Brain Levels Research Articles

Hepatocyte activation and liver injury following cerebral ischemia promote HMGB1-mediated hepcidin upregulation in hepatocytes and regulation of systemic iron levels

We previously reported that high mobility group box 1 (HMGB1), a danger-associated molecular pattern (DAMP), increases intracellular iron levels in the postischemic brain by upregulating hepcidin, a key regulator of iron homeostasis, triggering ferroptosis. Since hepatocytes are the primary cells that produce hepcidin and control systemic iron levels, we investigated whether cerebral ischemia induces hepcidin upregulation in hepatocytes. Following middle cerebral artery occlusion (MCAO) in a rodent model, significant liver injury was observed. This injury was evidenced by significantly elevated Eckhoff’s scores and increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, total iron levels were significantly elevated in the liver, with intracellular iron accumulation detected in hepatocytes. Hepcidin expression in the liver, which is primarily localized in hepatocytes, increased significantly starting at 3 h after MCAO and continued to increase rapidly, reaching a peak at 24 h. Interestingly, HMGB1 levels in the liver were also significantly elevated after MCAO, with the disulfide form of HMGB1 being the major subtype. In vitro experiments using AML12 hepatocytes showed that recombinant disulfide HMGB1 significantly upregulated hepcidin expression in a Toll-like receptor 4 (TLR4)- and RAGE-dependent manner. Furthermore, treatment with a ROS scavenger and a peptide HMGB1 antagonist revealed that both ROS generation and HMGB1 induction contributed to hepatocyte activation and liver damage following MCAO–reperfusion. In conclusion, this study revealed that cerebral ischemia triggers hepatocyte activation and liver injury. HMGB1 potently induces hepcidin not only in the brain but also in the liver, thereby influencing systemic iron homeostasis following ischemic stroke.

Current Advances and Material Innovations in the Search for Novel Treatments of Phenylketonuria.

Phenylketonuria (PKU) is a genetically inherited disease caused by a mutation of the gene encoding phenylalanine hydroxylase (PAH) and is the most common inborn error of amino acid metabolism. A deficiency of PAH leads to increased blood and brain levels of phenylalanine (Phe), which may cause permanent neurocognitive symptoms and developmental delays if untreated. Current management strategies for PKU consist of early detection through neonatal screening and implementation of a restrictive diet with minimal amounts of natural protein in combination with Phe-free supplements and low-protein foods to meet nutritional requirements. For milder forms of PKU, oral treatment with synthetic sapropterin (BH4), the cofactor of PAH, may improve metabolic control of Phe and allow for more natural protein to be included in the patient's diet. For more severe forms, daily injections of pegvaliase, a PEGylated variant of phenylalanine ammonia-lyase (PAL), may allow for normalization of blood Phe levels. However, the latter treatment has considerable drawbacks, notably a strong immunogenicity of the exogenous enzyme and the attached polymeric chains. Research for novel therapies of PKU makes use of innovative materials for drug delivery and state-of-the-art protein engineering techniques to develop treatments which are safer, more effective, and potentially permanent.

Simulation-based effective comparative analysis of neuron circuits for neuromorphic computation systems

The spiking neural networks (SNN) which are inspired by the human brain offers wider scope for application in the growth of neuromorphic computing systems due to their brain level computational capabilities, reduced power consumption, minimal data movement cost, and among other advantages. Spike-based neurons and synapses are the essential building blocks of SNN, and their efficient implementation is vital to its performance enhancement. In this regard, the design and implementation of spiking neurons have been the major focus among the researchers. In this paper, functioning of different leaky integrate fire (LIF)-based spiking neuron circuits like frequency adaptable CMOS-based LIF, resistor-capacitor-based (RC) LIF, and volatile memristor-based LIF are subjected to comparison. The work mainly focuses on revealing analysis of spike duration and amplitude, number of spikes produced during excitation period, threshold operation, field of application, and various other significant parameters of aforementioned neuron circuits. Extensive simulations of these circuits are carried out utilizing the Cadence Virtuoso simulation environment in order to validate their behavior. Further, a brief comparative analysis is executed considering into account the attributes like circuit complexity, supply voltage, firing rate, membrane capacitance, nature of input/output, refractory mechanism, and energy consumption per spike. This work seeks to assist researchers in selecting an appropriate LIF model to efficiently construct memristors and/or non-memristors based SNN for certain application.

Neuroprotective effects of punicalagin and/or micronized zeolite clinoptilolite on manganese-induced Parkinson's disease in a rat model: Involvement of multiple pathways.

Manganism, a central nervous system dysfunction correlated with neurological deficits such as Parkinsonism, is caused by the substantial collection of manganese chloride (MnCl2) in the brain. To explore the neuroprotective effects of natural compounds, namely, micronized zeolite clinoptilolite (ZC) and punicalagin (PUN), either individually or in combination, against MnCl2-induced Parkinson's disease (PD). Fifty male albino rats were divided into 5 groups (Gps). Gp I was used as the control group, and the remaining animals received MnCl2 (Gp II-Gp V). Rats in Gps III and IV were treated with ZC and PUN, respectively. Gp V received both ZC and PUN as previously reported for the solo-treated plants. ZC and/or PUN reversed the depletion of monoamines in the brain and decreased acetyl choline esterase activity, which primarily adjusted the animals' behavior and motor coordination. ZC and PUN restored the balance between glutamate/γ-amino butyric acid content and markedly improved the brain levels of brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and decreased glycogen synthase kinase-3 beta activity. ZC and PUN also inhibited inflammatory and oxidative markers, including nuclear factor kappa-light-chain-enhancer of activated B cells, Toll-like receptor 4, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 and caspase-1. Bcl-2-associated X-protein and B-cell leukemia/lymphoma 2 protein (Bcl-2) can significantly modify caspase-3 expression. ZC and/or PUN ameliorated PD in rats by decreasing the levels of endoplasmic reticulum (ER) stress markers (p-protein kinase-like ER kinase (PERK), glucose-regulated protein 78, and C/EBP homologous protein (CHOP)) and enhancing the levels of an autophagy marker (Beclin-1). ZC and/or PUN mitigated the progression of PD through their potential neurotrophic, neurogenic, anti-inflammatory, antioxidant, and anti-apoptotic activities and by controlling ER stress through modulation of the PERK/CHOP/Bcl-2 pathway.

GSP1-111 Modulates the Microglial M1/M2 Phenotype by Inhibition of Toll-like Receptor 2: A Potential Therapeutic Strategy for Depression.

Neuroinflammation plays a vital role in neurodegenerative diseases and neuropsychiatric disorders, and microglia and astrocytes chiefly modulate inflammatory responses in the central nervous system (CNS). Toll-like receptors (TLRs), which are expressed in neurons, astrocytes, and microglia in the CNS, are critical for innate immune responses; microglial TLRs can regulate the activity of these cells, inducing protective or harmful effects on the surrounding cells, including neurons. Therefore, regulating TLRs in microglia may be a potential therapeutic strategy for neurological disorders. We examined the protective effects of GSP1-111, a novel synthetic peptide for inhibiting TLR signaling, on neuroinflammation and depression-like behavior. GSP1-111 decreased TLR2 expression and remarkably reduced the mRNA expression of inflammatory M1-phenotype markers, including tumor necrosis factor (TNF)α, interleukin (IL)-1β, and IL-6, while elevating that of the M2 phenotype markers, Arg-1 and IL-10. In vivo, GSP1-111 administration significantly decreased the depression-like behavior induced by lipopolysaccharide (LPS) in a forced swim test and significantly reduced the brain levels of M1-specific inflammatory cytokines (TNFα, IL-1β, and IL-6). GSP1-111 prevented the LPS-induced microglial activation and TLR2 expression in the brain. Accordingly, GSP1-111 prevented inflammatory responses and induced microglial switching of the inflammatory M1 phenotype to the protective M2 phenotype. Thus, GSP1-111 could prevent depression-like behavior by inhibiting TLR2. Taken together, our results suggest that the TLR2 pathway is a promising therapeutic target for depression, and GSP1-111 could be a novel therapeutic candidate for various neurological disorders.

Intranasal Administration of Standardized Extract of Gotu Kola Leaves Against Nitroglycerine-Induced Recurrent Migraine-Like Pain in Rats

The present study aimed to determine the efficacy of intranasal administration of a standardized extract of Gotu kola, i.e., Centella asiatica (L.) Urban (INDCA-NS) with marker triterpenoids for the prevention of nitroglycerine- (NTG)-induced recurrent migraine in rats. Adult rats of both sexes in a group of 12 were administered intraperitoneal NTG (10 mg/kg) on alternate days (D1 to D9) and once daily intranasal solutions of either vehicle (saline, 50 µL/rat/day), sumatriptan (80 µL/rat/day of 12 mg/ml) as positive control, or INDCA-NS (10, 30, or 100 µg/rat/day) for 21 days. Behavioral and biochemical parameters related to concurrent migraine pain (facial expressions on the grimace scale, thermal hyperalgesia, mechanical allodynia, and plasma and brain levels of pituitary adenylate cyclase-activating polypeptide and nitric oxide), and stress (photophobia and cortisol levels in the brain and serum) were measured. The intranasal administration of INDCA-NS prevented NTG-induced migraine-like pain, photophobia, and stress in a dose-dependent manner. At the same time, sumatriptan alleviated pain and anxiety but not photophobia. In conclusion, the intranasal administration of INDCA-NS showed prophylactic efficacy against recurrent NTG-induced migraine pain in rats.

LDHB-deficient brain exhibits resistance to ischemic neuronal cell death due to increased vasodilation

Ischemic stroke triggers a cascade of metabolic and inflammatory events leading to neuronal death, particularly in the hippocampus. Here, we investigate the role of lactate metabolism in ischemic resistance using LDHB-deficient mice, which exhibit impaired lactate utilization. Contrary to expectations of severe neuronal damage due to metabolic defects, LDHB-deficient mice displayed significantly increased neuronal survival following ischemic insult. Magnetic resonance spectroscopy revealed elevated lactate levels in LDHB-deficient brains, which correlated with enhanced vasodilation of the posterior communicating artery (PComA) and increased extracellular PGE2 levels. These findings suggest that elevated lactate inhibits PGE2 reabsorption, promoting vasodilation and neuronal protection. Our results highlight lactate's potential role in neuroprotection and its therapeutic promise for ischemic stroke.

A novel deep learning‐based technique for driver drowsiness detection

AbstractEvery year, many people lose their lives because of road accidents. It is evident from statistics that drowsiness is one of the main causes of a large number of car accidents. In our research, we wish to solve this major problem by measuring the drowsiness level of the human brain while driving. The study aims to develop a novel technique to detect different alertness levels (i.e., awake, moderately drowsy, and maximally drowsy) of a person while driving. A hybrid model using a stacked autoencoder and hyperbolic tangent Long Short‐Term Memory (TLSTM) network with attention mechanism is designed for this purpose. The designed model uses different biopotential signals, such as electroencephalography (EEG), facial electromyography (EMG), and different biomarkers, such as pulse rate, respiration rate galvanic skin response, and head movement to detect a person's alertness level. Here, the stacked autoencoder model is used for automated feature extraction. TLSTM is used to predict a person's alertness level using stacked autoencoder network‐extracted features. The proposed model can classify awake, moderately drowsy, and maximally drowsy states of a person with accuracies of 99%, 98.3%, and 98.6%, respectively. The novel contributions of the paper includes (i) incorporation of an attention mechanism into the TLSTM network of the proposed hybrid model to focus on the emphatic states to enhance classification accuracy, and (ii) utilization of EEG, facial EMG, pulse rate, respiration rate, galvanic skin reaction, and head movement pattern to assess a person's alertness level.

Escape of Kdm6a from X chromosome is detrimental to ischemic brains via IRF5 signaling.

The role of chromatin biology and epigenetics in disease progression is gaining increasing recognition. Genes that escape X chromosome inactivation (XCI) can impact neuroinflammation through epigenetic mechanisms. Our prior research has suggested that the X escapee genes Kdm6a and Kdm5c are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that Kdm6a/5c demethylate H3K27Me3/H3K4Me3 in microglia respectively, and mediate the transcription of interferon regulatory factor 5 (IRF5) and IRF4, leading to microglial pro-inflammatory responses and exacerbated stroke injury. Aged (17-20 months) Kdm6a/5c microglial conditional knockout (CKO) female mice (one allele of the gene) were subjected to a 60-min middle cerebral artery occlusion (MCAO). Gene floxed females (two alleles) and males (one allele) were included as controls. Infarct volume and behavioral deficits were quantified 3 days after stroke. Immune responses including microglial activation and infiltration of peripheral leukocytes in the ischemic brain were assessed by flow cytometry. Epigenetic modification of IRF5/4 by Kdm6a/5c were analyzed by CUT&RUN assay. The demethylation of H3K27Me3 by kdm6a increased IRF5 transcription; meanwhile Kdm5c demethylated H3K4Me3 to repress IRF5. Both Kdm6a fl/fl and Kdm5c fl/fl mice had worse stroke outcomes compared to fl/y and CKO mice. Gene floxed females showed more robust expression of CD68 in microglia, elevated brain and plasma levels of IL-1β or TNF-α, after stroke. We concluded that IRF5 signaling plays a critical role in mediating the deleterious effect of Kdm6a; whereas Kdm5c's effect is independent of IRF5.

Assessing signs of central sensitization: A critical review of physiological measures in experimentally induced secondary hyperalgesia.

Central sensitization (CS) is believed to play a role in many chronic pain conditions. Direct non-invasive recording from single nociceptive neurons is not feasible in humans, complicating CS establishment. This review discusses how secondary hyperalgesia (SHA), considered a manifestation of CS, affects physiological measures in healthy individuals and if these measures could indicate CS. It addresses controversies about heat sensitivity changes, the role of tactile afferents in mechanical hypersensitivity and detecting SHA through electrical stimuli. Additionally, it reviews the potential of neurophysiological measures to indicate CS presence. Four databases, PubMed, ScienceDirect, Scopus and Cochrane Library, were searched using terms linked to 'hyperalgesia'. The search was limited to research articles in English conducted in humans until 2023. Evidence for heat hyperalgesia in the SHA area is sparse and seems to depend on the experimental method used. Minimal or no involvement of tactile afferents in SHA was found. At the spinal level, the threshold of the nociceptive withdrawal reflex (RIII) is consistently reduced during experimentally induced SHA. The RIII area and the spinal somatosensory potential (N13-SEP) amplitude are modulated only with long-lasting nociceptive input. At the brain level, pinprick-evoked potentials within the SHA area are increased. Mechanical pinprick hyperalgesia is the most reliable behavioural readout for SHA, while the RIII threshold is the most sensitive neurophysiological readout. Due to scarce data on reliability, sensitivity and specificity, none of the revised neurophysiological methods is currently suitable for CS identification at the individual level. Gathering evidence for CS in humans is a crucial research focus, especially with the increasing interest in concepts such as 'central sensitization-like pain' or 'nociplastic pain'. This review clarifies which readouts, among the different behavioural and neurophysiological proxies tested in experimental settings, can be used to infer the presence of CS in humans.

Administration of Lacticaseibacillus casei CSL3 in Swiss Mice with Immunosuppression Induced by Cyclophosphamide: Effects on Immunological, Biochemical, Oxidative Stress, and Histological Parameters.

The study aimed to evaluate the effects of supplementation with Lacticaseibacillus casei CSL3 in Swiss mice immunosuppressed with cyclophosphamide on immunological, biochemical, oxidative stress, and histological parameters. The animals were distributed into four groups (control, CSL3, cyclophosphamide, and CSL3 + cyclophosphamide), where two groups were treated with L. casei CSL3 (10 log CFU mL-1) for 30days, and two groups received chemotherapy (days 27 and 30-total dose of 250mgkg-1). Counts of lactic acid bacteria (LAB) and bile-resistant LAB in stool samples; blood count (erythrogram, leukogram, and platelets); serum total cholesterol levels; catalase enzyme activity; and thiobarbituric acid reactive substances (TBARS) levels in liver, kidney, and brain; IL-4 expression; IL-23, TNF-α, NF-κβ in the spleen; and histological changes in the liver, kidneys, and intestine were evaluated. The CSL3 + cyclophosphamide group showed a significant increase in bile-resistant LAB counts in feces (p = 0.0001), leukocyte counts, and expression of IL-23, TNF-α, and NF-κβ (p < 0.05) significantly reduced total cholesterol levels (p = 0.001) and protected liver damage of supplemented animals. For oxidative stress damage, the bacterium did not influence the results. It is concluded that the bacterium is safe at a concentration of 10 log CFU mL-1 and has probiotic potential due to its positive influence on the immune response and lipid metabolism.

The modulatory effect of oat on brain-derived neurotrophic factor, orexigenic neuropeptides, and dopaminergic signaling in obesity-induced rat model: a comparative study to orlistat.

Obesity is a non-communicable complex disease that is the fifth leading cause of death worldwide. According to a novel viewpoint, the brain plays a significant role in the central regulation of satiety and energy homeostasis. Because of its rich nutritional profile and versatile uses, oat (Avena sativa) is one of the most popular functional foods recommended by many nutritionists. The anti-obesity effect of oat was hypothesized, focusing on the brain as the target organ. In the current study, the interplay between brain biomarkers, obesity, and its related complications was evaluated in diet-induced obese rats for 25 weeks, in which 60 adult male white albino Wistar rats were divided into three control and seven treatment groups given oat extracts in a dose-dependent manner. Oat significantly improved obesity-related metabolic complications. In terms of brain function, oat significantly increased dopaminergic signaling, brain-derived neurotrophic factor levels, vaspin, irisin, and uncoupling protein-1 brain levels, while decreasing the expression of agouti-related peptide and neuropeptide Y (P-value < 0.05). The current study proposes oat supplementation as a new conceptual framework with numerous implications for hedonic and homeostatic mechanisms that control satiety. © 2024 Society of Chemical Industry.

Ferulic Acid-Loaded Nanostructure Maintains Brain Levels of ACh, Glutamate, and GABA and Ameliorates Anxiety and Memory Impairments Induced by the D-Galactose Aging Process in Rats.

Population aging is a global reality driven by increased life expectancy. This demographic phenomenon is intrinsically linked to the epidemic of cognitive disorders such as dementia and Alzheimer's disease, posing challenges for elderly and their families. In this context, the search for new therapeutic strategies to prevent or minimize cognitive impairments becomes urgent, as these deficits are primarily associated with oxidative damage and increased neuroinflammation. Ferulic acid (FA), a natural and potent antioxidant compound, is proposed to be nanoencapsulated to target the central nervous system effectively with lower doses and an extended duration of action. Here, we evaluated the effects of the nanoencapsulated FA on d-galactose (d-Gal)- induced memory impairments. Male Wistar adult rats were treated with ferulic acid-loaded nanocapsules (FA-Nc) or non-encapsulated ferulic acid (D-FA) for 8weeks concurrently with d-Gal (150mg/kg s.c.) injection. As expected, our findings showed that d-Gal injection impaired memory processes and increased anxiety behavior, whereas FA-Nc treatment ameliorated these behavioral impairments associated with the aging process induced by d-Gal. At the molecular level, nanoencapsulated ferulic acid (FA-Nc) ameliorated the decrease in ACh and glutamate induced by d-galactose (d-Gal), and also increased GABA levels in the dorsal hippocampus, indicating its therapeutic superiority. Additional studies are needed to elucidate the mechanisms underlying our current promising outcomes. Nanoscience applied to pharmacology can reduce drug dosage, thereby minimizing adverse effects while enhancing therapeutic response, particularly in neurodegenerative diseases associated with aging. Therefore, the strategy of brain-targeted drug delivery through nanoencapsulation can be effective in mitigating aging-related factors that may lead to cognitive deficits.

Comparative Pharmacokinetics and Tissue Distribution of Hexahydrocurcumin Following Intraperitoneal vs Oral Administration in Mice Using LC-MS/MS.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine hexahydrocurcumin (HHC) levels in mouse plasma, brain, liver, and kidneys using a negative ion mode electrospray ionization (ESI) source. Demonstrating a lower limit of quantification (LLOQ) of 5 ng/mL, the method showed excellent linearity across a concentration range of 5-500 ng/mL in all tested matrices. Precision evaluations reported a coefficient of variation (CV%) of less than 13.19% for both intraday and interday measurements, while accuracy ranged from 95.13 to 105.07% across all quality control levels. HHC extraction recovery was consistently observed between 70.18 and 93.28%, with a CV% deviation of less than 15%. In the pharmacokinetic evaluation of HHC in mice following a single intraperitoneal (IP) or oral administration, a noncompartment analysis was utilized. After IP administration (40 mg/kg), the C max value was 47.90 times higher than that achieved via oral administration. Peak plasma concentrations were observed approximately 5 min post-IP and 15 min post-oral dosing. The observed half-lives after these administrations were approximately 1.52 and 2.17 h for IP and oral routes, respectively. Oral administration revealed a relative bioavailability of only 12.28% compared with the IP route. Furthermore, following IP administration, the half-life values in brain, liver, and kidney were not significantly different but more than the half-life value found in plasma. The liver and kidney exhibited the highest concentrations of HHC, while the brain showed the least, suggesting that the hydrophobic nature of HHC impedes its passage through the blood-brain barrier. This study is the first to provide detailed insights into the pharmacokinetics and tissue distribution characteristics of HHC following oral and IP administration in mice, setting the stage for further focus on HHC as a potential new drug candidate.

Evaluation of Anti-Depressant Potential of Standardized Hydroethanolic Extract of S. barbata D. Don Using Chronic Unpredictable Mild Stress Model

Background: S. barbata D. Don is a Chinese herb, that belongs to the family Lami-aceae. It has established traditional use in ethnomedicine for treating various ailments, includ-ing mood disorders and sleep disorders, which led to growing interest in exploring its neuro-logical potential, particularly as a potential anti-depressant agent. Aims: This study explores the anti-depressant potential of the HSBE utilizing a Chronic Un-predictable Mild Stress-induced depression model in mice. Additionally, the research aims to elucidate the underlying mechanisms of action. Methods: Swiss albino mice were subjected to a 3-week CUMS paradigm and subsequently administered HSBE at doses of 200 and 400 mg/kg via oral administration. The behavioral alterations were evaluated using the FST, TST, OFT, and SPT. Brain levels of serotonin, dopa-mine, and nor-epinephrine were estimated in different brain regions (cortex, hippocampus, and hypothalamus) to uncover the molecular mechanism. Additionally, assays for monoamine oxi-dase-A, monoamine oxidase-B, and antioxidant enzyme activities were conducted. Plasma ni-trite and corticosterone levels were also measured to get further insight into potential mecha-nisms underlying the anti-depressant effects of HSBE. Results: HSBE significantly ameliorated depressive-like behavior induced by CUMS para-digm, as evidenced by reduced immobility in FST and TST, increased locomotor activity in OFT, and improved sucrose preference in SPT. Neurochemical analysis revealed a significant increase in serotonin, dopamine, and norepinephrine levels in the cortex, hippocampus, and hypothalamus of HSBE-treated mice, implying a potential regulation of monoaminergic neuro-transmitter levels. Moreover, biochemical analyses demonstrated a significant inhibition of both MAO-A and MAO-B activity, contributing to the increase of the brain levels of neuro-transmitters. The administration of HSBE also led to a significant enhancement of antioxidant enzyme activities and reduced brain lipid peroxidation, indicating a pronounced antioxidant effect of HSBE. Furthermore, decreased plasma nitrite and corticosterone levels provided ad-ditional insights into HSBE's potential multi-targeted anti-depressant mechanism. Conclusion: This study indicates that HSBE exhibits robust anti-depressant properties, sup-ported by behavioral, neurochemical, and biochemical alterations. These findings underscore the therapeutic promise of HSBE as a natural intervention for depressive disorders, warranting further clinical exploration.

Integration of cognitive-motor dual-task training in physical sessions of highly-skilled basketball players

ABSTRACT We investigated the effects of a cognitive-motor dual-task training (CMDT) integrated into a physical training circuit. Specific tests on sprint, agility, and cognitive processes associated with anticipatory event-related potential (ERP) components and behavioural performance during a cognitive discrimination response task (DRT) were evaluated before and after the intervention. Thirty skilled basketball players were recruited and divided into an experimental group executing the “physical CMDT” and a control group performing standard physical training. The CMDT session was performed by four athletes simultaneously who executed different circuits. One circuit was the CMDT, implemented with interactive devices thus engaging strong motor control, preparedness, and quick decision-making during task performance. Results on physical performance showed that only the experimental group improved in completion time on sprint (5.83%) and agility (3.55%) tests. At the brain level, we found that in the DRT the motor anticipation increased by over 50%, and the response time became 10% faster. Instead, regarding cognitive preparation, both protocols were equally effective and response accuracy parallelly increased in the post-test. In conclusion, the proposed “physical CMDT” integrated into a group session, can improve sprint and agility and the neural correlate of this effect is the increase of motor preparation in the premotor cortex in only five weeks.

ImputeHiFI: An Imputation Method for Multiplexed DNA FISH Data by Utilizing Single-Cell Hi-C and RNA FISH Data.

Although multiplexed DNA fluorescence in situ hybridization (FISH) enables tracking the spatial localization of thousands of genomic loci using probes within individual cells, the high rates of undetected probes impede the depiction of 3D chromosome structures. Current data imputation methods neither utilize single-cell Hi-C data, which elucidate 3D genome architectures using sequencing nor leverage multimodal RNA FISH data that reflect cell-type information, limiting the effectiveness of these methods in complex tissues such as the mouse brain. To this end, a novel multiplexed DNA FISH imputation method named ImputeHiFI is proposed, which fully utilizes the complementary structural information from single-cell Hi-C data and the cell type signature from RNA FISH data to obtain a high-fidelity and complete spatial location of chromatin loci. ImputeHiFI enhances cell clustering, compartment identification, and cell subtype detection at the single-cell level in the mouse brain. ImputeHiFI improves the recognition of cell-type-specific loops in three high-resolution datasets. In short, ImputeHiFI is a powerful tool capable of imputing multiplexed DNA FISH data from various resolutions and imaging protocols, facilitating studies of 3D genome structures and functions.

Pharmacokinetics of Psilocybin, a Tryptamine Alkaloid in Magic Mushroom (Psilocybe cubensis): A Systematic Review

ABSTRACT Psilocybin, a major indole alkaloid found in magic mushrooms (Psilocybe cubensis), has recently drawn attention as a breakthrough therapy to treat major depressive disorder. This review aimed to summarize and identify knowledge gaps concerning their pharmacokinetic characteristics of psilocybin and its active metabolite, psilocin. Original studies related to pharmacokinetics of psilocybin conducted in vitro, animals, and humans were systematically collected from PubMed, Scopus, and ScienceDirect, from their inceptions to November 2023. Twenty articles were included in this work and assessed for study quality. A comprehensive review of the pharmacokinetics of psilocybin and psilocin in both animals and humans was performed. Psilocybin is considered a prodrug that is dephosphorylated to psilocin by alkaline phosphatase. Following ingestion, the peak psilocin plasma and brain levels were rapidly achieved in a dose-dependent manner. Psilocin is metabolized primarily through both Phase I and Phase II processes with the half-life of 2–3 hours. This review also identified lack of some pharmacokinetic related information and limitations of available research that may help direct future investigations to better understand the pharmacokinetics and improve study design including dose selection and dosage optimization.

The NRF2 inducer CDDO-2P-Im provokes a reduction in amyloid β levels in Alzheimer's disease model mice.

Alzheimer's disease (AD) is the most common etiology of dementia. The transcription factor NF-E2-related factor 2 (NRF2) induces the expression of genes encoding phase II detoxification and antioxidant genes. NRF2 is regulated by Kelch-like ECH-associated protein 1 (KEAP1), and the KEAP1-NRF2 system is the key regulatory system involved in cytoprotection. To examine whether pharmacological induction of NRF2 expression alleviates AD phenotypes in vivo, we employed two AD mouse models, i.e., App NL-G-F/NL-G-F (AppNLGF) and APPV717I::TAUP301L (APP/TAU) mice. As the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11-dien-28-oyl)] (CDDO)-4(-pyridin-2-yl)-imidazole (CDDO-2P-Im) exhibits strong NRF2-inducing activity, we treated AD model mice with CDDO-2P-Im. We found that Aβ42 levels were markedly greater in the brains of AppNLGF mice than in those of APP/TAU mice. CDDO-2P-Im treatment significantly decreased Aβ42 levels, but not Aβ40 levels, in APP/TAU mice. Consequently, CDDO-2P-Im also decreased the ratio of Aβ42/Aβ40, a vital marker of amyloid plaque formation. LC-MS/MS analyses revealed that CDDO-2P-Im was delivered to the brains of the APP/TAU mice. CDDO-2P-Im induced the expression of detoxification and antioxidant gene targets of NRF2 and elevated reduced glutathione (GSH) levels in the mouse brain. These results support the notion that CDDO-2P-Im ameliorates AD-related pathologic changes.

Introducing Ion Mobility Mass Spectrometry in Brain Glycosaminoglycomics: Application to Chondroitin/Dermatan Sulfate Octasaccharide Domains.

Glycosaminoglycans (GAGs) are sulfated linear O-glycan chains abundantly expressed in the extracellular matrix (ECM). Among GAGs, chondroitin sulfate (CS) and dermatan sulfate (DS) play important roles at the brain level, where the distribution and location of the sulfates within the CS/DS chains are responsible for numerous biological events. The diversity of the neural hybrid CS/DS expressed in the brain and the need to elucidate their structure gave rise to considerable efforts toward the development of analytical methods able to discover novel regularly and irregularly sulfated domains. In this context, we report here the introduction of ion mobility separation (IMS) mass spectrometry (MS) in brain glycosaminoglycomics. Based on IMS MS and tandem MS (MS/MS) by collision-induced dissociation (CID), we have developed a powerful approach for the screening and structural analysis of neural CS/DS and optimized and validated the method for the structural analysis of octasaccharides that were released from brain proteoglycans by β-elimination and pooled after chain depolymerization using chondroitin AC lyase. The IMS MS data revealed the separation of CS/DS octamers into mobility families based on the amount of sulfation. Among the discovered oversulfated domains, of major biological importance is the pentasulfated-[4,5-Δ-GlcAGalNAc(IdoAGalNAc)3], for which the (-) nanoESI IMS CID MS/MS analysis disclosed through the presence of distinct drift times, the incidence of two isomers. Moreover, the generated fragment ions revealed an uncommon trisulfated motif and an uncommon pentasulfated motif. Hence, using IMS MS and CID MS/MS, novel brain-related CS/DS domains of atypical sulfation patterns were discovered and structurally characterized in detail.