The Neuroprotective Effect of Erythropoietin on the Optic Nerve and Spinal Cord in Rats with Experimental Autoimmune Encephalomyelitis through the Activation of the Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway.

Experimental autoimmune encephalomyelitis is a demyelinating disease that causes paralysis in laboratory rats. This condition lacks treatment that reverses damage to the myelin sheaths of neuronal cells. Therefore, in this study, treatment with EPO as a neuroprotective effect was established to evaluate the ERK 1/2 signaling pathway and its participation in the EAE model. EPO was administered in 5000 U/Kg Sprague Dawley rats. U0126 was used as an inhibitor of the ERK 1/2 pathway to demonstrate the possible activation of this pathway in the model. Spinal cord and optic nerve tissues were evaluated using staining techniques such as H&E and the Luxol Fast Blue myelin-specific technique, as well as immunohistochemistry of the ERK 1/2 protein. The EPO-treated groups showed a decrease in cellular sampling in the spinal cord tissues but mainly in the optic nerve, as well as an increase in the expression of the ERK 1/2 protein in both tissues. The findings of this study suggest that EPO treatment reduces cellular death in EAE-induced rats by regulating the ERK pathway.

Cathepsin C exacerbates EAE by promoting the expansion of Tfh cells and the formation of TLSs in the CNS.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) mediated by CD4+ T helper (Th) cells, and characterized by immune cell infiltration, demyelination and neurodegeneration, with no definitive cure available. Thus, it is pivotal and imperative to acquire more profound comprehension of the underlying mechanisms implicated in MS. Dysregulated immune responses are widely believed to play a primary role in the pathogenesis of MS. Recently, a plethora of studies have demonstrated the involvement of T follicular helper (Tfh) cells and tertiary lymphoid-like structures (TLSs) in the pathogenesis and progression of MS. Cathepsin C (CatC) is a cysteine exopeptidase which is crucial for the activation of immune-cell-associated serine proteinases in many inflammatory diseases in peripheral system, such as rheumatoid arthritis and septicemia. We have previously demonstrated that CatC is involved in neuroinflammation and exacerbates demyelination in both cuprizone-induced and experimental autoimmune encephalomyelitis (EAE) mouse models. However, the underlying immunopathological mechanism remains elusive. In the present study, we established a recombinant myelin oligodendrocyte glycoprotein 35-55 peptide-induced EAE model using conditional CatC overexpression mice to investigate the effects of CatC on the alteration of CD4+ Th subsets, including Th1, Th2, Th17, Tfh and T regulatory cells. Our findings demonstrated that CatC particularly enhanced the population of Tfh cell in the brain, resulting in the earlier onset and more severe chronic syndrome of EAE. Furthermore, CatC promoted the formation of TLSs in the brain, leading to persistent neuroinflammation and exacerbating the severity of EAE in the chronic phase. Conversely, treatment with AZD7986, a specific inhibitor of CatC, effectively attenuated the syndrome of EAE and its effects caused by CatC both in vivo and in vitro. These findings provide a novel insight into the critical role of CatC in innate and adaptive immunity in EAE, and specific inhibitor of CatC, AZD7986, may contribute to potential therapeutic strategies for MS.

Matrine protects against experimental autoimmune encephalomyelitis through modulating microglial ferroptosis.

Multiple sclerosis (MS) is an inflammatory demyelination neurodegenerative disease of the central nervous system (CNS). Ferroptosis has been implicated in a range of brain disorders, and iron-loaded microglia are frequently found in affected brain regions. However, the molecular mechanisms linking ferroptosis with MS have not been well-defined. The present study seeks to bridge this gap and investigate the impact of matrine (MAT), a herbal medicine with immunomodulatory capacities, on the regulation of oxidative stress and ferroptosis in the CNS of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CNS of EAE mice contained elevated levels of ferroptosis-related molecules, e.g., MDA, LPCAT3 and PTGS2, but decreased expression of antioxidant molecules, including GSH and SOD, GPX4 and SLC7A11. This pathogenic process was reversed by MAT treatment, together with significant reduction of disease severity and CNS inflammatory demyelination. Furthermore, the expression of PTGS2 and LOX was largely increased in microglia of EAE mice, accompanied with increased production of IL-6 and TNF-α, indicating a proinflammatory phenotype of microglia that undergo oxidative stress/ferroptosis, and their expression was significantly reduced after MAT treatment. Together, our results indicate that ferroptosis/inflammation plays an important role in the pathogenesis of CNS autoimmunity, and inhibiting ferroptosis-induced microglial activation/inflammation could be a novel mechanism underlying the therapeutic effects of MAT on CNS inflammatory demyelination in EAE.

Dysregulation of miR-223, miR-146a, and miR-193a Expression Profile in Acute and Chronic Phases of Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice.

Multiple sclerosis (MS) is a chronic autoimmune disease with an unknown etiology. The purpose of this research was to assess miR-223, miR-146a, and miR-193a in acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) mice to consider the possible role of these genes in the pathogenesis of MS. EAE induction was given by myelin oligodendrocyte glycoprotein peptide on female C57BL/6 mice. Clinical scores and other criteria were followed daily until day 21 for the acute group and day 77 for the chronic group. At the end of the course, inflammation and demyelination of the central nervous system (CNS) were assessed by histological analysis. MicroRNA expression levels were assessed by real-time PCR. EAE development attenuated in the chronic group, and histological analysis showed less infiltration and demyelination in the chronic group compared to the acute group. The upper expression of miR-223 is demonstrated in the acute phase of EAE. Moreover, the expression levels of miR-146a and miR-193a decreased in the chronic phase of EAE. MiR-223 showed a highly coordinated elevation in the acute phase both in vivo and in vitro. MiR-146a shares a pathway with miR-223 through effecting IL-6 expression. Further studies are needed to reveal their impact on EAE and possible applications as drug targets and biomarkers.

mRNA-delivery of IDO1 suppresses T cell-mediated autoimmunity.

Indoleamine-2,3-dioxygenase (IDO)1 degrades tryptophan, obtained through dietary intake, into immunoregulatory metabolites of the kynurenine pathway. Deficiency or blockade of IDO1 results in the enhancement of autoimmune severity in rodent models and increased susceptibility to developing autoimmunity in humans. Despite this, therapeutic modalities that leverage IDO1 for the treatment of autoimmunity remain limited. Here, we use messenger (m)RNA formulated in lipid nanoparticles (LNPs) to deliver a human IDO1 variant containing the myristoylation site of Src to anchor the protein to the inner face of the plasma membrane. This membrane-anchored IDO1 has increased protein production, leading to increased metabolite changes, and ultimately ameliorates disease in three models of T cell-mediated autoimmunity: experimental autoimmune encephalomyelitis (EAE), rat collagen-induced arthritis (CIA), and acute graft-versus-host disease (aGVHD). The efficacy of IDO1 is correlated with hepatic expression and systemic tryptophan depletion. Thus, the delivery of membrane-anchored IDO1 by mRNA suppresses the immune response in several well-characterized models of autoimmunity.

Ferritin loss in astrocytes reduces spinal cord oxidative stress and demyelination in the experimental autoimmune encephalomyelitis (EAE) model.

Demyelinating diseases such as multiple sclerosis (MS) cause myelin degradation and oligodendrocyte death, resulting in the release of toxic iron and iron-induced oxidative stress. Astrocytes have a large capacity for iron transport and storage, however the role of astrocytic iron homeostasis in demyelinating disorders is not completely understood. Here we investigate whether astrocytic iron metabolism modulates neuroinflammation, oligodendrocyte survival, and oxidative stress following demyelination. To this aim, we conditionally knock out ferritin in astrocytes and induce experimental autoimmune encephalomyelitis (EAE), an autoimmune-mediated model of demyelination. Ferritin ablation in astrocytes reduced the severity of disease in both the acute and chronic phases. The day of onset, peak disease severity, and cumulative clinical score were all significantly reduced in ferritin KO animals. This corresponded to better performance on the rotarod and increased mobility in ferritin KO mice. Furthermore, the spinal cord of ferritin KO mice display decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes. Correspondingly, the size of demyelinated lesions, iron accumulation, and oxidative stress were attenuated in the CNS of ferritin KO subjects, particularly in white matter regions of the spinal cord. Thus, deleting ferritin in astrocytes reduced neuroinflammation, oxidative stress, and myelin deterioration in EAE animals. Collectively, these findings suggest that iron storage in astrocytes is a potential therapeutic target to lessen CNS inflammation and myelin loss in autoimmune demyelinating diseases.

Assessing the legal, illegal, and gray ornamental trade of the critically endangered helmeted hornbill.

Monitoring wildlife trade dynamics is an important initial step for conservation action and demand reduction campaigns to reduce illegal wildlife trade. Studies often rely on one data source to assess a species' trade, such as seizures or the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) trade data. Each database provides useful information but is often incomplete. Combining information from multiple sources helps provide a more complete understanding of trade. A recent rapid increase in demand for helmeted hornbill (Rhinoplax vigil) casques (a brightly colored, solid keratinous rostrum) led to its uplisting to critically endangered on the International Union for Conservation of Nature Red List in 2015. However, there is little current information on what factors influence trade trends and what current levels of demand are. We combined data from CITES, seizure records, and previously underused, yet abundant, art and antique auction data to examine the global trade in helmeted hornbill casque products (HHPs). Three decades of auction data revealed that 1027 individual HHPs had been auctioned since 1992; total auction sales were over US$3 million from 1992 to 2021. The number of HHPs auctioned was greatest from 2011 to 2014, just after the global art boom (2009-2011), followed by a decline in volume and price. The auction data also revealed 2 possible markets for HHPs: true antique and speculative, defined by era, price, and trade patterns. Trends in illegal trade matched those of the auction market, but legal trade remained consistently low. Combining data sources from legal, illegal, and gray markets provided an overview of the dynamics of illegal trade in an endangered species. This approach can be applied to other wildlife markets to provide a more complete understanding of trade and demand at the market level to inform future demand reduction campaigns.

Análisis del comercio ornamental legal, ilegal y gris del cálao con casco, especie en peligro crítico Resumen El monitoreo de la dinámica del comercio de especies silvestres es un paso inicial importante para las acciones de conservación y las campañas de reducción de la demanda destinadas a reducir el comercio ilegal de especies silvestres. Los estudios suelen basarse en una sola fuente de datos para evaluar el comercio de una especie, como las incautaciones o los datos comerciales de la Convención sobre el Comercio Internacional de Especies Amenazadas de Fauna y Flora Silvestres (CITES). Cada base de datos proporciona información útil, pero a menudo incompleta. La combinación de información procedente de varias fuentes ayuda a comprender mejor el comercio. Un reciente y rápido aumento de la demanda de cascos (un casquete queratinoso, sólido y de colores brillantes) de cálao con casco (Rhinoplax vigil) hizo que en 2015 se incluyera en la Lista Roja de la Unión Internacional para la Conservación de la Naturaleza como especie en peligro crítico. Sin embargo, existe poca información actual sobre los factores que influyen en las tendencias del comercio y cuáles son los niveles actuales de demanda. Combinamos datos de CITES, registros de incautaciones y datos de subastas de arte y antigüedades previamente poco utilizados, aunque abundantes, para examinar el comercio mundial de productos de casquetes de cálao con casco (CCC). Tres décadas de datos de subastas revelaron que se habían subastado 1,027 CCC individuales desde 1992; las ventas totales en subasta superaron los tres millones de dólares entre 1992 y 2021. El número de CCC subastados fue mayor entre 2011 y 2014, justo después del boom del arte (2009­2011), seguido de un descenso en volumen y precio. Los datos de las subastas también revelaron dos posibles mercados para los CCC: el de las verdaderas antigüedades y el especulativo, definidos por la época, el precio y los patrones de comercio. Las tendencias del comercio ilegal coincidieron con las del mercado de subastas, pero el comercio legal se mantuvo bajo con constancia. Con la combinación de fuentes de datos de mercados legales, ilegales y grises, nuestros datos proporcionaron una visión general de la dinámica del comercio ilegal de una especie amenazada. Este enfoque puede aplicarse a otros mercados de especies silvestres para obtener un conocimiento más completo del comercio y la demanda a nivel de mercado que sirva de base a futuras campañas de reducción de la demanda.

Expert assessment of illegal collecting impacts on Venus flytraps and priorities for research on illegal trade.

Illegal collecting of wild Venus flytraps (Dionaea muscipula) for the horticultural trade represents a persistent threat to populations of the species across their endemic range in the coastal plain of North and South Carolina (United States). Although wild collecting of Venus flytraps is not a novel threat, there has been very little research on the impacts of collecting on the species' conservation to date or why an illegal trade persists alongside a legal one. We drew on qualitative expert stakeholder elicitation to contextualize the threat of illegal collecting to the long-term conservation of Venus flytraps in relation to other anthropogenic threats. Expert elicitation included botanical and conservation researchers, cognizant state and federal agency staff, land managers, and conservation nonprofit actors. The workshop included mapping of supply chain structures and prioritization of social and environmental harms. Expert consensus determined illegal collecting is an ongoing problem for Venus flytrap conservation, but habitat destruction, degradation, and fire suppression are the most significant threats to flytrap conservation. Supply chain analysis showed that observable social and environmental harms of the trade are focused at the supply stage and that less is known about transit and demand stages. Key research gaps identified include a lack of understanding of plant laundering practices relevant to a range of desirable plant taxa; the role of commercial nurseries in illicit horticultural supply chains; motivations for engaging in Venus flytrap collecting; and the persistent demand for illegally harvested plants when cultivated, legally obtainable plants are readily available. Our findings and methodology are relevant to a range of ornamental plants affected by illegal trade for which robust social data on illegal collecting drivers are lacking.

Evaluación experta del impacto de la colecta ilegal de venus atrapamoscas y las prioridades de investigación sobre el mercado ilegal Resumen La colecta ilegal de venus atrapamoscas (Dionaea muscipula) silvestres para el mercado de horticultura representa una amenaza constante para las poblaciones de la especie a lo largo de su distribución endémica en la planicie costera de Carolina del Norte y del Sur, Estados Unidos. Aunque esta colecta no es una amenaza novedosa, a la fecha se ha investigado muy poco sobre su impacto en la conservación de la especie o por qué el mercado ilegal persiste a la par del legal. Partimos del conocimiento cualitativo de los actores expertos para contextualizar la amenaza de la colecta ilegal para la conservación a largo plazo de la venus atrapamoscas en relación con otras amenazas antropogénicas. Este conocimiento involucró a investigadores de la conservación y la botánica, personal consciente de agencias federales y estatales y actores de la conservación sin fines de lucro. El taller incluyó el mapeo de las estructuras de las cadenas de suministro y la priorización de los daños sociales y ambientales. El consenso de los expertos determinó que la colecta ilegal es un problema continuo para la conservación de la venus atrapamoscas, pero la destrucción y degradación del hábitat, así como la contención de incendios son las amenazas más significativas. El análisis de las cadenas de suministro mostró que los daños ambientales y sociales observables en el mercado se enfocan en la fase de suministro y que se sabe poco sobre las fases de tránsito y demanda. Los vacíos de investigación más importantes incluyen la falta de entendimiento de las prácticas de lavado de plantas relevantes para un rango de taxones deseables de plantas; el papel de los viveros comerciales en las cadenas de suministro de la horticultura ilícita; los motivos para participar en la colecta de venus atrapamoscas; y la demanda continua de plantas cosechadas ilegalmente cuando ya hay disponibilidad de plantas cultivadas que se obtienen legalmente. Nuestros descubrimientos y metodología son relevantes para una gama de plantas ornamentales afectadas por el mercado ilegal para las cuales hay carencia de datos sociales sólidos sobre los factores de colecta ilegal.

An assessment of potential interventions to reduce the totoaba illegal trade market.

The illegal trade in totoaba (Totoaba macdonaldi) is causing adverse social, ecological, and economic impacts. This illegal activity is accelerating the overexploitation of totoaba and pushing the critically endangered vaquita (Phocoena sinus) closer to extinction. Despite extensive efforts to recover vaquita populations, scant attention has been given to the totoaba trade as an independent issue. As a result, data on the totoaba trade are limited, which hampers robust analyses and development of effective interventions to reduce illegal harvesting. We used a previously developed framework specifically designed to examine dynamics of illegal markets and guide measures to mitigate illegal use of totoaba. This framework separates markets into 3 analytical levels: characterization of participating actors (e.g., fishers, intermediaries); examination of how actors interact within the market (e.g., organization of supply chains); and assessment of the overall market dynamics that result from these interactions (e.g., factors determining price and quantity). We reviewed existing literature (108 initial articles) and interviewed key market actors, academics, and nongovernmental organization experts (14) to obtain data for this framework. Our findings offer an overview of the totoaba illegal market operation, highlighting intervention points (e.g., customs agents) and areas where additional information is required to decrease information gaps (e.g., US local market). We describe the structure and complexity of this market, emphasizing the influential role of organized crime in shaping its dynamics (e.g., controlling prices paid to fishers and stockpiling). By providing a systematic and in-depth understanding of the market operation, we aimed to establish a benchmark for effective interventions and future research aimed at reducing uncertainties. Our results provide a crucial step toward addressing this critical issue and can help facilitate development of effective strategies to combat the illegal totoaba trade and promote biodiversity conservation more broadly.

Evaluación de las intervenciones potenciales para reducir el mercado ilegal de la totoaba Resumen El mercado ilegal de totoaba (Totoaba macdonaldi) causa impactos sociales, ecológicos y económicos adversos. Esta actividad ilegal acelera la sobreexplotación de la totoaba y acerca a la extinción a la vaquita marina (Phocoena sinus), especie en peligro crítico de extinción. A pesar de los grandes esfuerzos por recuperar las poblaciones de vaquita, el comercio de totoaba recibe poca atención como problema independiente. Como resultado, los datos sobre este comercio son limitados, lo que dificulta el análisis sólido y el desarrollo de intervenciones eficaces para reducir la captura ilegal. Utilizamos un marco desarrollado previamente y diseñado específicamente para examinar la dinámica de los mercados ilegales y orientar las medidas para mitigar el uso ilegal de la totoaba. Este marco separa los mercados en tres niveles analíticos: caracterización de los actores participantes (por ejemplo, pescadores, intermediarios); análisis de cómo interactúan los actores dentro del mercado (por ejemplo, organización de las cadenas de suministro); y evaluación de la dinámica general del mercado que resulta de estas interacciones (por ejemplo, factores que determinan el precio y la cantidad). Revisamos la bibliografía existente (108 artículos iniciales) y entrevistamos a actores clave del mercado, académicos y expertos de organizaciones no gubernamentales (14) para obtener datos para este marco. Nuestras conclusiones ofrecen una visión general del funcionamiento del mercado ilegal de totoaba y destacan los puntos de intervención (por ejemplo, los agentes aduanales) y las áreas en las que se requiere información adicional para reducir los vacíos informativos (por ejemplo, el mercado local estadunidense). Describimos la estructura y complejidad de este mercado, destacando el influyente papel de la delincuencia organizada en la configuración de su dinámica (por ejemplo, controlando los precios pagados a los pescadores y el almacenamiento). Al proporcionar una comprensión sistemática y en profundidad del funcionamiento del mercado, pretendemos establecer un punto de referencia para intervenciones eficaces y futuras investigaciones encaminadas a reducir las incertidumbres. Nuestros resultados suponen un paso crucial para abordar esta cuestión crítica y pueden ayudar a facilitar el desarrollo de estrategias eficaces para combatir el comercio ilegal de totoaba y promover la conservación de la biodiversidad de forma más amplia.

Creating a more inclusive approach to wildlife trade management.

Global wildlife trade involves a diverse array of species. Although sustainable trade underpins livelihoods for communities worldwide, unsustainable trade, whether legal or illegal, threatens thousands of species and can lead to extinctions. From plants and fungi to fish, amphibians, mammals, invertebrates, and reptiles, a diverse array of species across taxa are affected by trade. Attention to wildlife trade has increased in recent years, but its focus has largely remained on a narrow range of high-profile species, with taxa deemed less charismatic frequently overlooked, despite some having significant trade volumes and levels of threat to wild populations. These biases can hamper effective policy interventions, reduce awareness of wider threats from trade, and prevent conservation efforts from focusing on the most pressing issues. It is important to broaden the scope of research and policy discussions and create a more inclusive approach to trade management. The diversity of approaches to wildlife trade can be improved by expanding monitoring of trade to a wider variety of taxa; collecting fundamental ecological data to underpin assessments of trade sustainability; improving and codesigning conservation interventions with key stakeholders and trade actors; and developing appropriate strategies for managing the supply, trade, and demand in diverse wildlife products to ensure species and livelihoods are protected.

Creación de un enfoque más inclusivo para la gestión del mercado de vida silvestre Resumen El mercado global de vida silvestre involucra a una diversa gama de especies. Mientras que el mercado sustentable apoya al sustento de las comunidades, el mercado insostenible, sea legal o ilegal, amenaza a miles de especies y puede causar extinciones. Desde plantas y hongos hasta peces, anfibios, mamíferos, invertebrados y reptiles, una diversa gama de especies de diferentes taxones se ve afectada por el mercado. Aunque la atención hacia el mercado de vida silvestre ha aumentado en años recientes, su enfoque ha sido principalmente en especies de perfil elevado, por lo que se suele ignorar a taxones considerados menos carismáticos, a pesar de que algunos cuenten con importantes volúmenes de comercio o niveles de amenaza para las poblaciones silvestres. Estos sesgos pueden complicar las intervenciones políticas eficientes, reducir la conciencia sobre las amenazas mayores del comercio y prevenir que los esfuerzos de conservación se enfoquen en los temas más urgentes. Es importante que se amplíe el objetivo de la investigación y las discusiones políticas y se cree un enfoque más inclusivo para la gestión del mercado. Se puede mejorar la diversidad de enfoques sobre el mercado de vida silvestre con la expansión del monitoreo del mercado hacia una mayor variedad de taxones; la colecta de datos ecológicos fundamentales para sostener los análisis sobre la sustentabilidad del mercado; la mejora y el diseño de las intervenciones de conservación conjuntamente con los actores clave del mercado; y el desarrollo de estrategias adecuadas para la gestión de la oferta, comercio y demanda de diferentes productos de vida silvestre para asegurar que se protejan las especies y el sustento de las comunidades.

Targeting CNS myeloid infiltrates provides neuroprotection in a progressive multiple sclerosis model.

Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11b+ cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach.

Vortioxetine ameliorates experimental autoimmune encephalomyelitis model of multiple sclerosis in mice via activation of PI3K/Akt/CREB/BDNF cascade and modulation of serotonergic pathway signaling.

Multiple sclerosis (MS) is a chronic condition characterized by immune cell infiltration and cytokine overproduction that led to myelin sheath inflammatory assaults, thus causing axonal destruction. The former consequently provokes motor impairment and psychological disorders. Markedly, depression is one of the most prevalent lifelong comorbidities that negatively impacts the quality of life in MS patients. Vortioxetine (VTX), a multi-modal molecule prescribed to manage depression and anxiety disorder, additionally, it displays a promising neuroprotective properties against neurodegenerative diseases such as Alzheimer's and Parkinson's. To this end, the present study investigated the potential therapeutic efficacy of VTX against experimental autoimmune encephalomyelitis (EAE) model of MS in mice. Notably, treatment with VTX significantly ameliorated EAE-induced motor disability, as evident by enhanced performance in open field, rotarod and grip strength tests, alongside a reduction in immobility time during the forced swimming test, indicating a mitigation of the depressive-like behavior; outcomes that were corroborated with histological examinations and biochemical analyses. Mechanistically, VTX enhanced serotonin levels by inhibiting both serotonin transporter (SERT) and indoleamine 2,3-dioxygenase (IDO) enzyme, thereby promoting the activation of serotonin 1A (5-HT1A) receptor. The latter triggered the stimulation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) cascade that entailed activation/phosphorylation of cAMP response element-binding protein (CREB). This activation increased brain derived neurotrophic factor (BDNF) and myelin basic protein (MBP) contents that mitigated demyelination in the corpus callosum. Furthermore, VTX suppressed phospho serine 536 nuclear factor kappa B (pS536 NF-κB p65) activity and reduced tumor necrosis factor-alpha (TNF-α) production. The results underscore VTX's beneficial effects on disease severity in EAE model of MS in mice by amending both inflammatory and neurodegenerative components of MS progression.

Jung, the Rebirth Motif and Psychedelics I: Documenting Jung's Contact with the British Pioneers.

C. G. Jung wrote very little about psychedelic drugs and he took a sceptical view of them. However, he was sufficiently impressed by Aldous Huxley's 1954 account of taking mescaline, The Doors of Perception, to invite Huxley to visit him in Switzerland. Huxley declined Jung's invitation but Huxley's collaborator Humphry Osmond met Jung instead. This paper documents Jung's contact with the British pioneers of psychedelics research and presents the scant material illuminating his views about these drugs. It also determines the efforts of British psychiatrist Ronald Sandison, who was the first to develop an "explicitly Jungian approach" to psychedelic-assisted psychotherapy (Hill, 2013), and it highlights a connection between Sandison's initiative and the Society of Analytical Psychology (SAP) through the involvement of two SAP members: Margot Cutner, Sandison's colleague, and Michael Fordham, who supervised a trainee working with one of Sandison's former patients. Despite Jung's objections to the use of psychedelics, Sandison and Cutner developed ground-breaking protocols during the 1950s and they were among the first to document the phenomenon of "spiritual rebirth symbolized in the birth experience known to many LSD therapists" (Sandison, 2001). In two companion papers, I consider Jung's treatment of the rebirth motif in his commentary on The Tibetan Book of the Dead, which later became a central text in the psychedelic movement, and I chart the evolution in psychedelics research from an association with schizophrenia during the 1950s to the mystical paradigms of the 1960s and beyond.

C.G. Jung a très peu écrit sur les drogues psychédéliques et il avait à leur égard une attitude sceptique. Cependant il fut suffisamment impressionné par le récit d'Aldous Huxley de son expérience avec la mescaline en 1954, Les Portes de la Perception, pour inviter Huxley à lui rendre visite en Suisse. Huxley déclina l'invitation de Jung mais son collaborateur Humphry Osmond rencontra Jung à sa place. Cet article rend compte des contacts de Jung avec les recherches des pionniers britanniques en matière de drogues psychédéliques. Il présente aussi le peu de matériel qui illustre ses opinions concernant ces drogues. L'article explore les efforts du psychiatre britannique Ronald Sandison ­ qui fut le premier à développer une « approche spécifiquement jungienne ¼ à la psychothérapie assistée par des drogues psychédéliques ­ et il souligne un lien entre l'initiative de Sandison et The Society of Analytical Psychology (SAP) par l'implication de deux de ses membres : Margot Cutner, collègue de Sandison, et Michael Fordham, qui supervisa un candidat sur son travail avec un des anciens patients de Sandison. Malgré les objections de Jung sur l'utilisation des drogues psychédéliques, Sandison et Cutner ont développé des protocoles très innovants durant les années 1950 et furent parmi les premiers à documenter le phénomène de la « renaissance spirituelle symbolisée par l'expérience de naissance, bien connue par la plupart des thérapeutes utilisant le L.S.D. ¼ (Sandison, 2001). Dans deux articles apparentés j'examine la manière dont Jung a traité le motif de la renaissance dans son commentaire sur Le Livre des Morts Tibétain, qui devint par la suite un texte central dans le mouvement psychédélique, et je retrace l'évolution dans la recherche sur les drogues psychédéliques à partir d'une association avec la schizophrénie dans les années 1950 et jusqu'aux paradigmes mystiques des années 1960 et au­delà.

C. G. Jung escribió muy poco sobre las drogas psicodélicas y adoptó una postura escéptica hacia ellas. Sin embargo, quedó lo suficientemente impresionado por el relato, Las Puertas de la Percepción, que Aldous Huxley hizo en 1954 en referencia a su consumo de mescalina, como para invitar a Huxley a visitarle en Suiza. Huxley declinó la invitación, pero en su lugar Jung se reunió con Humphry Osmond, colaborador de Huxley. Este artículo documenta el contacto de Jung con los pioneros británicos en investigación psicodélica y presenta el escaso material que da cuenta de las opiniones de estos, sobre dichas drogas. También determina los esfuerzos del psiquiatra británico Ronald Sandison, que fue el primero en desarrollar un "enfoque explícitamente Junguiano" de la psicoterapia asistida por psicodélicos (Hill, 2013), y destaca una conexión entre la iniciativa de Sandison y la Sociedad de Psicología Analítica (SAP) a través de la participación de dos miembros de la SAP: Margot Cutner, colega de Sandison, y Michael Fordham, quien supervisaba a un candidato a analista que trabajaba con uno de los antiguos pacientes de Sandison. A pesar de las objeciones de Jung al uso de psicodélicos, Sandison y Cutner desarrollaron innovadores protocolos durante la década de 1950 y fueron los primeros en documentar el fenómeno del "renacimiento espiritual simbolizado en la experiencia del nacimiento conocida por muchos terapeutas del LSD" (Sandison, 2001). En dos artículos complementarios, considero el tratamiento que Jung da al motivo del renacimiento en su comentario sobre El Libro Tibetano de los Muertos, que más tarde se convirtió en un texto central del movimiento psicodélico, y trazo la evolución de la investigación sobre psicodélicos desde su asociación con la esquizofrenia durante la década de 1950 hasta los paradigmas místicos de la década de 1960 y posteriores.

Phagolysosomal resistance hypothesized to be a danger signal.

Antigen presenting cells sometimes require T cell "help" to kill and decompose microbes they capture, especially when those microbes resist effector molecules including nitric oxide and reactive oxygen species. Pathogens are more likely to resist those effectors, shared by the innate and adaptive immune systems, than are commensals. Does such resistance alert the immune system to the danger posed by those pathogens? Several lines of evidence suggest this occurs. Mouse studies showed a surprising exacerbation, not alleviation of experimental autoimmune encephalomyelitis, by suppression of nitric oxide production, but only when the suppression was applied to animals undergoing vaccination with myelin. In contrast, animals receiving T cells activated by vaccination without suppression of nitric oxide benefitted from reduced autoimmune cytotoxicity when nitric oxide production was suppressed after adoptive transfer. Vaccinia and adenovirus suppress nitric oxide production and have been successful vaccine platforms, also consistent with the above phagolysosomal resistance hypothesis. The hypothesis solves a long-standing quandary-how can nitric oxide protect against both infection and autoimmunity, especially autoimmune diseases for which it seems a major effector? The importance of physical linkage between epitopes, first proposed in Bretscher's Two-Step, Two-Signal theory dependent on B cells, is extended to include phagolysosomal resistance in general, plus a corollary proposition that the immune system detects resistance to dissociation of high-affinity pathogenic ligands from host binding sites to make neutralizing antibodies.

Measuring the performance of Antarctic Treaty decision-making.

Agreements reached at the Antarctic Treaty Consultative Meetings (ATCMs) are among the primary means for addressing Antarctic conservation and environmental protection issues. However, according to contemporary scholars, Antarctic Treaty decision-making is becoming increasingly unresponsive to the rising environmental challenges in the region. We assessed the performance of Antarctic Treaty decision-making by measuring the rate and diversity of decision-making over the last 6 decades. To measure the rate, we counted the number of inputs and outputs of ATCMs and calculated the time taken for legally binding outputs to enter into force. To measure diversity, we calculated the range of topics addressed by the inputs and outputs of ATCMs. The average number of agreements reached per ATCM increased from 1961 to 2022. Although the diversity of Antarctic topics discussed at ATCMs remained consistently high, the diversity of topics on which legally binding agreements were adopted declined significantly. Antarctic issues-including those of highest priority-are now almost entirely dealt with through nonbinding, soft-law agreements. It is plausible that this move away from binding decisions reflects a dynamic governance institution evolving to respond to new pressures. However, we suggest that the change reveals a concerning shift in decision-making behavior and performance, unique to the treaty's history. Soft law is beneficial in some cases, but its overuse diminishes accountability and transparency, significantly reducing the parties' abilities to understand and measure their performance, including the outcomes and impacts of decisions. Although the rate and diversity of ATCM inputs and outputs provide only a partial view of decision-making performance, the exploration of these metrics provides a foundation for asking essential questions about the impacts of Antarctic Treaty governance on the region's environmental protection and conservation.

Medida del desempeño de las decisiones del Tratado Antártico Resumen Los acuerdos logrados en las Reuniones Consultivas del Tratado Antártico (RCTA) son uno de los principales medios para abordar las cuestiones de conservación y protección ambiental de la Antártida. Sin embargo, según los académicos contemporáneos, la toma de decisiones del Tratado Antártico es cada vez menos receptiva a los crecientes retos ambientales de la región. Evaluamos el rendimiento de las decisiones del Tratado Antártico con la medida del ritmo y la diversidad de la toma de decisiones en las últimas seis décadas. Para medir el ritmo, contamos el número de entradas y salidas de las RCTA y calculamos el tiempo que tardan en entrar en vigor los resultados con vinculación jurídica. Para medir la diversidad, calculamos la gama de temas abordados por las entradas y salidas de las RCTA. El número medio de acuerdos alcanzados por cada RCTA aumentó de 1961 a 2022. Sin embargo, mientras que la diversidad de temas antárticos debatidos en las RCTA se mantuvo constantemente alta, la diversidad de temas sobre los que se adoptaron acuerdos con vinculación jurídica disminuyó significativamente. Las cuestiones antárticas ­incluidas las de máxima prioridad­ se abordan ahora casi en su totalidad mediante acuerdos no vinculantes y de derecho indicativo. Es plausible que este alejamiento de las decisiones vinculantes refleje una institución de gestión dinámica que evoluciona para responder a nuevas presiones. Sin embargo, sugerimos que el cambio revela una modificación preocupante en el comportamiento y los resultados de la toma de decisiones, único en la historia del tratado. El derecho indicativo es benéfico en algunos casos, pero su uso excesivo disminuye la responsabilidad y la transparencia, lo que reduce significativamente la capacidad de las partes para comprender y medir su rendimiento, incluidos los resultados y los impactos de las decisiones. Aunque la tasa y la diversidad de las entradas y salidas de las RCTA sólo proporcionan una visión parcial del rendimiento de la toma de decisiones, la exploración de estas métricas proporciona una base para plantear preguntas esenciales sobre los impactos de la gestión del Tratado Antártico para la protección y conservación ambiental de la región.

Impaired olfactory performance and anxiety-like behavior in a rat model of multiple sclerosis are associated with enhanced adenosine signaling in the olfactory bulb via A1R, A2BR, and A3R.

The present study shows that animals with experimental autoimmune encephalomyelitis (EAE) exhibit olfactory dysfunction and impaired general cognitive abilities, as well as anxiety-like behavior. Olfactory dysfunction occurs on average at 2 dpi, well before the onset of the first motor signs of EAE (8-10 dpi). After the initial olfactory dysfunction, the EAE animals show a fluctuation in olfactory performance that resembles the relapsing-remitting course of human MS. The study also shows severe neuroinflammation in the olfactory bulb (OB), with numerous infiltrated CD4+ T cells and peripheral macrophages in the superficial OB layers, marked microgliosis, and massive induction of TNF-α, IL-1ß, and IL-6. Reduced tyrosine hydroxylase activity in the glomerular layer, pronounced granule cell atrophy, and reduced numbers of type B neuroblasts in the rostral migratory stream also indicate altered plasticity of the neuronal network in the OB. Considering the exceptionally high purinome expression in the OB, the possible involvement of purinergic signaling was also investigated. The study shows that macrophages infiltrating the OB overexpress A3R, while highly reactive microglia overexpress the adenosine-producing enzyme eN/CD73 as well as A2BR, A3R, and P2X4R. Given the simultaneous induction of complement component C3, the results suggest that the microglial cells develop a functional phenotype of phagocytizing microglia. The study also demonstrates transcriptional and translational upregulation of A1R in mitral and tufted cells, which likely influence resting network activity in OB and likely contribute to olfactory dysfunction in EAE. Overall, our study shows that olfactory dysfunction and altered social and cognitive behavior in EAE are associated with increased adenosine signaling via A1R, A2BR, and A3R.

atRA Attenuates High Salt-Driven EAE Mainly Through Suppressing Th17-Like Regulatory T Cell Response Mediated by the Inhibition of IL-23R Signaling Pathway.

High salt diet (HSD) is implicated in numerous disorders, which boosts Th17 cell development and weakens immunosuppressive function of regulatory T cells (Treg cells) Treg cells, leading to the exacerbation of EAE. However, little is known regarding the harness of excessive proinflammatory responses evoked by HSD. Here we show that atRA, a key vitamin A metabolite with multifaceted immunoregulatory properties has the potential in inhibiting the proinflammatory reaction of high salt. Treatment with atRA in vivo elicited the Treg generation in cervical and axillary lymph nodes (CALs), and in CNS of experimental autoimmune encephalomyelitis (EAE). Meanwhile, the proportion of Th17-like Treg cells (RORγt-positive or GM-CSF-positive Treg cells) decreased in CALs. atRA also inhibited IL-17A expression in CD4+ effector T cells. In-vitro mechanistic studies showed that atRA inhibit IL-23R but not SGK1 expression in Treg cells and this results in maintained immunosuppressive function of Treg cells even in the presence of IL-6 and high salt. Furthermore, treatment of EAE with anti-IL-23R mAb attenuated HSD-provoked EAE progress. This was associated with a reduction in the number of CNS-infiltrating Th17 cells and an increase of CAL-Treg cells. Mechanically, treatment with atRA significantly promoted LP-CD103+CD11c+ dendritic cells, a subgroup of cells most closely involved in endogenous retinoic acid metabolism, and enhanced intestinal Aldh1a1 and Rdh10 expression from HSD-fed EAE mice. Interestingly, anti-IL-23R mAb administration also reduced IL-23R expression in Treg cells, along with the increased proportion of LP-CD103+CD11c+ dendritic cells and Rdh10 mRNA expression. In conclusion, administration of atRA might be a way to combat the proinflammatory effects of HSD. Meanwhile, systematic inhibition of IL-23R also had a moderate therapeutic potential in inhibiting inflammatory effects of high salt, which may serve as a basis for the identification of novel therapeutic strategies against HSD-driven autoimmune disorders.

Alterations in the Hypothalamic-Pituitary-Adrenal Axis as a Response to Experimental Autoimmune Encephalomyelitis in Dark Agouti Rats of Both Sexes.

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, usually diagnosed during the reproductive period. Both MS and its commonly used animal model, experimental autoimmune encephalomyelitis (EAE), exhibit sex-specific features regarding disease progression and disturbances in the neuroendocrine and endocrine systems. This study investigates the hypothalamic-pituitary-adrenal (HPA) axis response of male and female Dark Agouti rats during EAE. At the onset of EAE, Crh expression in the hypothalamus of both sexes is decreased, while males show reduced plasma adrenocorticotropic hormone levels. Adrenal gland activity is increased during EAE in both males and females, as evidenced by enlarged adrenal glands and increased StAR gene and protein expression. However, only male rats show increased serum and adrenal corticosterone levels, and an increased volume of the adrenal cortex. Adrenal 3ß-HSD protein and progesterone levels are elevated in males only. Serum progesterone levels of male rats are also increased, although testicular progesterone levels are decreased during the disease, implying that the adrenal gland is the source of elevated serum progesterone levels in males. Our results demonstrate a sex difference in the response of the HPA axis at the adrenal level, with male rats showing a more pronounced induction during EAE.

Interleukin-10 contrasts inflammatory synaptopathy and central neurodegenerative damage in multiple sclerosis.

Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing-remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1ß in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients' CSF and EAE mice striatum, IL-10 and IL-1ß expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1ß-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1ß-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS.

The Antidepressant- and Anxiolytic-Like Effects of the Phosphodiesterase Type-5 Inhibitor Tadalafil are Associated with the Modulation of the Gut-Brain Axis During CNS Autoimmunity.

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.