immature tau isoforms that are less efficient in stabilizing microtubules and may also be more prone to hyperphosphorylation. The molecular mechanism for this amyloid-tau interaction remains to be determined, but may have potential implications for the understanding of the underlying neuropathological processes in Alzheimer's disease.

Rehabilitating a brain with Alzheimer's: a proposal.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, originating sporadically in the population aged over 65 years, and advanced age is the principal risk factor leading to AD development. In spite of the large amount of research going on around the globe and all the information now available about AD, there is still no origin or triggering process known so far. Drugs approved for the treatment of AD include tacrine, donepezil, rivastigmine, galantamine, and memantine. These may delay or slow down the degenerative process for a while, but they can neither stop nor reverse its progression. Because that this might be due to a lack of effect of these drugs on degenerating neurons, even when they are able to potentiate the brain in nondegenerative conditions, we propose here an alternative therapy consisting of initial repair of neuronal membranes followed by conventional drug therapies. The rehabilitation of neurons in a degeneration process would enable the drugs to act more effectively on them and improve the effects of treatment in AD patients.

Enfermedad de Alzheimer: inmunidad y diagnóstico / Alzheimer’s disease: immunity and diagnosis

Introducción. La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo de evolución lenta que presenta deterioro cognitivo, pérdida progresiva de la memoria y trastornos en la conducta. El principal factor de riesgo es la edad avanzada. Actualmente, no existe cura para esta enfermedad, por lo que se ha hecho importante el esfuerzo por descubrir métodos de diagnóstico más temprano y de fácil acceso, y tratamientos más efectivos. esarrollo. A escala global se están realizando numerosas investigaciones centradas en la prevención, diagnóstico y tratamiento de la EA. Aquí se revisan los principales aspectos involucrados en el proceso patológico de la enfermedad, con un enfoque en los cambios que generan una respuesta inmune y los posibles marcadores diagnósticos propuestos. Conclusiones. Hoy en día se cuenta con numerosa información sobre la EA; sin embargo, aún es importante continuar la investigación que permita mejorar la calidad de vida de estos pacientes mediante diagnósticos más tempranos y precisos y tratamientos más adecuados (AU)

Introduction. Alzheimer’s disease is a slowly progressing neurodegenerative disease that presents cognitive impairment, progressive loss of memory and conduct disorders. The main risk factor is advanced age. There is currently no cure for this disease and, consequently, important efforts have been made to describe readily accessible methods that allow it to be diagnosed earlier, as well as more effective treatments. Development. A great amount of research focused on the prevention, diagnosis and treatment of Alzheimer’s disease is being carried out around the world. In this study we review the main aspects involved in the pathological process of the disease, with emphasis on the changes that generate an immune response and the possible diagnostic markers that have been proposed. Conclusions. Today, a large body of information on Alzheimer’s disease is available. Nevertheless, it is still important to continue with research that allows these patients to improve their quality of life by means of earlier and more accurate diagnoses, as well as more appropriate treatments (AU)

[Alzheimer's disease: immunity and diagnosis]. / Enfermedad de Alzheimer: inmunidad y diagnostico.

INTRODUCTION: Alzheimer's disease is a slowly progressing neurodegenerative disease that presents cognitive impairment, progressive loss of memory and conduct disorders. The main risk factor is advanced age. There is currently no cure for this disease and, consequently, important efforts have been made to describe readily accessible methods that allow it to be diagnosed earlier, as well as more effective treatments. DEVELOPMENT: A great amount of research focused on the prevention, diagnosis and treatment of Alzheimer's disease is being carried out around the world. In this study we review the main aspects involved in the pathological process of the disease, with emphasis on the changes that generate an immune response and the possible diagnostic markers that have been proposed. CONCLUSIONS: Today, a large body of information on Alzheimer's disease is available. Nevertheless, it is still important to continue with research that allows these patients to improve their quality of life by means of earlier and more accurate diagnoses, as well as more appropriate treatments.