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Role of B vitamins in modulating homocysteine and metabolic pathways linked to brain atrophy: Metabolomics insights from the VITACOG trial.
INTRODUCTION: Elevated total homocysteine (tHcy) is a major predictor of brain atrophy, cognitive decline, and Alzheimer's disease (AD) progression. The VITACOG trial, a randomized, placebo-controlled study in mild cognitive impairment (MCI), previously showed that B vitamin supplementation lowered tHcy, slowing brain atrophy and cognitive decline; however, the underlying mechanisms remained unclear. METHODS: We used untargeted, multi-platform metabolomics, with nuclear magnetic resonance and liquid chromatography-mass spectrometry to analyze serum samples from 89 B vitamin-treated and 84 placebo-treated MCI participants over a 2 year follow-up period. RESULTS: Multivariate modeling distinguished treated from placebo groups with 91.2 ± 1.8% accuracy. B vitamin supplementation induced significant metabolic reprogramming, lowering quinolinic acid, α-ketoglutarate, α-ketobutyrate, glucose, and glutamate. DISCUSSION: These findings reveal that B vitamins influence metabolic pathways beyond tHcy reduction, particularly the tricarboxylic acid cycle and glutamine-glutamate cycling, critical for brain energy homeostasis and neurotransmission. This metabolic signature supports B vitamin supplementation as a strategy for slowing MCI progression. HIGHLIGHTS: Nuclear magnetic resonance and multi-platform liquid chromatography tandem mass spectrometry metabolomics were performed on serum samples from 89 B vitamin-treated and 84 placebo participants in the VITACOG trial. Multi-platform metabolomics revealed B vitamin-driven metabolic reprogramming, achieving 91% classification accuracy. B vitamin supplementation modulates key neuroprotective metabolic pathways. Regulation of energy metabolism and neurotransmission by B vitamins contributes to brain health in elderly individuals. B vitamins demonstrate potential as an adjunct therapy in mild cognitive impairment, potentially mitigating progression to Alzheimer's disease.
Comparative Neuroplasticity in Frontal- and Lateral-Eyed Mammals With Induced-Binocular Vision Dysfunction: Insights From Monocular Deprivation Models.
Visual cortical plasticity during early postnatal life is profoundly shaped by species-specific ocular anatomy and ecological demands. This review synthesizes comparative evidence on how monocular deprivation (MD)-a classical model of amblyopia-affects visual system development in frontal- versus lateral-eyed mammals. Frontal-eyed species, including cats and primates, exhibit extensive binocular field overlaps and columnar architecture in the primary visual cortex (V1), making them highly susceptible to MD-induced shifts in ocular dominance and synaptic remodeling. In contrast, lateral-eyed species such as rodents and ungulates possess limited binocular overlaps and lack well-defined ocular dominance columns yet still demonstrate significant MD-induced plasticity involving callosal reorganization, glial activation, and extracellular matrix remodeling. We examine shared and divergent cellular mechanisms underpinning these responses, including the role of parvalbumin-expressing interneurons, perineuronal nets, and neuromodulators like BDNF and NRG1. Rodent models support the notion that even in the absence of classical columnar organization, lateral-eyed species can undergo region-specific structural remodeling in V1 following MD. These distinctions underscore how binocular integration circuits are fine-tuned through extended critical periods in frontal-eyed species, whereas plasticity in lateral-eyed species is more diffusely distributed. The integration of cross-species data revealed conserved principles of visual cortical plasticity and identified mechanisms potentially targetable for amblyopia therapy. Understanding the ecological and anatomical context of plasticity allows for a more accurate interpretation of animal models and supports the development of precision strategies for visual rehabilitation. This comparative framework expands the scope of amblyopia research and offers new avenues for translational interventions.
Elevated Acetylation of MFN2 is Accompanied by the Disruption of Mitochondrial Energy Metabolism and Inflammation in a Mouse Model of Depression.
Mitofusin-2 (MFN2) is recognized as an important regulator of mitochondrial function. The activity of MFN2 is increased by deacetylation, but while MFN2 levels have been reported to be increased in major depressive disorder, the relationship between acetylation status of MFN2, mitochondrial energy production, and inflammation in depression-like disease in rodents has not been studied. Here, we induced a depression-like syndrome in mice with a 14-day-long chronic restraint stress (CRS) model, and the levels of acetylated MFN2 and SIRT1 activity were measured. The interaction of MFN2 with complex I was identified by immunoprecipitation, and the levels of mitochondrial metabolites were measured by GC-MS. MFN2 levels were unaltered by CRS, but SIRT1 expression and activity were reduced in the CRS-exposed mice, and levels of acetylated MFN2 were significantly increased. CRS affected mitochondrial energy metabolism by reducing the expression and activity of complexes I-V, decreasing levels of NAD+ and ATP synthase, and diminishing ATP production. Thus, while the expression of Mfn2 was unchanged by CRS, the inhibition of MFN2 deacetylation, via loss of SIRT1 activity, was associated with impaired mitochondrial oxidative phosphorylation, increased oxidative stress markers, and increased levels of inflammatory markers under the control of the SIRT1 target NFκB. The results presented here highlight the profound influence of acetylation/deacetylation-mediated control associated with depression-like behaviors.
Thio-NHS esters are non-innocent protein acylating reagents.
N-Hydroxysuccinimide (NHS)-ester derivatives are widely used reagents in biological chemistry and chemical biology. Their efficacy relies critically on the exclusive chemoselectivity of activated acyl over that of the imidic acyl moieties in the succinimide. Here, through systematic structural variation that modulates acyl reactivity, coupled with a statistically controlled ultra-rapid screen for unknown modifications in tandem mass spectra as well as lysine profiling across complex lysine environments, including those within proteomes containing many thousands of proteins, we reveal that ring-opening to afford N-succinamide derivatives is a present, sometimes dominant, side-reaction. The extent of side-reaction is shown to be site-dependent, with side-reaction and desired reaction occurring within the same protein substrate. The resulting formation of bioconjugates with unintended, unstable linkages and modifications suggests the re-evaluation of: (i) known commercial reagents; and (ii) functional conclusions previously drawn using NHS esters in areas as diverse as antibody-drug biotherapy, vaccination and cross-link-enabled structural analyses.
Circadian rhythms in metabolism and mental health: a reciprocal regulatory network with implications for metabolic and neuropsychiatric disorders
Circadian rhythms orchestrate metabolism and brain function, aligning internal physiological processes with the 24-hour day–night cycle. Growing evidence highlights a reciprocal relationship between circadian regulation, metabolism, and neurobiological processes. Circadian disruption impairs glucose and lipid homeostasis, alters neurotransmitter and endocrine signalling, and triggers stress response, forming a feedback loop that impacts metabolism and brain function. These disturbances are implicated in many conditions, such as obesity, diabetes, depression, and bipolar disorder. This review examines recent advances in the interplay between circadian regulation, metabolism, and mental health, emphasising shared molecular mechanisms and their role in disease progression. Understanding these connections may ultimately inform therapeutic strategies that integrate circadian-based approaches to improve treatments for metabolic and psychiatric disorders.
Evidence that 5-HT2A receptor signalling efficacy and not biased agonism differentiates serotonergic psychedelic from non-psychedelic drugs.
BACKGROUND AND PURPOSE: Serotonergic psychedelic drugs are under investigation as therapies for various psychiatric disorders, including major depression. Although serotonergic psychedelic drugs are 5-HT2A receptor agonists, some such agonists are not psychedelic, potentially due to differences in 5-HT2A receptor ligand bias or signalling efficacy. Here, we investigated 5-HT2A receptor signalling properties of selected psychedelic and non-psychedelic drugs. EXPERIMENTAL APPROACH: Gq-coupled (Ca2+ and IP1) and β-arrestin2 signalling effects of six psychedelic drugs (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe and DOI) and three non-psychedelic drugs (lisuride, TBG and IHCH-7079) were characterised using SH-SY5Y cells expressing human 5-HT2A receptors. Ligand bias and signalling efficacy were measured using concentration-responses curves, compared with 5-HT. The generality of findings was tested using rat C6 cells which express endogenous 5-HT2A receptors. KEY RESULTS: In SH-SY5Y cells, all psychedelic drugs were partial agonists at both 5-HT2A receptor signalling pathways and none showed significant ligand bias. In comparison, the non-psychedelic drugs were not distinguishable from psychedelic drugs in terms of ligand bias properties but exhibited the lowest 5-HT2A receptor signalling efficacy of all drugs tested. The latter result was confirmed in C6 cells. CONCLUSION AND IMPLICATIONS: In summary, all psychedelic drugs tested were unbiased, partial 5-HT2A receptor agonists. Importantly, the non-psychedelic drugs lisuride, TBG and IHCH-7079 were discriminated from psychedelic drugs, not through ligand bias but rather by low efficacy. Therefore, low 5-HT2A receptor signalling efficacy may explain why some 5-HT2A receptor agonists are not psychedelic, although a larger panel of drugs should be tested to confirm this idea.
P21-Activated Kinase 2 as a Novel Target for Ventricular Tachyarrhythmias Associated with Cardiac Adrenergic Stress and Hypertrophy.
Ventricular arrhythmias associated with cardiac adrenergic stress and hypertrophy pose a significant clinical challenge. We explored ventricular anti-arrhythmic effects of P21-activated kinase 2 (Pak2), comparing in vivo and ex vivo cardiomyocyte-specific Pak2 knockout (Pak2cko) or overexpression (Pak2ctg) murine models, under conditions of acute adrenergic stress, and hypertrophy following chronic transverse aortic constriction (TAC). Pak2 was downregulated 5 weeks following the latter TAC challenge. Cellular physiological, optical action potential and Ca2+ transient, measurements, demonstrated increased incidences of triggered ventricular arrhythmias, and prolonged action potential durations (APD) and altered Ca2+ transients with increases in their beat-to beat variations, in Pak2cko hearts. Electron microscopic, proteomic, and molecular biological methods revealed a mitochondrial localization of stress-related proteins on proteomic and phosphoproteomic analyses, particularly in TAC stressed Pak2cko mice. They further yielded accompanying evidence for mitochondrial oxidative stress, increased reactive oxygen species (ROS) biosynthesis, reduced mitochondrial complexes I-V, diminished ATP synthesis and elevated NADPH oxidase 4 (NOX4) levels. Pak2 overexpression and the novel Pak2 activator JB2019A ameliorated these effects, enhanced cardiac function and decreased the frequencies of triggered ventricular arrhythmias. Pak2 activation thus protects against ventricular arrhythmia associated with cardiac stress and hypertrophy, through unique mechanisms offering potential novel therapeutic anti-arrhythmic targets.
p21-Activated Kinases Present a New Drug Target for Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM), primarily involving mutations in sarcomeric proteins, is the most common form of inherited heart disease and a leading cause of sudden death in young adults and athletes. HCM patients present with cardiac hypertrophy, fibrosis, and diastolic dysfunction often in a progressive manner. Despite significant progress made in understanding the molecular genetic basis of HCM, there remains a lack of effective and specific treatment for preventing disease progression in HCM. This article first provides an overview of recent progress in understanding the pathogenic basis of disease progression in HCM, in particular dysfunctional calcium handling, mitochondrial impairment, and endoplasmic reticulum stress. This article then analyses the evidence for critical roles of the multifunctional enzymes P21-activated kinase-1 and 2 (Pak1/2) in the heart and our opinion on their therapeutic value as a promising druggable target in pathological hypertrophy and associated ventricular arrhythmias.
Clinically relevant niclosamide concentrations modulate TMEM16A and CaV1.2 channels to control artery tone and capillary diameter
AbstractBackground and PurposeTMEM16A Ca2+‐gated Cl− channels mediate depolarisation of contractile vascular cells. The anthelmintic niclosamide was reported to modulate the TMEM16A channel, suggesting possible repurposing for vascular pharmacology. Here, we investigate the mechanism of TMEM16A modulation by niclosamide and explore its effect on the function of a range of vessel types.Experimental ApproachPatch‐clamp electrophysiology, alongside genetically encoded systems to modulate plasmalemmal PIP2 content, was used to define the mechanism of action of niclosamide on the TMEM16A channel. Vascular contractility was investigated using isometric tension recordings of isolated rat arteries and differential interference contrast imaging of capillary diameter in rat brain slices.Key ResultsIn low intracellular free Ca2+ concentrations ([Ca2+]i), clinically relevant niclosamide concentrations inhibited or enhanced heterologous TMEM16A currents at positive or negative membrane potentials (Vm), respectively. In saturating [Ca2+]i, niclosamide inhibited the channel at each Vm tested, independent of plasmalemmal PIP2 levels. Niclosamide caused a transient contraction of isolated aortae and mesenteric and pulmonary arteries but dampened responses to phenylephrine, a Gq protein‐coupled receptor (GqPCR) agonist. Niclosamide reduced brain cortical pericyte constriction evoked by endothelin‐1. Unlike Ani9, a selective TMEM16A inhibitor, niclosamide reduced arterial response to elevated extracellular K+. Niclosamide also inhibited heterologous and native voltage‐gated Ca2+ (CaV) currents in smooth muscle cells.Conclusion and ImplicationsNiclosamide dampened vascular responses to GqPCR stimulation due to concomitant modulation of TMEM16A and CaV channels. Elucidating the molecular pharmacology of niclosamide supports its potential use in disorders of altered vessel tone including stroke, hypertension and vascular dementia.
Increased c-Fos immunoreactivity in anxiety-related brain regions following paroxetine discontinuation.
Selective serotonin reuptake inhibitor (SSRI) therapy cessation often induces a disabling discontinuation syndrome, including increased anxiety. We recently reported that SSRI discontinuation induced behavioural changes in mice, which we hypothesise arose from activated anxiety circuitry. Here, we investigated the effect of discontinuation from the SSRI paroxetine on the expression of the activity-dependent gene c-fos in selected anxiety-related midbrain and forebrain regions. Male mice were injected daily with paroxetine (10 mg/kg) or saline for 12 days, then treatment was either continued or discontinued for two or five days. Mice were then tested on the elevated plus maze (EPM) and tissue collected 90 min later. Brain sections including the dorsal (DRN) and median raphe nucleus, periaqueductal grey, hippocampus, prefrontal cortex, and amygdala were processed for c-Fos immunoreactivity. Two days after paroxetine discontinuation, when mice showed elevated anxiety-like behaviour on the EPM, increased c-Fos immunoreactivity was evident in the DRN and ventral hippocampus, but not in any other region examined, compared to saline-treated controls. Increased c-Fos in the DRN was evident in TPH2-immunopositive neurons as well as neurons doubled-labelled for TPH2 and VGLUT3, suggesting activation of 5-HT-glutamate co-releasing neurons. Five days after paroxetine discontinuation, increased c-Fos immunoreactivity was evident in the DRN, but mice no longer exhibited increased anxiety. These findings suggest that, under these conditions, paroxetine discontinuation is associated with a short-lasting activation of anxiety-promoting circuitry limited to DRN 5-HT neurons and the hippocampus. This circuitry may contribute to symptoms such as anxiety that are a feature of SSRI discontinuation syndrome.
Systematic review and meta-analysis of microbiota-gut-astrocyte axis perturbation in neurodegeneration, brain injury, and mood disorders
Background: Astrocytes are essential for preserving homeostasis, maintaining the blood-brain barrier, and they are a key element of the tripartite neuronal synapse. Despite such multifaceted roles, their importance as contributors to the microbiota-gut-brain axis studies, which typically focus on microglia and neurons, has been largely overlooked. This meta-analysis provides the first systematic review of the microbiota-gut-astrocyte (MGA) axis in vivo, integrating findings across distinct neurological diseases. Methods: A systematic narrative review was conducted per PRISMA guidelines. The search term employed for PubMed was “Microbiota"[MeSH] AND (astrocyte OR glial) NOT (Review[Publication Type]) and for Web of Science, Embase, and Scopus, “Microbio∗ AND (astrocyte OR glial)” with filters applied to exclude review articles. Searches were completed by May 9th, 2024. Data extracted included study models, interventions, and outcomes related to astrocyte biology and rodent behaviour. SYRCLE's risk of bias tool was used to assess individual study designs. Results: 53 studies met the inclusion criteria, covering rodent models of stroke and traumatic (acute) brain injury, chronic neurodegenerative diseases including Alzheimer's and Parkinson's disease and other heterogeneous models of cognitive impairment and affective disorders. Significant heterogeneity in methodology was observed between studies. Five studies had a high risk of bias, and 15 were low risk. Astrocyte biology, typically measured by GFAP expression, was increased in neurodegeneration and acute brain injury models but varied significantly in mood disorder models, depending on the source of stress. Common findings across diseases included altered gut microbiota, particularly an increased Bacteroidetes/Firmicutes ratio and compromised gut barrier integrity, linked to increased GFAP expression. Faecal microbiota transplants and microbial metabolite analyses suggested a direct impact of the gut microbiota on astrocyte biology and markers of neuroinflammation. Conclusions: This review and meta-analysis describes the impact of the gut microbiota on astrocyte biology, and argues that the MGA axis is a promising therapeutic target for neurological disorders. However, it is clear that our understanding of the relationship between the gut microbiota and astrocyte behaviour is incomplete, including how different subtypes of astrocytes may be affected. Future studies must adopt new, multi-dimensional studies of astrocyte function and dysfunction, to elucidate their role in disease and explore the therapeutic potential of gut microbiota modulation.