Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

Hutchinson–Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEThe Progeria Research FoundationMinisterio de Ciencia e Innovaciónpu

Health and social correlates of dementia in oldest-old Mexican-origin populations

Introduction: Substantial gaps in research remain across oldest-old ethnic populations while the burden of dementia increases exponentially with age among Mexican and Mexican American older adults. Methods: Prevalence and correlates of dementia among individuals ≥82 years of age were examined using two population-based cohort studies: The Mexican Health and Aging Study (MHAS, n = 1078, 2012) and the Hispanic Established Populations for the Epidemiologic Study of the Elderly (HEPESE, n = 735, 2012-2013). The analytic MHAS and HEPESE samples had an average age of 86.4 and 88.0 years, 1.2 and 1.8 women to men, and 2.7 and 5.1 average years of education, respectively. Results: We identified 316 (29.2%) and 267 (36.3%) cases of likely dementia in the MHAS and HEPESE cohorts, respectively. For Mexicans but not Mexican Americans, age-adjusted prevalence rates of likely dementia were higher in women than men. For both populations prevalence rates increased with age and decreased with education for Mexican Americans but not for Mexicans. In both populations, odds of likely dementia increased with age. Health insurance for the low-income was significantly associated with higher odds of likely dementia for Mexican American men and women and Mexican women but not men. Living in extended households increased the odds of likely dementia in women, but not in men for both studies. Multiple cardiovascular conditions increased the odds of likely dementia for Mexicans but not for Mexican Americans. Discussion: Our study provides evidence of the high burden of dementia among oldest-old Mexicans and Mexican Americans and its association with health and social vulnerabilities

New Trends in Aging Drug Discovery

Aging is considered the main risk factor for many chronic diseases that frequently appear at advanced ages. However, the inevitability of this process is being questioned by recent research that suggests that senescent cells have specific features that differentiate them from younger cells and that removal of these cells ameliorates senescent phenotype and associated diseases. This opens the door to the design of tailored therapeutic interventions aimed at reducing and delaying the impact of senescence in life, that is, extending healthspan and treating aging as another chronic disease. Although these ideas are still far from reaching the bedside, it is conceivable that they will revolutionize the way we understand aging in the next decades. In this review, we analyze the main and well-validated cellular pathways and targets related to senescence as well as their implication in aging-associated diseases. In addition, the most relevant small molecules with senotherapeutic potential, with a special emphasis on their mechanism of action, ongoing clinical trials, and potential limitations, are discussed. Finally, a brief overview of alternative strategies that go beyond the small molecule field, together with our perspectives for the future of the field, is provided.Depto. de Ingeniería Química y de MaterialesDepto. de Química OrgánicaSección Deptal. de Química Orgánica (Óptica y Optometría)Fac. de Ciencias QuímicasFac. de Óptica y OptometríaTRUEMinisterio de Ciencia e Innovación de Españapu

Do cacti form soil seed banks? An evaluation using species from the Southern Central Andes

There is controversy over whether cactus species form soil seed banks. Although it is commonly assumed that cacti do not form seed banks, very few studies have evaluated them. In this work, we analysed whether cactus species form soil seed banks, studying seed distribution, seed density and seed longevity in the Southern Central Andes. Soil samples were collected in two microhabitats (under nurse plants and in bare areas) at 12 selected sites. We determined seed presence–absence, density and distribution for 32 native cactus species. Seed longevity for six of these species was determined through a burial experiment. We recorded viable seeds for 62.5% of the 32 evaluated species, finding variation in seed density between microenvironments and among populations. In some species, the highest seed density was found under potential nurse plants. Seed germination and seed viability decreased with burial time, with seed longevity always being <24 months after burial. Our results show strong evidence that cactus species do form seed banks. Seed density can vary between microenvironments and among populations, suggesting that cactus–nurse plant associations can also be explained by differential seed dispersal and not only by differential establishment. We found that Echinopsis and Gymnocalycium species form short-term seed banks. Our results will help to better understand the population dynamics of cactus species, a focal species group for conservation actions because many of them are threatened by human activities.Fil: Lindow López, Lucía Teresa. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Escuela de Agronomía. Laboratorio de Investigaciones Botánicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Galindez, Guadalupe. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Escuela de Agronomía. Laboratorio de Investigaciones Botánicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sühring, Silvia Susana. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Escuela de Agronomía. Laboratorio de Investigaciones Botánicas; ArgentinaFil: Pastrana Ignes, Valeria Andrea. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Escuela de Agronomía. Laboratorio de Investigaciones Botánicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gorostiague, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Escuela de Agronomía. Laboratorio de Investigaciones Botánicas; ArgentinaFil: Gutiérrez, Angela Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Escuela de Agronomía. Laboratorio de Investigaciones Botánicas; ArgentinaFil: Ortega Baes, Francisco Pablo. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Escuela de Agronomía. Laboratorio de Investigaciones Botánicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Fetal undernutrition induces resistance artery remodeling and stiffness in male and female rats independent of hypertension

Fetal undernutrition programs hypertension and cardiovascular diseases, and resistance artery remodeling may be a contributing factor. We aimed to assess if fetal undernutrition induces resistance artery remodeling and the relationship with hypertension. Sprague–Dawley dams were fed ad libitum (Control) or with 50% of control intake between days 11 and 21 of gestation (maternal undernutrition, MUN). In six-month-old male and female offspring we assessed blood pressure (anesthetized and tail-cuff); mesenteric resistance artery (MRA) structure and mechanics (pressure myography), cellular and internal elastic lamina (IEL) organization (confocal microscopy) and plasma MMP-2 and MMP-9 activity (zymography). Systolic blood pressure (SBP, tail-cuff) and plasma MMP activity were assessed in 18-month-old rats. At the age of six months MUN males exhibited significantly higher blood pressure (anesthetized or tail-cuff) and plasma MMP-9 activity, while MUN females did not exhibit significant differences, compared to sex-matched controls. MRA from 6-month-old MUN males and females showed a smaller diameter, reduced adventitial, smooth muscle cell density and IEL fenestra area, and a leftward shift of stress-strain curves. At the age of eighteen months SBP and MMP-9 activity were higher in both MUN males and females, compared to sex-matched controls. These data suggest that fetal undernutrition induces MRA inward eutrophic remodeling and stiffness in both sexes, independent of blood pressure level. Resistance artery structural and mechanical alterations can participate in the development of hypertension in aged females and may contribute to adverse cardiovascular events associated with low birth weight in both sexesThis research was funded by Ministerio de Ciencia, Inovación y Universidades (Spain), grant number RTI2018-097504-B-I0

Potential use of chemoprotectants against the toxic effects of cyanotoxins: A review

Cyanobacterial toxins, particularly microcystins (MCs) and cylindrospermopsin (CYN), are responsible for toxic effects in humans and wildlife. In order to counteract or prevent their toxicity, various strategies have been followed, such as the potential application of chemoprotectants. A review of the main substances evaluated for this aim, as well as the doses and their influence on cyanotoxin-induced toxicity, has been performed. A search of the literature shows that research on MCs is much more abundant than research on CYN. Among chemoprotectants, antioxidant compounds are the most extensively studied, probably because it is well known that oxidative stress is one of the toxic mechanisms common to both toxins. In this group, vitamin E seems to have the strongest protectant effect for both cyanotoxins. Transport inhibitors have also been studied in the case of MCs, as CYN cellular uptake is not yet fully elucidated. Further research is needed because systematic studies are lacking. Moreover, more realistic exposure scenarios, including cyanotoxin mixtures and the concomitant use of chemoprotectants, should be considered

Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.This work was supported by grants from The Progeria Research Foundation (PRF 2016-65) and the Spanish MINECO (PID2019-106279RB-I00, PID2019-108489RBI00). The authors thank Fundación La Caixa (A.G.), CEI Moncloa (N.I.M.-R.), MINECO (F.J.O.-N. and M.B.) and Ministerio de Ciencia, Innovación y Universidades (N.K.-F.) for predoctoral fellowships. The authors thank C. López-Otín for kindly donating LmnaG609G/G609G progeroid and their corresponding wild-type fibroblasts and UCM’s CAIs Cytometry and Fluorescence Microscopy, Genomics, NMR, and Mass Spectrometry, for their assistance. The CNIC is supported by the Ministerio de Ciencia e Innovación, the Instituto de Salud Carlos III, and the pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant SEV-2015- 0505). The generation of the antiprogerin antibody was funded by the Wellcome Trust (098291/Z/12/Z to S.N.).S

Immunohistochemical approach to study Cylindrospermopsin distribution in tilapia (Oreochromis niloticus) under different exposure conditions

Cylindrospermopsin (CYN) is a cytotoxic cyanotoxin produced by several species of freshwater cyanobacteria (i.e., Aphanizomenon ovalisporum). CYN is a tricyclic alkaloid combined with a guanidine moiety. It is well known that CYN inhibits both protein and glutathione synthesis, and also induces genotoxicity and the alteration of different oxidative stress biomarkers. Although the liver and kidney appear to be the main target organs for this toxin based on previous studies, CYN also affects other organs. In the present study, we studied the distribution of CYN in fish (Oreochromis niloticus) under two different exposure scenarios using immunohistochemical (IHC) techniques. In the first method, fish were exposed acutely by intraperitoneal injection or by gavage to 200 μg pure CYN/Kg body weight (bw), and euthanized after 24 h or five days of exposure. In the second method, fish were exposed by immersion to lyophilized A. ovalisporum CYN-producing cells using two concentration levels (10 or 100 μg/L) for two different exposure times (7 or 14 days). The IHC was carried out in liver, kidney, intestine, and gills of fish. Results demonstrated a similar pattern of CYN distribution in both experimental methods. The organ that presented the most immunopositive results was the liver, followed by the kidney, intestine, and gills. Moreover, the immunolabeling signal intensified with increasing time in both assays, confirming the delayed toxicity of CYN, and also with the increment of the dose, as it is shown in the sub-chronic assay. Thus, IHC is shown to be a valuable technique to study CYN distribution in these organism

SMARTeaching: Uso de dispositivos móviles en el aula y eficacia de las clases presenciales

Sección Deptal. de Bioquímica y Biología Molecular (Biológicas)Fac. de Ciencias BiológicasFALSEsubmitte

Identifying Triggers of Alcohol Craving to Develop Effective Virtual Environments for Cue Exposure Therapy

Background: Many studies have indicated that alcohol craving is a core mechanism in the acquisition, maintenance, and precipitation of relapse in alcohol use disorder (AUD). A common treatment approach in AUD is cue exposure therapy (CET). New technologies like virtual reality (VR) have the potential to enhance the effectiveness of CET by creating realistic scenarios in naturalistic environments. In this study, we aimed to determine relevant triggers of alcohol craving in patients with AUD. Methods: We enrolled 75 outpatients diagnosed with AUD according to the DSM-5 criteria Participants completed the Alcohol Use Disorder Identification Test and a self-administered questionnaire to assess alcohol craving. The variables included in the craving questionnaire were as follows: presence of others, situations, time of the day, day of the week, mood, and type of alcoholic beverage. Results: Greater levels of alcohol craving were seen in many situations, including being at a party, in a restaurant, in a bar or pub, and at home. Drinking alone and drinking with two or more friends were equally associated with higher levels of craving. Drinking at night and drinking at weekends also emerged as triggers for alcohol craving. Emotional states like anxiety or tension, sadness, stress, frustration, or irritability were highly associated with urges to drink alcohol. The alcoholic drinks most highly associated with increased levels of craving were beer, wine, and whisky. Gender and age implications were discussed. Conclusion: This study is part of a larger project aiming to develop and validate CET based on VR technology for patients with AUD who are resistant to classical treatment. The identified triggers have been used to develop relevant VR environments for CET, and further research is ongoing to implement our findings