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- ÍtemSmall molecules to perform big roles: The search for Parkinson's and Huntington's disease therapeutics(2023) Pérez, Rodrigo; Cisternas, Marisol; Sepúlveda, Denisse; Troncoso, Paulina; Vidal, ReneNeurological motor disorders (NMDs) such as Parkinson's disease and Huntington's disease are characterized by the accumulation and aggregation of misfolded proteins that trigger cell death of specific neuronal populations in the central nervous system. Differential neuronal loss initiates the impaired motor control and cognitive function in the affected patients. Although major advances have been carried out to understand the molecular basis of these diseases, to date there are no treatments that can prevent, cure, or significantly delay the progression of the disease. In this context, strategies such as gene editing, cellular therapy, among others, have gained attention as they effectively reduce the load of toxic protein aggregates in different models of neurodegeneration. Nevertheless, these strategies are expensive and difficult to deliver into the patients' nervous system. Thus, small molecules and natural products that reduce protein aggregation levels are highly sought after. Numerous drug discovery efforts have analyzed large libraries of synthetic compounds for the treatment of different NMDs, with a few candidates reaching clinical trials. Moreover, the recognition of new druggable targets for NMDs has allowed the discovery of new small molecules that have demonstrated their efficacy in pre-clinical studies. It is also important to recognize the contribution of natural products to the discovery of new candidates that can prevent or cure NMDs. Additionally, the repurposing of drugs for the treatment of NMDs has gained huge attention as they have already been through clinical trials confirming their safety in humans, which can accelerate the development of new treatment. In this review, we will focus on the new advances in the discovery of small molecules for the treatment of Parkinson's and Huntington's disease. We will begin by discussing the available pharmacological treatments to modulate the progression of neurodegeneration and to alleviate the motor symptoms in these diseases. Then, we will analyze those small molecules that have reached or are currently under clinical trials, including natural products and repurposed drugs.
- ÍtemGABAergic Regulation of Astroglial Gliotransmission through Cx43 Hemichannels(2022) Jiménez, Ivanka; Reyes, Rachel; Lemunao, Yordan; Cárdenas, Kevin; Castro, Raimundo; Peña, Francisca; Lucero, Claudia; Prieto, Juan; Retamal, Mauricio; Orellana, Juan; Stehberg, JimmyGamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. It is produced by interneurons and recycled by astrocytes. In neurons, GABA activates the influx of Cl- via the GABAA receptor or efflux or K+ via the GABAB receptor, inducing hyperpolarization and synaptic inhibition. In astrocytes, the activation of both GABAA and GABAB receptors induces an increase in intracellular Ca2+ and the release of glutamate and ATP. Connexin 43 (Cx43) hemichannels are among the main Ca2+-dependent cellular mechanisms for the astroglial release of glutamate and ATP. However, no study has evaluated the effect of GABA on astroglial Cx43 hemichannel activity and Cx43 hemichannel-mediated gliotransmission. Here we assessed the effects of GABA on Cx43 hemichannel activity in DI NCT1 rat astrocytes and hippocampal brain slices. We found that GABA induces a Ca2+-dependent increase in Cx43 hemichannel activity in astrocytes mediated by the GABAA receptor, as it was blunted by the GABAA receptor antagonist bicuculline but unaffected by GABAB receptor antagonist CGP55845. Moreover, GABA induced the Cx43 hemichannel-dependent release of glutamate and ATP, which was also prevented by bicuculline, but unaffected by CGP. Gliotransmission in response to GABA was also unaffected by pannexin 1 channel blockade. These results are discussed in terms of the possible role of astroglial Cx43 hemichannel-mediated glutamate and ATP release in regulating the excitatory/inhibitory balance in the brain and their possible contribution to psychiatric disorders.
- ÍtemOtotoxicity Induced by Platinum-Based Chemotherapy(2022) Cortés, Ignacio; Retamal, Mauricio; Gormaz, JuanPlatinum-based treatments can trigger ototoxicity during cancer treatment. Patients commonly develop bilateral, irreversible sensorineural hearing loss, which is especially critical in the pediatric population, requiring long-term follow-up due to potential detrimental hearing-loss effects on language and social development. The prevalence of ototoxicity following platinum-based chemotherapy in this group is not well established, but incidences as high as 90% have been reported. Among the adult population, it has been reported that up to 80% of patients may develop ototoxicity. Thus, this condition may be an important cause of decreasing quality of life in cancer survivors. From a clinical point of view, ototoxicity induced by platinum-based chemotherapy exhibits auditory manifestations as well as vestibular symptoms and tinnitus. Ototoxicity can clinically manifest within hours to days following the first chemotherapy cycle or even years after treatment. High-frequency hearing loss typically occurs first, and it can evolve to involve middle frequencies in a dose-dependent manner. Mechanistically, platinum-based chemotherapy induced ototoxicity is mainly caused from the production of pathological levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. Clinically controversial data have been obtained from several trials and thus have increased interest in the development of strategies to protect patients from ototoxicity without altering the anticancer effects of platinum-based treatments.
- ÍtemPromoting the Participation of “Hard-to-Reach” Migrant Populations in Qualitative Public Health Research during the COVID-19 Pandemic in Chile(2023) Blukacz, Alice; Cabieses, Báltica; Obach, Alexandra; Carreño, Alejandra; Álvarez, María; Madrid, Paula; Rada, IsabelThe COVID-19 pandemic has further deepened socioeconomic and health inequities worldwide, especially among populations experiencing social vulnerability, such as international migrants. Sustained lockdowns and social distancing have raised challenges to conducting public health research with hard-to-reach populations. This study aims at exploring strategies to recruit “hard-to-reach” international migrants for qualitative public health research during the pandemic in Chile, based on the authors’ experience. A retrospective qualitative evaluation process was carried out on the recruitment processes of three qualitative research projects focused on international migrants in Chile. All projects were implemented during the COVID-19 pandemic, demanding complementary and flexible strategies: (i) social media; (ii) snowball sampling; (iii) referrals from social workers and pro-migrant and migrant-led organizations; (iv) vaccination centers and healthcare centers; and (v) community-based recruitment. The strategies are qualitatively evaluated around seven emerging qualitative categories: (i) feasibility during lockdown periods; (ii) speed of recruitment; (iii) geographical coverage; (iv) sample diversity; (v) proportion of successful interviews; (vi) ethical considerations; and (vii) cost. Engaging hard-to-reach international migrants in public health research during the pandemic required constantly adapting recruitment strategies. Furthermore, relying on strategies that were not only Internet-based promoted the participation of populations with limited access to the Internet and low-digital literacy.
- ÍtemHypertensive Nephropathy: Unveiling the Possible Involvement of Hemichannels and Pannexons(2022) Lucero, Claudia; Prieto, Juan; Marambio, Lucas; Balmazabal, Javiera; Alvear, Tanhia; Vega, Matías; Barra, Paola; Retamal, Mauricio; Orellana, Juan; Gómez, GonzaloHypertension is one of the most common risk factors for developing chronic cardiovascular diseases, including hypertensive nephropathy. Within the glomerulus, hypertension causes damage and activation of mesangial cells (MCs), eliciting the production of large amounts of vasoactive and proinflammatory agents. Accordingly, the activation of AT1 receptors by the vasoactive molecule angiotensin II (AngII) contributes to the pathogenesis of renal damage, which is mediated mostly by the dysfunction of intracellular Ca2+ ([Ca2+]i) signaling. Similarly, inflammation entails complex processes, where [Ca2+]i also play crucial roles. Deregulation of this second messenger increases cell damage and promotes fibrosis, reduces renal blood flow, and impairs the glomerular filtration barrier. In vertebrates, [Ca2+]i signaling depends, in part, on the activity of two families of large-pore channels: hemichannels and pannexons. Interestingly, the opening of these channels depends on [Ca2+]i signaling. In this review, we propose that the opening of channels formed by connexins and/or pannexins mediated by AngII induces the ATP release to the extracellular media, with the subsequent activation of purinergic receptors. This process could elicit Ca2+ overload and constitute a feed-forward mechanism, leading to kidney damage.