DNA Methylation of BDNF and RASA2 Genes Is Associated With Cognitive Function in Postmenopausal Women With Breast Cancer.

OBJECTIVES: To determine associations among DNA methylation of brain-derived neurotrophic factor (BDNF) and RAS p21 protein activator 2 (RASA2) genes with processing speed and perceived cognitive function. SAMPLE & SETTING: This was a cross-sectional, secondary analysis of baseline data from a randomized controlled trial, the Exercise Program in Cancer and Cognition Study. METHODS & VARIABLES: Data included M values for DNA methylation of the BDNF and RASA2 genes; processing speed, objectively measured using the Grooved Pegboard and Digit Vigilance Test scores; and perceived cognitive function, self-reported using the Patient Assessment of Own Functioning Inventory. Regression analysis was conducted. RESULTS: Greater methylation of cg21291635 of the BDNF gene (p = 0.01) and cg20247102 of the RASA2 gene (p = 0.013) were associated with poorer processing speed, whereas greater methylation of cg20108357 of the BDNF gene (p < 0.001) and cg00567892 of the RASA2 gene (p = 0.019) were associated with better perceived cognitive function. IMPLICATIONS FOR NURSING: Gene methylation variations were demonstrated, suggesting the genes' potential roles and two possible distinct mechanisms of cognitive function in cancer. .

A reliable and quick method for screening alternative splicing variants for low-abundance genes.

Alternative splicing (AS) is a universal phenomenon in eukaryotes, and it is still challenging to identify AS events. Several methods have been developed to identify AS events, such as expressed sequence tags (EST), microarrays and RNA-seq. However, EST has limitations in identifying low-abundance genes, while microarray and RNA-seq are high-throughput technologies, and PCR-based technology is needed for validation. To overcome the limitations of EST and shortcomings of high-throughput technologies, we established a method to identify AS events, especially for low-abundance genes, by reverse transcription (RT) PCR with gene-specific primers (GSPs) followed by nested PCR. This process includes two major steps: 1) the use of GSPs to amplify as long as the specific gene segment and 2) multiple rounds of nested PCR to screen the AS and confirm the unknown splicing variants. With this method, we successfully identified three new splicing variants, namely, GenBank Accession No. HM623886 for the bdnf gene (GenBank GeneID: 12064), GenBank Accession No. JF417977 for the trkc gene (GenBank GeneID: 18213) and GenBank Accession No. HM623888 for the glb-18 gene (GenBank GeneID: 172485). In addition to its reliability and simplicity, the method is also cost-effective and labor-intensive. In conclusion, we developed an RT-nested PCR method using gene-specific primers to efficiently identify known and novel AS variants. This approach overcomes the limitations of existing methods for detecting rare transcripts. By enabling the discovery of new isoforms, especially for low-abundance genes, this technique can aid research into aberrant splicing in disease. Future studies can apply this method to uncover AS variants involved in cancer, neurodegeneration, and other splicing-related disorders.

Centella asiatica extract ameliorates deoxygenation-induced neurological dysfunction in zebrafish larvae.

Background: Oxygen deprivation (OD) is a critical condition that can lead to brain damage and even death. Current hypoxia management approaches are limited in effectiveness. Centella asiatica (CA), known for its neuroprotective properties, offers a potential alternative for OD treatment. Aims: This study aims to investigate the neuroprotective effects of CA on the expression of brain-derived neurotrophic factor (BDNF) and vesicular glutamate transporter 1 (VGLUT1) in zebrafish larvae under oxygen-deficient conditions. Methods: Zebrafish embryos were subjected to low oxygen levels (1.5 mg/l) 0-2 hours post-fertilization (hpf) until 3 days post-fertilization (dpf), simulating the early stages of OD. Subsequent treatment involved varying concentrations of CA (1.25-5 µg/ml) up to 9 days post-fertilization. The expression levels of BDNF and VGLUT1 were measured using PCR methods. Statistical analysis was conducted using a two-way analysis of variance to evaluate the impact of CA on the expression of BDNF and VGLUT1 in zebrafish larvae aged 3 and 9 dpf in oxygen-deprived conditions. Results: CA significantly influenced the expression of BDNF and VGLUT1 under OD (p < 0.001). An increase in BDNF expression (p < 0.001) and a decrease in VGLUT1 (p < 0.01) were observed in zebrafish larvae experiencing OD and treated with CA. There was no significant difference in BDNF and VGLUT1 expression across age variations in zebrafish larvae at 3 dpf and 9 dpf in the treatment groups (p > 0.05). CA concentration of 2.5 µg/ml effectively enhanced BDNF and reduced VGLUT1 in 3-9 dpf zebrafish larvae. Conclusion: CA demonstrates potential as a neuroprotective agent, modulating increased BDNF expression and reduced VGLUT1 under OD conditions. These findings lay a foundation for further research in developing therapies for oxygen deficiency.

Analysis of the BDNF Gene rs6265 Polymorphism in a Group of Women with Alcohol Use Disorder, Taking into Account Personality Traits.

It seems that BDNF has a direct influence on the brain pathways and is typically engaged during the processing of rewards. A surge in BDNF levels in the ventral tegmental area (the region from which the dopaminergic neurons of the mesocorticolimbic dopamine system originate and extend to the dorsolateral and ventromedial striatum) triggers a state of reward similar to that produced by opiates in animal studies. The aims of the study were (1) to analyze the association of the BDNF gene rs6265 polymorphism with AUD (alcohol use disorder) in women, (2) analyze personality and anxiety in alcohol-dependent and control woman, and (3) conduct an interaction analysis of rs6265 on personality, anxiety, and alcohol dependence. Our study found a notable interaction between the anxiety (trait and state), neuroticism, rs6265, and AUD. The alcohol AUD G/A genotype carriers revealed higher level of the anxiety trait (p < 0.0001) and neuroticism (p < 0.0001) compared to the control group with G/A and G/G genotypes. The alcohol use disorder subjects with the G/A genotype displayed higher levels of an anxiety state than the control group with G/A (p < 0.0001) and G/G (p = 0.0014) genotypes. Additionally, the alcohol use disorder subjects with the G/G genotype obtained lower levels of agreeability compared to the controls with G/A (p < 0.0001) and G/G (p < 0.0001) genotypes. Our study indicates that anxiety (trait and state) and neuroticism are interacting with the BDNF gene rs6265 polymorphism in alcohol-dependent women. Characteristics like anxiety (both as a trait and a state) and neuroticism could have a significant impact on the mechanism of substance dependency, particularly in females who are genetically susceptible. This is regardless of the reward system that is implicated in the emotional disruptions accompanying anxiety and depression.

Ameliorated Effects of Fucoidan on Dextran Sulfate Sodium-Induced Ulcerative Colitis and Accompanying Anxiety and Depressive Behaviors in Aged C57BL/6 Mice.

Fucoidan has shown better effects on the improvement of acute ulcerative colitis (UC). However, the specific mechanisms by which fucoidan improves UC-related behavioral disorders in aged mice, especially its effect on the gut-brain axis, remain to be further explored. C57BL/6 male mice aged 8 months were gavaged with 400 or 100 mg/kg bw day fucoidan for five consecutive weeks, with UC being induced by ad libitum to dextran sulfate sodium (DSS) solution in the fifth week. The results showed that fucoidan ameliorated UC and accompanying anxiety- and depressive-like behaviors with downregulated expressions of (NOD)-like receptor family and pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteine aspartate-specific protease-1 (Caspase-1) and interlekin-1ß (IL-1ß), and elevated mRNA levels of brain-derived neurotrophic factor (Bdnf) and postsynaptic-density protein 95 (Psd-95) in cortex and hippocampus. Furthermore, fucoidan improved the permeability of intestinal barrier and blood-brain barrier and restored the abnormal structure of the gut microbiota with a significantly decreased ratio of Firmicutes to Bacteroidota (F/B) and obviously increased abundance of Akkermansia. As a diet-derived bioactive ingredient, fucoidan might be a better alternative for the prevention of UC and accompanying anxiety- and depressive-like behaviors.

A rare olive compound oleacein functions as a TrkB agonist and mitigates neuroinflammation both in vitro and in vivo.

BACKGROUND: Neuroinflammation is widely acknowledged as a characteristic feature of almost all neurological disorders and specifically in depression- and anxiety-like disorders. In recent years, there has been significant attention on natural compounds with potent anti-inflammatory effects due to their potential in mitigating neuroinflammation and neuroplasticity. METHODS: In the present study, we aimed to evaluate the neuroprotective effects of oleacein (OC), a rare secoiridoid derivative found in extra virgin olive oil. Our goal was to explore the BDNF/TrkB neurotrophic activity of OC and subsequently assess its potential for modulating neuroinflammatory response using human neuroblastoma cells (SH-SY5Y cells) and an in vivo model of depression induced by lipopolysaccharide (LPS)-mediated inflammation. RESULTS: In SH-SY5Y cells, OC exhibited a significant dose-dependent increase in BDNF expression. This enhancement was absent when cells were co-treated with inhibitors of BDNF's receptor TrkB, as well as downstream molecules PI3K and MEK. Whole-transcriptomics analysis revealed that OC upregulated cell cycle-related genes under normal conditions, while downregulating inflammation-associated genes in LPS-induced conditions. Furthermore, surface plasmon resonance (SPR) assays demonstrated that OC exhibited a stronger and more stable binding affinity to TrkB compared to the positive control, 7,8-dihydroxyflavone. Importantly, bioluminescence imaging revealed that a single oral dose of OC significantly increased BDNF expression in the brains of Bdnf-IRES-AkaLuc mice. Furthermore, oral administration of OC at a dosage of 10 mg/kg body weight for 10 days significantly reduced immobility time in the tail suspension test compared to the LPS-treated group. RT-qPCR analysis revealed that OC significantly decreased the expression of pro-inflammatory cytokines Tnfα, Il6, and Il1ß, while simultaneously enhancing Bdnf expression, as well as both pro and mature BDNF protein levels in mice hippocampus. These changes were comparable to those induced by the positive control antidepressant drug fluoxetine. Additionally, microarray analysis of mouse brains confirmed that OC could counteract LPS-induced inflammatory biological events. CONCLUSION: Altogether, our study represents the first report on the potential antineuroinflammatory and antidepressant properties of OC via modulation of BDNF/TrkB neurotrophic activity. This finding underscores the potential of OC as a natural therapeutic agent for depression- and anxiety-related disorders.

Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis.

Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung fibrosis we performed single cell RNA-sequencing of bleomycin-injured lungs from young and aged mice. Analysis reveals activated cell states enriched for hypoxia, glycolysis and YAP/TAZ activity in ACKR1+ venous and TrkB+ capillary endothelial cells. Endothelial cell activation is prevalent in lungs of aged mice and can also be detected in human fibrotic lungs. Longitudinal single cell RNA-sequencing combined with lineage tracing demonstrate that endothelial activation resolves in young mouse lungs but persists in aged ones, indicating a failure of the aged vasculature to return to quiescence. Genes associated with activated lung endothelial cells states in vivo can be induced in vitro by activating YAP/TAZ. YAP/TAZ also cooperate with BDNF, a TrkB ligand that is reduced in fibrotic lungs, to promote capillary morphogenesis. These findings offer insights into aging-related lung endothelial cell dysfunction that may contribute to defective lung injury repair and persistent fibrosis.

BCI Improves Alcohol-Induced Cognitive and Emotional Impairments by Restoring pERK-BDNF.

Binge drinking causes a range of problems especially damage to the nervous system, and the specific neural mechanism of brain loss and behavioral abnormalities caused by which is still unclear. Extracellular regulated protein kinases (ERK) maintain neuronal survival, growth, and regulation of synaptic plasticity by phosphorylating specific transcription factors to regulate expression of brain-derived neurotrophic factor (BDNF). Dual-specific phosphatase 1 (DUSP1) and DUSP6 dephosphorylate tyrosine and serine/threonine residues in ERK1/2 to inactivate them. To investigate the molecular mechanism by which alcohol affects memory and emotion, a chronic intermittent alcohol exposure (CIAE) model was established. The results demonstrated that mice in the CIAE group developed short-term recognition memory impairment and anxiety-like behavior; meanwhile, the expression of DUSP1 and DUSP66 in the mPFC was increased, while the levels of p-ERK and BDNF were decreased. Micro-injection of DUSP1/6 inhibitor BCI into the medial prefrontal cortex (mPFC) restored the dendritic morphology by reversing the activity of ERK-BDNF and ultimately improved cognitive and emotional impairment caused by CIAE. These findings indicate that CIAE inhibits ERK-BDNF by increasing DUSP1/6 in the mPFC that may be associated with cognitive and emotional deficits. Consequently, DUSP1 and DUSP6 appear to be potential targets for the treatment of alcoholic brain disorders.

The P2X7 Hypothesis of Central Post-Stroke Pain.

The present study examined how P2X7 receptor knockout (KO) modulates central post-stroke pain (CPSP) induced by lesions of the ventrobasal complex (VBC) of the thalamus in behaviors, molecular levels, and electrical recording tests. Following the experimental procedure, the wild-type and P2X7 receptor KO mice were injected with 10 mU/0.2 µL type IV collagenase in the VBC of the thalamus to induce an animal model of stroke-like thalamic hemorrhage. Behavioral data showed that the CPSP group induced thermal and mechanical pain. The P2X7 receptor KO group showed reduced thermal and mechanical pain responses compared to the CPSP group. Molecular assessments revealed that the CPSP group had lower expression of NeuN and KCC2 and higher expression of GFAP, IBA1, and BDNF. The P2X7 KO group showed lower expression of GFAP, IBA1, and BDNF but nonsignificant differences in KCC2 expression than the CPSP group. The expression of NKCC1, GABAa receptor, and TrkB did not differ significantly between the control, CPSP, and P2X7 receptor KO groups. Muscimol, a GABAa agonist, application increased multiunit numbers for monitoring many neurons and [Cl-] outflux in the cytosol in the CPSP group, while P2X7 receptor KO reduced multiunit activity and increased [Cl-] influx compared to the CPSP group. P2X4 receptor expression was significantly decreased in the 100 kDa but not the 50 kDa site in the P2X7 receptor KO group. Altogether, the P2X7 hypothesis of CPSP was proposed, wherein P2X7 receptor KO altered the CPSP pain responses, numbers of astrocytes and microglia, CSD amplitude of the anterior cingulate cortex and the medial dorsal thalamus, BDNF expression, [Cl-] influx, and P2X4 expression in 100 kDa with P2X7 receptors. The present findings have implications for the clinical treatment of CPSP symptoms.

The Neuroprotective Effects of Oroxylum indicum Extract in SHSY-5Y Neuronal Cells by Upregulating BDNF Gene Expression under LPS Induced Inflammation.

The brain-derived neurotrophic factor (BDNF) plays a crucial role during neuronal development as well as during differentiation and synaptogenesis. They are important proteins present in the brain that support neuronal health and protect the neurons from detrimental signals. The results from the present study suggest BDNF expression can be increase up to ~8-fold by treating the neuroblastoma cells SHSY-5Y with an herbal extract of Oroxylum indicum (50 µg/mL) and ~5.5-fold under lipopolysaccharides (LPS)-induced inflammation conditions. The Oroxylum indicum extract (Sabroxy) was standardized to 10% oroxylin A, 6% chrysin, and 15% baicalein. In addition, Sabroxy has shown to possess antioxidant activity that could decrease the damage caused by the exacerbation of radicals during neurodegeneration. A mode of action of over expression of BDNF with and without inflammation is proposed for the Oroxylum indicum extract, where the three major hydroxyflavones exert their effects through additive or synergistic effects via five possible targets including GABA, Adenoside A2A and estrogen receptor bindings, anti-inflammatory effects, and reduced mitochondrial ROS production.

Combination of induced pluripotent stem cell-derived motor neuron progenitor cells with irradiated brain-derived neurotrophic factor over-expressing engineered mesenchymal stem cells enhanced restoration of axonal regeneration in a chronic spinal cord injury rat model.

BACKGROUND: Spinal cord injury (SCI) is a disease that causes permanent impairment of motor, sensory, and autonomic nervous system functions. Stem cell transplantation for neuron regeneration is a promising strategic treatment for SCI. However, selecting stem cell sources and cell transplantation based on experimental evidence is required. Therefore, this study aimed to investigate the efficacy of combination cell transplantation using the brain-derived neurotrophic factor (BDNF) over-expressing engineered mesenchymal stem cell (BDNF-eMSC) and induced pluripotent stem cell-derived motor neuron progenitor cell (iMNP) in a chronic SCI rat model. METHOD: A contusive chronic SCI was induced in Sprague-Dawley rats. At 6 weeks post-injury, BDNF-eMSC and iMNP were transplanted into the lesion site via the intralesional route. At 12 weeks post-injury, differentiation and growth factors were evaluated through immunofluorescence staining and western blot analysis. Motor neuron differentiation and neurite outgrowth were evaluated by co-culturing BDNF-eMSC and iMNP in vitro in 2-dimensional and 3-dimensional. RESULTS: Combination cell transplantation in the chronic SCI model improved behavioral recovery more than single-cell transplantation. Additionally, combination cell transplantation enhanced mature motor neuron differentiation and axonal regeneration at the injured spinal cord. Both BDNF-eMSC and iMNP played a critical role in neurite outgrowth and motor neuron maturation via BDNF expression. CONCLUSIONS: Our results suggest that the combined transplantation of BDNF- eMSC and iMNP in chronic SCI results in a significant clinical recovery. The transplanted iMNP cells predominantly differentiated into mature motor neurons. Additionally, BDNF-eMSC exerts a paracrine effect on neuron regeneration through BDNF expression in the injured spinal cord.

Analysis of potential microRNA biomarkers for multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating autoimmune neurodegenerative disorder for which no specific blood biomarker is available. MicroRNAs (miRNAs) have been investigated for their diagnostic potential in MS. However, MS-associated miRNAs are rarely replicated in different MS populations, thus impeding their use in clinical testing. Here, we evaluated the fold expression of seven reported MS miRNAs associated with MS incidence and clinical characteristics in 76 MS patients and 75 healthy control plasma samples. We found miR-23a-3p to be upregulated in relapsing-remitting MS (RRMS), while miR-326 was downregulated. MiR-150-5p and -320a-3p were significantly downregulated in secondary progressive MS (SPMS) patients compared to RRMS. High disability was associated with low miR-320a-3p, whereas low BDNF levels were associated with upregulation of miR-150-5p and downregulation of miR-326 expression in the total cohort. MiR-23a-3p and miR-326 showed significant diagnostic sensitivity, specificity, and accuracy for RRMS diagnosis. In addition, miR-150-5p and miR-320a-3p had comparable significant diagnostic test performance metrics distinguishing SPMS from RRMS. Therefore, there is potential for including miR-23a-3p and miR-326 in an RRMS diagnostic miRNA panel. Moreover, we have shown that miR-150-5p and miR-320a-3p could be novel RRMS conversion to SPMS biomarkers. The use of these miRNAs in MS diagnosis and prognosis warrants further investigation.

The influence of hippocampal dopamine D2 receptor losses on episodic-memory decline across 5 years is moderated by BDNF and KIBRA polymorphisms.

Losses in dopamine (DA) functioning may contribute to aging-related decline in cognition. Hippocampal DA is necessary for successful episodic memory formation. Previously, we reported that higher DA D2 receptor (D2DR) availability in hippocampus is beneficial for episodic memory only in older carriers of more advantageous genotypes of well-established plasticity-related genetic variations, the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. Extending our observations to the longitudinal level, the current data show that individuals with one or no beneficial BDNF and KIBRA genotype (n = 80) decline more in episodic memory across five years, without any contribution of losses in hippocampal D2DR availability to memory decline. Although carriers of two beneficial genotypes (n = 39) did not decline overall in episodic memory, losses of hippocampal D2DR availability were predictive of episodic-memory decline among these individuals. Our findings have implications for interventions targeting DA modulation to enhance episodic memory in aging, which may not benefit all older individuals.

In vivo bioluminescence imaging revealed the change of the time window of BDNF expression in the brain elicited by a single bout of exercise following repeated exercise.

Exercise increases the expression of brain-derived neurotrophic factor (BDNF) in the brain and contributes to cognitive and sensorimotor functions. This study aimed to elucidate how repeated exercise modifies BDNF expression elicited by a single bout of exercise in the brain using in vivo bioluminescence imaging (BLI). Bdnf-luciferase (Luc) mice with the firefly luciferase gene inserted at the translation start point of the Bdnf gene were used for BLI to monitor changes in BDNF expression in the brain. The treadmill exercise at a speed of 10 m/s for 60 min was repeated 5 days a week for 4 weeks. BLI in individual subjects was repeated four times: before the exercise intervention, on the first exercise day, and 14 and 28 days after the start of the intervention. Each BLI was performed after a single bout of exercise and monitored for 8 h after exercise. Repetitive BLI showed that the exercise regimen enhanced BDNF expression in the brain, specifically at 4-8 h after a single bout of exercise. Repeated exercise for 2 weeks accelerated the start of enhancement after a single bout of exercise, but not after 4 weeks of repeated exercise. This study showed that repeated exercise modulated the time window of exercise-enhanced BDNF expression, suggesting that repeated exercise could change the sensitivity of gene expression to a single bout of exercise. These findings can be attributed to the advantages of in vivo BLI, which allowed us to precisely measure the time course of BDNF expression after repeated exercise in individual subjects.

Knockdown of thioredoxin interacting protein in Müller cells attenuates photoreceptor apoptosis in streptozotocin-induced diabetic mouse model.

We explored the effect of inhibition of thioredoxin interacting protein (Txnip) on neuroprotection in Müller cells under high glucose. Wild-type (WT) and Txnip knockout (Txnip-/-) mice were used to establish a streptozotocin (STZ)-induced diabetes model and a Müller cells high glucose model. We detected BDNF expression and PI3K/AKT/CREB pathway activation levels in the retina and Müller cells of each group in vivo and in vitro experiments. The Txnip-/- STZ group showed higher expression of BDNF and phosphorylation of PI3K/AKT/CREB in retina, and less retinal photoreceptor apoptosis was observed in Txnip-/- diabetic group than in WT. After using an inhibitor of PI3K signaling pathway, BDNF expression was reduced; In vitro co-cultured with Müller cells in different groups, 661 W cells showed different situations, Txnip-/- Müller cells maximum downregulated Cleaved-caspase 3 expression in 661 W, accompanied by an increase in Bcl-2/Bax ratio. These findings indicate that inhibiting endogenous Txnip in mouse Müller cells can promote their expression and secretion of BDNF, thereby reducing HG induced photoreceptor apoptosis and having important neuroprotective effects on DR. The regulation of BDNF expression by Txnip may be achieved by activating the PI3K/AKT/CREB pathway. This study suggests that regulating Txnip may be a potential target for DR treatment.

Ketogenic Diet Induced Shifts in the Gut Microbiome Associate with Changes to Inflammatory Cytokines and Brain-Related miRNAs in Children with Autism Spectrum Disorder.

In this interventional pilot study, we investigated the effects of a modified ketogenic diet (KD) on children with autism spectrum disorder (ASD). We previously observed improved behavioral symptoms in this cohort following the KD; this trial was registered with Clinicaltrials.gov (NCT02477904). This report details the alterations observed in the microbiota, inflammation markers, and microRNAs of seven children following a KD for a duration of 4 months. Our analysis included blood and stool samples, collected before and after the KD. After 4 months follow up, we found that the KD led to decreased plasma levels of proinflammatory cytokines (IL-12p70 and IL-1b) and brain-derived neurotrophic factor (BDNF). Additionally, we observed changes in the gut microbiome, increased expression of butyrate kinase in the gut, and altered levels of BDNF-associated miRNAs in the plasma. These cohort findings suggest that the KD may positively influence ASD sociability, as previously observed, by reducing inflammation, reversing gut microbial dysbiosis, and impacting the BDNF pathway related to brain activity.

Pegylated polymeric micelles of boswellic acid-selenium mitigates repetitive mild traumatic brain injury: Regulation of miR-155 and miR-146a/BDNF/ Klotho/Foxo3a cue.

This study aims to explore the protective machinery of pegylated polymeric micelles of boswellic acid-selenium (PMBS) against secondary neuronal damage triggered by mild repetitive traumatic brain injury (RTBI). After PMBS characterization in terms of particle size, size distribution, zeta potential, and transmission electronic microscopy, the selected formula was used to investigate its potency against experimental RTBI. Five groups of rats were used; group 1 (control) and the other four groups were subjected to RTBI. Groups 2 was RTBI positive control, while 3, 4, and 5 received boswellic acid (BSA), selenium (SEL), and PMBS, respectively. The open-field behavioral test was used for behavioral assessment. Subsequently, brain tissues were utilized for hematoxylin and eosin staining, Nissl staining, Western blotting, and ELISA in addition to evaluating microRNA expression (miR-155 and miR-146a). The behavioral changes, oxidative stress, and neuroinflammation triggered by RTBI were all improved by PMBS. Moreover, PMBS mitigated excessive glutamate-induced excitotoxicity and the dysregulation in miR-155 and miR-146a expression. Besides, connexin43 (Cx43) expression as well as klotho and brain-derived neurotrophic factor (BDNF) were upregulated with diminished neuronal cell death and apoptosis because of reduced Forkhead Box class O3a(Foxo3a) expression in the PMBS-treated group. The current study has provided evidence of the benefits produced by incorporating BSA and SEL in PEGylated polymeric micelles formula. PMBS is a promising therapy for RTBI. Its beneficial effects are attributed to the manipulation of many pathways, including the regulation of miR-155 and miR-146a expression, as well as the BDNF /Klotho/Foxo3a signaling pathway.

Neuroplasticity-related genes correlate with individual differences in distinct phases of oxycodone self-administration in male rats.

Opioid use disorder (OUD) is a chronic condition associated with long-lasting molecular and behavioral changes. Animals with prolonged access to opioids develop behaviors similar to human OUD. Identifying associated molecular changes can provide insight to underpinnings that lead to or maintain OUD. In pilot studies, we identified several miRNA targets that are altered by the administration of oxycodone. We selected mir182 for follow up as it was recently shown to be dysregulated in plasma of men administered oxycodone. In addition, mir182 is increased in reward-related brain regions of male rats following exposure to various addictive substances. The present study utilizes a long-access oxycodone self-administration paradigm to examine changes in mir182 and its mRNA targets associated with neuroplasticity, which may be involved in the maintenance of OUD-like phenotype in rats. Male rats were trained to self-administer oxycodone (0.1 mg/kg/infusion, i. v.) for 6 h daily sessions for 12 days. Each animal had a yoked saline control that received matched saline infusions. Animals were then tested on a progressive ratio schedule to measure motivation to obtain a single infusion of oxycodone. Drug seeking was measured following 28 days of forced abstinence using a 90-min cued/test. RTqPCR was utilized to measure mir182 and mRNA targets related to neuroplasticity (wnt3, plppr4, pou3f3, tle4, cacna2d, and bdnf) from the nucleus accumbens. Data revealed that animals responded on a continuum for oxycodone. When divided into two groups termed high- and low responders, animals diverged during self-administration acquisition and maintained differences in behavior and gene expression throughout the study. mir182 was upregulated in the nucleus accumbens of both high and low responders and negatively correlated with tle4, which showed a strong negative correlation with reinstatement behavior. mRNA target levels were correlated with behaviors associated with increased severity of OUD behavior in male rats.

Sarcopenia as a Risk Factor for Alzheimer's Disease: Genetic and Epigenetic Perspectives.

Sarcopenia, defined as the age-associated loss of muscle mass and increased fragility with age, is increasing worldwide. The condition often precedes the development of Alzheimer's disease, thereby decreasing the levels of mobility and physical activity in those affected. Indeed, the loss of muscle mass has, in some studies, been associated with an increased risk of Alzheimer's disease and other dementias. However, a detailed understanding of the interplay between both conditions is not available and needs to be thoroughly addressed. In the following review, we focus on several genes, specifically APOE, BDNF, ACE, FTO, and FNDC5, that have been associated with both conditions. We also discuss the epigenetic regulation of each of these genes along with non-coding RNAs (ncRNAs) that may have a role in the development of both the sarcopenic and Alzheimer's disease phenotypes. Finally, we assert that the application of systems biology will unravel the relationship between sarcopenia and Alzheimer's disease and believe that the prevention of muscle loss in older age will reduce the incidence of debilitating cognitive decline.

Interaction between miR-142-3p and BDNF Val/Met Polymorphism Regulates Multiple Sclerosis Severity.

MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1ß), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1ß in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1ß levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1ß-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.