The central nervous system (CNS) relies on complex and dynamic interactions between neurons and glial cells. Among glial cells, astrocytes regulate the chemical environment surrounding neurons and supply essential nutrients for brain metabolism whereas microglia, the resident macrophages of the CNS, play critical roles in homeostasis, defense, and responses to injury. Both microglia and astrocytes contribute to the regulation of excitotoxicity and inflammation mediated by the metabolism of tryptophan (Trp) via the kynurenine pathway. Trp metabolism generates several bioactive metabolites, including quinolinic acid (QUIN) and kynurenic acid (KYNA), which have opposing effects. QUIN, produced by activated microglia, acts as an agonist for NMDA receptors; excessive stimulation of these receptors can lead to excitotoxicity and neuronal death. Conversely, KYNA, primarily produced by astrocytes via kynurenine 2,3-aminotransferases (KAT), acts as an NMDA receptor antagonist, conferring neuroprotection by mitigating excitotoxicity. Dysregulation of the Trp metabolism is implicated in many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis, as well as in various neuropsychiatric disorders. This review examines the cellular and molecular mechanisms underlying Trp metabolism in glial cells, highlighting the unique contributions of each glial phenotype, the implications for CNS pathologies, and the potential biomarkers and therapeutic targets for restoring homeostasis and preventing disease progression.

The progression of chronic obstructive pulmonary disease (COPD) is characterized by functional changes in the airways. The lung–gut axis and gut microbiota (GM) have been linked to the pathophysiology of airway diseases. Regarding COPD, studies have shown that GM alterations could be related the stages of this disease. However, the relationship between GM and clinical, biochemical and immunological parameters in patients with COPD are not well understood. The aim of this study was to compare the relative abundance of specific groups of beneficial gut bacteria between COPD patients and healthy controls (CTLs) in order to evaluate relationships with metabolic and inflammatory markers in COPD. Methods: We included 16 stable COPD patients and 16 healthy volunteer CTLs. The relative abundances of Bifidobacterium spp. (Bf) and Akkermansia muciniphila (Akk) bacteria and the Bacteroidetes and Firmicutes phyla were assessed by qPCR. Pulmonary function was evaluated by spirometry, biochemical parameters by colorimetric methods and plasma cytokine levels by cytometric bead array analysis. Results: The Firmicutes/Bacteroides ratio was related to emergency hospital visits and six-minute walk test (6MWT) results. Furthermore, the relative abundance of Bf was associated with plasma concentrations of glucose, triglycerides, HDL-C and IL-10. In addition, Firmicutes levels and the Firmicutes/Bacteroidetes ratio were associated with the IL-12/IL-10 ratio, while Akk abundance was linked to IL-12 levels. Conclusions: The present findings suggest that the abundance of beneficial bacteria in the GM could influence clinical presentation and immunoregulation in COPD.

The imbalance between the overproduction of reactive species and antioxidant mechanisms can result in astrogliosis and oxidative stress associated with neurodegeneration. Based on the described antioxidant activity of naturally occurring flavonoids, this study evaluated the antioxidant mechanisms of the flavonoid naringenin and the senecioic acid ester derivatives in cortical astrocytes. Naringenin and (S)-naringenin were purified from Citrus paradisi, and from them 7,4-O-disenecioic ester naringenin, (S)-7,4-O-disenecioic ester naringenin, and 7-O-senecioic ester naringenin were synthesized and tested for antioxidant activity by the free-radical scavenging reaction with DPPH. The flavonoids’ toxicity and glutathione (GS) depletion were determined in rat astrocyte cultures; the effects on the astrocytes’ reactivity was determined by the expression of the glial fibrillary acidic protein (GFAP) and by measuring nitric oxide (NO) production in astrocytes treated with lipopolysaccharide (LPS, 1 µg/mL/24 h). The compounds (1–10 μM) presented antioxidant effects, and the (S)-7,4′-O-disenecioic ester naringenin was the most effective. The compounds (1–100 μM) were not toxic to the astrocytes, also promoting an antioxidant effect by increasing GSH. Moreover, naringenin, (S)-7,4′-O-disenecioic ester naringenin, and 7-O-senecioc ester naringenin mitigated the astrocyte reactivity induced by LPS, reducing GFAP expression and NO production. These findings indicate that naringenin and senecioic acid ester derivatives present a pharmacological potential as antioxidant and anti-inflammatory compounds for brain diseases via the modulation of astrocyte response.

Introduction: studies have highlighted the importance of gut microbiota (GM) to the host immune defenses, influencing the hostdevelopment and physiology. Changes in the composition and diversity of GM have been detected in some disease and could beimplicated in the pathophysiological mechanisms of them. Objective: the purpose of this study was to show an overview of thecurrent knowledge about the GM of patients with airway diseases (AD). Methodology: the literature search was performed in fourdatabases, using a combination of the descriptors: “Gastrointestinal Microbiome”, “Gut Microbiome”, “Gut Microbiota”, “Cystic Fibrosis”(CF), “Asthma”, “Pulmonary Hypertension” (HP) and/or “Chronic Obstructive Pulmonary Disease” (COPD). Results: fifteen studieswere herein included: ten of CF and five of asthma. No study about other AD matched the inclusion criteria. In all studies about CF,changes were detected in GM, particularly quantitative and qualitative microbial changes. For asthma, data showed changes in GMalso including a reduction of microbial richness, evenness and diversity and in the Bacteroidetes/Firmicutes ratio. Conclusions: thecurrent data indicate the existence of GM changes in AD. However, due to the few studies for asthma and the lack of investigationson HP and COPD, it was not possible to confirm whether these GM changes are observed in other AD. Furthermore, this review showsthe necessity of more studies in this area to characterize dysbiosis and which alterations are more frequent observed in AD patients.

The cells in the central nervous system (CNS) can adapt to injury and inflammation through structural and functional changes, many of which are mediated by the kynurenine pathway (KP). Studies using glia–neuron co-cultures showed that the biflavonoid agathisflavone (FAB), purified from the leaves of Cenostigma pyramidale Tul., a plant native to the Brazilian caatinga, exerts strong neuroprotective effects. This study evaluated whether agathisflavone (1 µM) modulates these responses in human and murine astrocytes and microglia exposed to inflammatory activation with lipopolysaccharide (LPS, 1 µg/mL), excitotoxic activation of NMDA receptors with quinolinic acid (QUIN, 500 µM), or inhibition of the KP rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) with 1-methyl tryptophan (1-MT, 1.5 μM). Co-treatment with FAB increased astrocyte viability relative to LPS, QUIN, or 1-MT alone, by up to 35% (p < 0.05), while reducing GFAP overexpression and other features of reactive astrogliosis. FAB decreased the proportion of Iba-1⁺ microglia, indicating anti-inflammatory effects. When combined with QUIN or 1-MT, FAB reversed the elevation of iNOS (p < 0.0001) and reduced IL1β upregulation. FAB also modulated KP activity in a cell type-specific manner. In astrocytes, FAB with QUIN or with 1-MT increased IDO activity, whereas in microglia, FAB alone reduced it. In microglia, kynurenine-3-monooxygenase (KMO) expression was significantly increased under FAB+QUIN or FAB+1-MT (p < 0.0001). Finally, astrocyte-conditioned medium from FAB-treated cells increased the viability of neuron-like PC12 cells by up to 40%. Collectively, these findings show that FAB confers cytoprotective and anti-inflammatory actions on glial cells, modulates KP signalling in a context-dependent manner, and supports neuronal survival under neuroinflammatory conditions.

Background/Objectives: Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative condition characterized by neurofibrillary tangles, neuronal loss, cognitive impairment, and accumulation of β-amyloid plaques. Considering the limitations of current treatments, which present adverse effects and only alleviate symptoms without modifying disease progression, there is an urgent need for new therapeutic approaches. This study aimed to investigate the neuroprotective potential of synthetic derivatives of (1E,4E)-1,5-bis[(het)aryl]penta-1,4-dien-3-ones, focusing on the inhibition of the cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), targets directly related to the cholinergic deficit observed in AD. Methods: The compounds were initially synthesized by aldol condensation reactions, with subsequent physicochemical characterization. They were then subjected to in silico assays that demonstrated high binding affinity to the active sites of AChE and BChE. The derivatives were evaluated in vitro for their inhibitory activity on these enzymes and in vivo in an experimental model of AD induced by streptozotocin in Wistar rats. Results: The synthesized derivatives showed favorable predicted interactions with the active sites of AChE and BChE, supporting their potential as cholinesterase inhibitors. In vitro assays demonstrated inhibitory activity against both enzymes, with selected derivatives showing improved activity compared with the parent scaffold. In the in vivo model, treatment with the selected compounds was associated with neuroprotective effects, suggesting preservation of nervous tissue integrity under AD-like conditions. Conclusions: These findings indicate that derivatives may represent promising candidates for further investigation as multitarget agents for AD. The study reinforces the relevance of integrating organic synthesis, molecular modeling, enzymatic assays, and in vivo evaluation in the search for new therapeutic strategies for neurodegenerative diseases.