Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis

Astrocytes have emerged as critical elements for the maintenance and function of the central nervous system. The expression on their cell membrane of RAGE and TLR4 receptors makes astrocytes susceptible to High-mobility group box 1 (HMGB1), a nuclear protein typically released in the extracellular milieu by living cells experiencing physiological stress conditions or by damaged cells. Here, we show that the interaction of HMGB1 with normal spinal cord astrocytes induces the astrocytic production of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Multiple investigations suggest a role for HMGB1 in amyotrophic lateral sclerosis (ALS). Yet, no mechanistic information on the implication of HMGB1 signaling in this disorder is currently available. We demonstrate that non-transgenic and transgenic SOD1WT spinal motor neurons exhibit only a basal nucleus-to-cytoplasm shuttling of the HMGB1 protein. Conversely, in SOD1G93A ALS mouse spinal cords, HMGB1 significantly translocates from the nucleus to the cytoplasm of motor neurons, thereby suggesting that it may be eventually released in the extracellular environment during the progression of the disease. We postulate that extracellular HMGB1 can paracrinally interact with the neighboring astrocytes in an attempt to counteract the neurodegenerative process. Yet, at variance with normal cells, SOD1G93A-expressing astrocytes show impaired capacity to raise BDNF and GDNF levels upon HMGB1 stimulation. Our data suggest that HMGB1 have a potential to promote neuroprotective actions by healthy astrocytes. However, this neurotrophic response is disrupted in ALS astrocytes. This indicates that diseased astroglial cells may exacerbate motor neuron degeneration in ALS because of the loss of their neurosupportive functions

The BH4 domain of Bcl-XL rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals

Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1G93A mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP3)-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP3 can prompt IP3 receptor (IP3R)-mediated Ca2+ release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca2+ signaling that occurs downstream of mGluR5 in hSOD1G93A-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca2+ concentrations ([Ca2+]i) in the absence of spontaneous oscillations. The interaction of IP3Rs with the anti-apoptotic protein Bcl-XL was previously described to prevent cell death by modulating intracellular Ca2+ signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-XL, fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca2+ oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1G93A mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for AL

Biofumigation experiences in Argentina

Artículo publicado en el sitio de Harper Adams University. Centre for Integrated Pest Management. International Biofumigation Network recopila información del uso de la biofumigación en cultivos hortícolas en distintas regiones de nuestro país.EEA San PedroFil: Mitidieri, Mariel Silvina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Peralta, Romina. Universidad Nacional de Rosario; ArgentinaFil: Barbieri, Martín Osvaldo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Brambilla, María Virginia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Piris, Estela Beatriz. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Sasia, Fabiana. Profesional actividad privada; ArgentinaFil: Obregón, Verónica Gabriela. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bella Vista; ArgentinaFil: Vasquez, Pablo Antonio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Alto Valle; ArgentinaFil: Reybet, Graciela. Universidad Nacional del Comahue; ArgentinaFil: Baron, Claudio. Corporación del Mercado Central de Buenos Aires; Argentina

Biofumigation Experiences in Argentina : Short Report

Biofumigation experiences in Argentina have been held along a wide territory, and have proved to be much more effective when combined with solarization. These practices have been successfully implemented, allowing the disinfection of soils in a sustainable manner and the improvement of their physical, chemical and biological properties. In Corrientes a subtropical province specialized in off season production, incorporation of chicken and cattle manure into the greenhouse soil prior to solarization was effective against Ralstonia solanacearum, Pythium aphanidermatum, Rhizoctonia solani and Sclerotium rolfsii, other biofumigants essayed were pine tree fallen leaves, grass, cabbage and sorghum. In the centre of Argentina, horticultural and ornamental crops are grown under mild winter climate. Biosolarization (biofumigation + solarization) was effective controlling Pyrenochaeta lycopersici, Fusarium solani, Sclerotium rolfsii and Sclerotinia sclero tiorum, weeds and damping off pathogens, as well as nematodes like Nacobbus aberrans, Helycotylenchus and Criconemella. The amendments used were chicken manure, broccoli, sorghum, tomato and pepper crop debris, mustard, rapeseed and Brassica campestris. At the west of the country, in Mendoza a province with arid and continental weather, summer is hot, and good control of strawberry diseases as Phytophthora, Rhizoctonia, Phytium, Verticilium, Macrophomina, and nematodes as Meloidogyne, Ditylenchus has been achieved using rapeseed as fumigant in the greenhouse. In Bahía Blanca, a city at the south of Buenos Aires province with a colder weather Meloidogyne hapla was controlled using cattle manure and cauliflower in spring and summer in the greenhouse, nematode s of the same genus were controlled in winter using Melia azedarach seeds as fumigant. At the North of Patagonia, a semiarid region with hot summers but very cold winters, weeds in onion open field nurseries were controlled in summer using chicken manure and cabbage. Similar results were obtained at the northwest of Rio Negro province, were weeds were controlled using cabbage in spring for open field tomato crops. In the same province Fusarium oxysporum in onion was controlled using cabbage in autumn and summer.EEA San PedroFil: Mitidieri, Mariel Silvina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Peralta, Romina. Universidad Nacional de Rosario; ArgentinaFil: Barbieri, Martín Osvaldo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Brambilla, María Virginia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Piris, Estela Beatriz. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Obregón, Verónica Gabriela. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bella Vista; ArgentinaFil: Vásquez, Pablo Antonio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Alto Valle; ArgentinaFil: Iriarte, Liliana. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; ArgentinaFil: Reybet, Graciela. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; ArgentinaFil: Barón, Claudio. Universidad de Buenos Aires. Facultad de Agronomía; ArgentinaFil: Cuellas, Marisol Virginia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Área Metropolitana de Buenos Aires. Agencia de Extensión Rural La Plata; ArgentinaFil: Garbi, Mariana. Universidad Nacional de Luján. Departamento de Tecnología; ArgentinaFil: Martínez, Susana. Universidad Nacional del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Amoia, Rita Paula. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Área Metropolitana de Buenos Aires. Agencia de Extensión Rural La Plata; ArgentinaFil: Delmazzo, Pablo Ricardo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Área Metropolitana de Buenos Aires. Agencia de Extensión Rural La Plata; ArgentinaFil: Sordo, María Del Huerto. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Agencia de Extensión Rural Monte Vera; ArgentinaFil: Adlercreutz, Enrique. INTA, Estación Experimental Agropecuaria Balcarce, Agencia de Extensión Mar del Plata, ArgentinaFil: Puerta, Analia Veronica. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Floricultura; ArgentinaFil: Puerta, Analia Veronica. Universidad Nacional de Luján. Departemento de Tecnología; Argentin

Contemporary lipid-lowering management and risk of cardiovascular events in homozygous familial hypercholesterolaemia: insights from the Italian LIPIGEN Registry

Aims: The availability of novel lipid-lowering therapies (LLTs) has remarkably changed the clinical management of homozygous familial hypercholesterolaemia (HoFH). The impact of these advances was evaluated in a cohort of 139 HoFH patients followed in a real-world clinical setting. Methods and results: The clinical characteristics of 139 HoFH patients, along with information about LLTs and low-density lipoprotein cholesterol (LDL-C) levels at baseline and after a median follow-up of 5 years, were retrospectively retrieved from the records of patients enrolled in the LIPid transport disorders Italian GEnetic Network-Familial Hypercholesterolaemia (LIPIGEN-FH) Registry. The annual rates of major atherosclerotic cardiovascular events (MACE-plus) during follow-up were compared before and after baseline. Additionally, the lifelong survival free from MACE-plus was compared with that of the historical LIPIGEN HoFH cohort. At baseline, LDL-C level was 332 ± 138 mg/dL. During follow-up, the potency of LLTs was enhanced and, at the last visit, 15.8% of patients were taking quadruple therapy. Consistently, LDL-C decreased to an average value of 124 mg/dL corresponding to a 58.3% reduction (Pt < 0.001), with the lowest value (∼90 mg/dL) reached in patients receiving proprotein convertase subtilisin/kexin type 9 inhibitors and lomitapide and/or evinacumab as add-on therapies. The average annual MACE-plus rate in the 5-year follow-up was significantly lower than that observed during the 5 years before baseline visit (21.7 vs. 56.5 per 1000 patients/year; P = 0.0016). Conclusion: Our findings indicate that the combination of novel and conventional LLTs significantly improved LDL-C control with a signal of better cardiovascular prognosis in HoFH patients. Overall, these results advocate the use of intensive, multidrug LLTs to effectively manage HoFH

Exploring Novel Molecular Targets for the Treatment of High-Grade Astrocytomas Using Peptide Therapeutics: An Overview

Diffuse astrocytomas are the most aggressive and lethal glial tumors of the central nervous system (CNS). Their high cellular heterogeneity and the presence of specific barriers, i.e., blood–brain barrier (BBB) and tumor barrier, make these cancers poorly responsive to all kinds of currently available therapies. Standard therapeutic approaches developed to prevent astrocytoma progression, such as chemotherapy and radiotherapy, do not improve the average survival of patients. However, the recent identification of key genetic alterations and molecular signatures specific for astrocytomas has allowed the advent of novel targeted therapies, potentially more efficient and characterized by fewer side effects. Among others, peptides have emerged as promising therapeutic agents, due to their numerous advantages when compared to standard chemotherapeutics. They can be employed as (i) pharmacologically active agents, which promote the reduction of tumor growth; or (ii) carriers, either to facilitate the translocation of drugs through brain, tumor, and cellular barriers, or to target tumor-specific receptors. Since several pathways are normally altered in malignant gliomas, better outcomes may result from combining multi-target strategies rather than targeting a single effector. In the last years, several preclinical studies with different types of peptides moved in this direction, providing promising results in murine models of disease and opening new perspectives for peptide applications in the treatment of high-grade brain tumors

Withaferin A Inhibits Nuclear Factor-κB-Dependent Pro-Inflammatory and Stress Response Pathways in the Astrocytes

Several lines of evidence suggest that astrocytes play a key role in modulating the immune responses of the central nervous system (CNS) to infections, injuries, or pathologies. Yet, their contribution to these processes remains mostly elusive. Astroglia are endowed with a wide range of toll-like receptors (TLR) by which they can sense infectious agents as well as endogenous danger signals released by damaged cells. Here we demonstrate that the activation of astrocytic TLR4 by bacterial lipopolysaccharide (LPS) challenge can promote nuclear factor κB (NF-κB)-dependent induction of pro-inflammatory and stress response mediators, particularly Tumor Necrosis Factor α (TNFα), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). Since the steroid lactone Withaferin A was described to inhibit NF-κB activity in different cell types, we next determined the impact of this natural compound towards the identified astrocytic signalling pathway. Innate immune activation was induced by stimulation of the LPS/TLR4 axis in spinal cord astrocytes. We provide evidence that both pre-treating and post-treating the cells with Withaferin A attenuate astrocytic NF-κB activity as well as the consequent production of TNFα, COX-2, and iNOS induced by stimulation of the LPS/TLR4 pathway. This study suggests that Withaferin A may be an eligible candidate for the treatment of neuroinflammatory and stress conditions characterized by an important astrocytic input

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down or halt neurodegeneration. Yet, in the last few years, our knowledge of the importance of glial cells to maintain the central nervous system homeostasis in health conditions has increased exponentially, along with our awareness of their fundamental and multifaced role in pathological conditions. Among glial cells, astrocytes emerge as promising therapeutic targets in various neurodegenerative disorders. In this review, we present the latest evidence showing the astonishing level of specialization that astrocytes display to fulfill the demands of their neuronal partners as well as their plasticity upon injury. Then, we discuss the controversies that fuel the current debate on these cells. We tackle evidence of a potential beneficial effect of cell therapy, achieved by transplanting astrocytes or their precursors. Afterwards, we introduce the different strategies proposed to modulate astrocyte functions in neurodegeneration, ranging from lifestyle changes to environmental cues. Finally, we discuss the challenges and the recent advancements to develop astrocyte-specific delivery systems