Sirtuins and redox signaling interplay in neurogenesis, neurodegenerative diseases, and neural cell reprogramming

Since the discovery of Neural Stem Cells (NSCs) there are still mechanism to be clarified, such as the role of mitochondrial metabolism in the regulation of endogenous adult neurogenesis and its implication in neurodegeneration. Although stem cells require glycolysis to maintain their stemness, they can perform oxidative phosphorylation and it is becoming more and more evident that mitochondria are central players, not only for ATP production but also for neuronal differentiation's steps regulation, through their ability to handle cellular redox state, intracellular signaling, epigenetic state of the cell, as well as the gut microbiota-brain axis, upon dietary influences. In this scenario, the 8-oxoguanine DNA glycosylase (OGG1) repair system would link mitochondrial DNA integrity to the modulation of neural differentiation. On the other side, there is an increasing interest in NSCs generation, from induced pluripotent stem cells, as a clinical model for neurodegenerative diseases (NDs), although this methodology still presents several drawbacks, mainly related to the reprogramming process. Indeed, high levels of reactive oxygen species (ROS), associated with telomere shortening, genomic instability, and defective mitochondrial dynamics, lead to pluripotency limitation and reprogramming efficiency's reduction. Moreover, while a physiological or moderate ROS increase serves as a signaling mechanism, to activate differentiation and suppress self-renewal, excessive oxidative stress is a common feature of NDs and aging. This ROS-dependent regulatory effect might be modulated by newly identified ROS suppressors, including the NAD(+)-dependent deacetylase enzymes family called Sirtuins (SIRTs). Recently, the importance of subcellular localization of NAD synthesis has been coupled to different roles for NAD in chromatin stability, DNA repair, circadian rhythms, and longevity. SIRTs have been described as involved in the control of both telomere's chromatin state and expression of nuclear gene involved in the regulation of mitochondrial gene expression, as well as in several NDs and aging. SIRTs are ubiquitously expressed in the mammalian brain, where they play important roles. In this review we summarize the current knowledge on how SIRTs-dependent modulation of mitochondrial metabolism could impact on neurogenesis and neurodegeneration, focusing mainly on ROS function and their role in SIRTs-mediated cell reprogramming and telomere protection

Heart failure, oxidative stress and allopurinol

Oxidative stress is one of the new and most intriguing pathogenetic hypotheses of heart failure; it involves various mechanisms such as endothelial dysfunction, mechanoenergetic uncoupling and apoptosis. Xanthine oxidase, a key enzyme in purine catabolism, is overexpressed in patients with heart failure, and it is also an important source of oxidizing activity molecules (free radicals, superoxide anion, oxygen peroxide, etc…). Allopurinol competitively inhibits the action of xanthine oxidase and effectively counters oxidative stress. It could thus prove useful in the treatment of heart failure: in fact it is the only drug that has been proven able to lower O2 consumption of dysfunctioning myocardium. The Authors briefly review the xanthine oxido-reductase enzyme system and in particular analyse the latest evidence reported in the literature on allopurinol in the treatment of heart failure

Eosinophilic gastroenteritis: a case report and review of the literature

BackgroundEosinophilic gastroenteritis (EoG) is a rare disease of unknown etiology characterized by patchy or diffuse eosinophilic infiltration of the gastrointestinal tract wall. As clinical presentation and endoscopic/ radiological findings are nonspecific, diagnosis may only be ascertained by histologic findings.Clinical case This article presents a case of EoG with associated colonic involvement but without peripheral eosinophilia. Although no allergy could be demonstrated, the clinical symptoms and histologic pattern of diffuse eosinophilic mucosal infiltration disappeared after steroid therapy, as discovered by a careful endoscopic follow-up.Discussion Current concepts of this complex disorder and a review of the literature are presented

Heart failure with preserved systolic function: prevalence and clinical features in a cohort of patients admitted to internal medicine units. The study PRESYF-HF Tuscany.

Background. There is uncertainty about the prevalence and clinical characteristics of heart failure (HF) patients with preserved systolic function (PRESYF). Aim. To analyze the prevalence and clinical characteristics of patients with PRESYF in an unselected cohort of subjects consecutively hospitalized for HF. Methods. The study cohort included 338 patients consecutively admitted for HF at 24 Internal Medicine units homogeneously settled in Tuscany area (Italy). We did not have any criteria for exclusion. All patients had an echocardiographic measure of left ventricular ejection fraction (LVEF) within 72 hours from hospital admission. Patients with LVEF > 50% were considered to have PRESYF. Results. The patients with PRESYF were 112 (33,1%), those with depressed systolic function (DESYF) 226 (66,9%). In the group PRESYF were prevalent female sex, hypertensive etiology, and elevated BMI. The distribution for classes of age shows a great frequency of PRESYF in the elderly. Conclusion. About one third of patients admitted for HF have a PRESYF. They are different compared to those with DESYF. A correct identification of this form of HF may be important in clinical practice for more targeted therapeutic options and for prognostic implications

Extended flow cytometry characterization of normal bone marrow progenitor cells by simultaneous detection of aldehyde dehydrogenase and early hematopoietic antigens: implication for erythroid differentiation studies

<p>Abstract</p> <p>Background</p> <p>Aldehyde dehydrogenase (ALDH) is a cytosolic enzyme highly expressed in hematopoietic precursors from cord blood and granulocyte-colony stimulating factor mobilized peripheral blood, as well as in bone marrow from patients with acute myeloblastic leukemia. As regards human normal bone marrow, detailed characterization of ALDH⁺cells has been addressed by one single study (Gentry <it>et al</it>, 2007). The goal of our work was to provide new information about the dissection of normal bone marrow progenitor cells based upon the simultaneous detection by flow cytometry of ALDH and early hematopoietic antigens, with particular attention to the expression of ALDH on erythroid precursors. To this aim, we used three kinds of approach: i) multidimensional analytical flow cytometry, detecting ALDH and early hematopoietic antigens in normal bone marrow; ii) fluorescence activated cell sorting of distinct subpopulations of progenitor cells, followed by <it>in vitro </it>induction of erythroid differentiation; iii) detection of ALDH⁺cellular subsets in bone marrow from pure red cell aplasia patients.</p> <p>Results</p> <p>In normal bone marrow, we identified three populations of cells, namely ALDH⁺CD34⁺, ALDH^-CD34⁺and ALDH⁺CD34^-(median percentages were 0.52, 0.53 and 0.57, respectively). As compared to ALDH^-CD34⁺cells, ALDH⁺CD34⁺cells expressed the phenotypic profile of primitive hematopoietic progenitor cells, with brighter expression of CD117 and CD133, accompanied by lower display of CD38 and CD45RA. Of interest, ALDH⁺CD34^-population disclosed a straightforward erythroid commitment, on the basis of three orders of evidences. First of all, ALDH⁺CD34^-cells showed a CD71^bright, CD105⁺, CD45^-phenotype. Secondly, induction of differentiation experiments evidenced a clear-cut expression of glycophorin A (CD235a). Finally, ALDH⁺CD34^-precursors were not detectable in patients with pure red cell aplasia (PRCA).</p> <p>Conclusion</p> <p>Our study, comparing surface antigen expression of ALDH⁺/CD34⁺, ALDH^-/CD34⁺and ALDH⁺/CD34^-progenitor cell subsets in human bone marrow, clearly indicated that ALDH⁺CD34^-cells are mainly committed towards erythropoiesis. To the best of our knowledge this finding is new and could be useful for basic studies about normal erythropoietic differentiation as well as for enabling the employment of ALDH as a red cell marker in polychromatic flow cytometry characterization of bone marrow from patients with aplastic anemia and myelodysplasia.</p

Erectile dysfunction and mobile phone applications: Quality, content and adherence to European Association guidelines on male sexual dysfunction

Introduction: Nowadays numerous mobile health applications (MHA) have been developed to assist and simplify the life of patients affected by erectile dysfunction (ED), however the scientific quality and the adherence to guidelines are not yet addressed and solved. Materials and methods: On 17 January 2022, we conducted a search in the Apple App Store and Google Play Store.We reviewed all mobile apps from iTunes App Store and Google Play Store for ED and evaluated different aspects as well as their usage in screening, prevention, management, and their adherence to EAU guidelines. Results: A total of 18 apps were reviewed. All apps are geared towards the patient and provide information about diagnoses and treatment of ED. Conclusions: MHA represent an integral part of patients' lives, and apps providing services for male sexual dysfunction are constantly increasing. Despite this the overall quality is still low. Although many of these devices are useful in ED, the problems of scientific validation, content, and quality are not yet solved. Further work is needed to improve the quality of apps and developing new accessible, user designed, and high-quality apps

Natural treatments for erectile dysfunction: A focus on mobile health applications

To the Editor, Erectile dysfunction (ED) is defined as the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance. ED represents one of the most important male sexual dysfunctions with a prevalence of 52% and affecting more than 150 million men worldwide (estimated to be 322 million worldwide for 2025) [...

Postural adjustment in experimental leg length difference evaluated by means of thermal infrared imaging

Limb length discrepancy (LLD) is defined as a condition in which limbs are unequal. The asymmetric load of body segments secondary to LLD may cause a tonic contraction of back and lower limb muscles, thus resulting in subtle cutaneous temperature variations. The aim of this study was to test the capability of high-resolution thermal infrared (IR) imaging to measure the cutaneous temperature short-term adaptation, potentially associated with 'forced' LLD conditions. An experimental LLD, obtained by placing a 20 mm foot support under the dominant foot, was used. IR imaging on 18 male healthy volunteers was performed in three experimental conditions of standing position: (T(0)) neutral posture; (T(1)) experimental LLD; (T(2)) neutral posture as in T(0). Temperature variations were evaluated on the cutaneous projection of postural muscles bellies. Significant and specific temperature variations among conditions were ipsilaterally observed on the tibialis anterior, gastrocnemius, quadriceps and latissimus dorsi muscles. Specific patterns characterized the cutaneous temperature as a consequence of the muscle activity associated with the posture variation. IR imaging was able to highlight specific functional activations. The method is non-invasive and it can be repeated without any discomfort for the physiopathological and clinical evaluation of LLD patients

Cytotoxic Effect of Progesterone, Tamoxifen and Their Combination in Experimental Cell Models of Human Adrenocortical Cancer

Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER-β over the ER-α.Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER-α/β signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC50: MUC-1 cells: 67.58 µM (95%CI: 63.22-73.04), ACC115m cells: 51.76 µM (95%CI: 46.45-57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC50: 5.43 µM (95%CI: 5.18-5.69 µM) mainly involving ER-β, as their nuclear localization increased after tamoxifen: Δ A.U. treated vs untreated: 12 h: +27.04% (p < 0.01); 24 h: +36.46% (p < 0.0001). This effect involved the SF-1 protein reduction: Pg: -36.34 ± 9.26%; tamoxifen: -46.25 ± 15.68% (p < 0.01). Finally, in a cohort of 36 ACC samples, immunohistochemistry showed undetectable/low level of ERs, while PgR demonstrated a higher expression. In conclusion, ACC experimental cell models expressed PgR and low levels of ER in line with data obtained in patient tissues, thus limiting the possibility of a clinical approach targeting ER. Interestingly, Pg exerted cytotoxicity also in metastatic ACC cells, although with low potency. Keywords: ACC cell lines; ACC primary cells; adrenocortical carcinoma; estrogen receptors; progesterone receptors; tamoxifen

Premature ejaculation in the era of mobile health application: A current analysis and evaluation of adherence to EAU guidelines

Introduction: Several mobile health applications (MHAs) have been developed to assist and improve the quality of life of patients affected by premature ejaculation, but the scientific quality and adherence to guidelines are not yet addressed. Materials and methods: On 25 May 2022, we conducted a search in the Apple App Store and Google Play Store. We reviewed all mobile apps from Apple App Store and Google Play Store for premature ejaculation and evaluated their usage in screening, prevention, management, and adherence to EAU guidelines. Results: In total 9 MHA were reviewed. All MHAs are geared towards the patient and provide information about diagnoses and treatment of PE. The mean score were 2.87, 3.69, 2.77, 2.55, 2.86 for Engagement, Functionality, Aesthetics, Information, and Subjective quality respectively. MHAs reported low and medium adherence to EAU guidelines. Conclusions: MHAs provide different services in many medical fields, including male sexual dysfunction. Their development is constantly increasing, but the problems of scientific validation, content, and quality are not yet solved. Much future research is necessary to improve the quality of the apps and promote new user designed, and high-quality apps