Neuronal Growth Factor Research Articles

Methylcobalamin as a candidate for chronic peripheral neuropathic pain therapy: review of molecular pharmacology actiona.

Chronic peripheral neuropathic pain therapy currently focuses on modulating neuroinflammatory conditions. Methylcobalamin (MeCbl), a neuroregenerative agent, modulates neuroinflammation. This review aimed to explore the molecular pharmacology action of MeCbl as a chronic peripheral neuropathic pain therapeutic agent. MeCbl plays a role in various cellular processes and may have therapeutic potential in neurodegenerative diseases. Intracellular MeCbl modulates inflammation by regulating the activity of T lymphocytes and natural killer cells as well as secretion of inflammatory cytokines, namely, tumor necrosis factor-α, interleukin-6, interleukin-1β, epidermal growth factor, and neuronal growth factor. MeCbl can reduce pain symptoms in chronic neuropathic pain conditions by decreasing excitation and hyperpolarization-induced ion channel activity in medium-sized dorsal root ganglion (DRG) neurons and the expression of transient receptor potential ankyrin 1, transient receptor potential cation channel subfamily M member 8, phosphorylated p38MAPK, transient receptor potential cation channel subfamily V members 1 and 4 in the DRG, and the voltage-gated sodium channel in axons.

CD2AP is Co-Expressed with Tropomyosin-Related Kinase A and Ras-Related Protein Rab-5A in Cholinergic Neurons of the Murine Basal Forebrain.

Basal forebrain cholinergic neurons project to the hippocampus and cortex, are critical for learning and memory, and are central to the pathogenesis of Alzheimer's disease (AD). GWAS have consistently shown that genomic variants at the CD2AP gene locus are associated with significant increased risk of AD. GWAS studies have also shown that genetic variants in endocytosis genes, including RAB5A , significantly increase susceptibility to AD. Previous work in our lab has shown that CD2AP functions as a docking-scaffold/adaptor protein as a coordinator of nerve growth factor (NGF) and trophic signaling in neurons. We have also demonstrated that CD2AP positively regulates Rab5-mediated mechanisms of endocytosis in primary sensory neurons. The purpose of this study was to perform an in vivo characterization of CD2AP expression in cholinergic neurons of the brain regions most relevant to AD pathogenesis and to investigate the colocalization of CD2AP and Rab5 in cholinergic neurons of the murine basal forebrain. Brain tissue was perfused, harvested from ChAT BAC -eGFP transgenic mice (N=4 male, N=4 female; aged 10 mo), where cholinergic neurons (co-) express green fluorescence protein (GFP) in central and peripheral neurons that express choline acetyltransferase (ChAT). Frozen tissue sections were used to assess the specificity of the reporter in mouse brain along with localization of both CD2AP and Rab5 (co-) expression using immunofluorescence (IF) analysis of ChAT-GFP+ neurons and primary antibodies against ChAT, CD2AP and Rab5. Image J software was used to develop and optimize a colocalization assay for CD2AP and Rab5 puncta. Experiments were repeated in a follow-up cohort of aged-adult mice (N=2 male, N=2 female; aged 18 mo). IF expression of CD2AP was quantified in the basal forebrain, diagonal band of Broca (vDB), and striatal regions and compared to results from the cortical regions of the adult mouse brain. Colocalization of CD2AP was observed in the cell bodies of ChAT-GFP+ neurons of the striatum, vDB and basal forebrain regions, where CD2AP expression intensity as well as the number of cell bodies with positive signal increased incrementally. Colocalization analyses revealed near-complete overlap of CD2AP and Rab5 expression in ChAT-GFP+ cholinergic neurons of the basal forebrain region. We conclude that cholinergic neurons express CD2AP in healthy adult and aged-adult mouse brains. These data provide the first evidence of quantifiable CD2AP protein expression of cholinergic neurons specific to the diagonal band of Broca (vDB) and basal forebrain. Together with previous research from our lab, these data support a role for CD2AP in the pathogenesis of AD through orchestration of endocytosis and retrograde signaling. Ongoing studies are underway to verify these findings in a novel AD mouse model that incorporates the humanized variant of CD2AP , created by MODEL-AD, where we aim to further investigate how CD2AP variants may affect mechanistic components of Rab5 endocytosis as well as subsequent survival of cholinergic neurons in the context of known amyloid beta and Tau pathologies.

From Gut to Brain: Uncovering Potential Serum Biomarkers Connecting Inflammatory Bowel Diseases to Neurodegenerative Diseases.

Inflammatory bowel diseases (IBDs) are characterized by chronic gastrointestinal inflammation due to abnormal immune responses to gut microflora. The gut-brain axis is disrupted in IBDs, leading to neurobiological imbalances and affective symptoms. Systemic inflammation in IBDs affects the brain's inflammatory response system, hormonal axis, and blood-brain barrier integrity, influencing the gut microbiota. This review aims to explore the association between dysregulations in the gut-brain axis, serum biomarkers, and the development of cognitive disorders. Studies suggest a potential association between IBDs and the development of neurodegeneration. The mechanisms include systemic inflammation, nutritional deficiency, GBA dysfunction, and the effect of genetics and comorbidities. The objective is to identify potential correlations and propose future research directions to understand the impact of altered microbiomes and intestinal barrier functions on neurodegeneration. Serum levels of vitamins, inflammatory and neuronal damage biomarkers, and neuronal growth factors have been investigated for their potential to predict the development of neurodegenerative diseases, but current results are inconclusive and require more studies.

DNA origami scaffold promoting nerve guidance and regeneration.

Self-assembly of biological elements into biomimetic cargo carriers for targeting and delivery is a promising approach. However, it still holds practical challenges. We developed a functionalization approach of DNA origami (DO) nanostructures with neuronal growth factor (NGF) for manipulating neuronal systems. NGF bioactivity and its interactions with the neuronal system were demonstrated in vitro and in vivo models. The DO elements fabricated by molecular self-assembly have manipulated the surrounding environment through static spatially and temporally controlled presentation of ligands to the cell surface receptors. Our data showed effective bioactivity in differentiating PC12 cells in vitro. Furthermore, the DNA origami NGF (DON) affected the growth directionality and spatial capabilities of dorsal root ganglion neurons in culture by introducing a chemotaxis effect along a gradient of functionalized DO structures. Finally, we showed that these elements provide enhanced axonal regeneration in a rat sciatic nerve injury model in vivo. This study is a proof of principle for the functionality of DO in neuronal manipulation and regeneration. The approach proposed here, of an engineered platform formed out of programmable nanoscale elements constructed of DO, could be extended beyond the nervous system and revolutionize the fields of regenerative medicine, tissue engineering, and cell biology.

Brain-derived Neurotrophic Factor Level and Gene Polymorphism as Risk Factors for Depression in Patients with type 2 Diabetes Mellitus- A Case-Controlled Study.

Diabetes mellitus and depression are comorbidities that can be caused by each other. Brain-derived neurotrophic factor (BDNF) functions as a neuronal growth factor. It maintains the functional integrity of the nervous system. To study the possible association between BDNF levels and gene polymorphism with depression in patients diagnosed with type 2 diabetes mellitus. The Elisa technique measured BDNF, and rs6265 gene polymorphism was detected using real-time PCR. Depression was assessed utilizing a clinical interview tool designed to establish the diagnosis of depression and differentiate it from other psychiatric diseases. BDNF levels were significantly lower in patients with type 2 diabetes mellitus and symptoms of depression than in patients with type 2 diabetes mellitus and no symptoms of depression (82.6±16.1. Vs 122± 17.47, p˂ 0.001). There was a statistically significant difference in BDNF levels in patients with diabetes among the three genotypes of the BDNF gene (p-value < 0.001). Val/ Val carriers had the highest serum BDNF levels, and Met/ Met carriers had the lowest serum BDNF levels. Subgroup analysis showed statistically significant genotype-related differences in serum BDNF levels among the three subgroups in the Depression group. Val/ Val carriers had the highest serum BDNF levels, and Met/ Met carriers had the lowest serum BDNF levels. BDNF Val66Met polymorphism had no significant association with the presence of depression, yet there was a trend towards significance (p = 0.05) Conclusion: In this pilot, Low levels of BDNF were associated with depression in patients with type 2 diabetes. Carriers of the Met/ Met allele have the lowest serum BDNF levels. Multicenter studies with more participants are required.

The effect of vitamin D on neurite length and neurite elongation velocity during development

AbstractBackgroundStudies have shown that vitamin D plays an important role in the brain (1). In an animal model of nerve trauma, vitamin D2 (ergocalciferol) was shown to be a potent neuromodulatory compound that increases axogenesis, axon diameter, and physiological maturation (2). In addition, the administration of high‐dose vitamin D3 (cholecalciferol) has been demonstrated to enhance the number of preserved or newly formed axons at the proximal end, axon diameter at the distal end, and neurite myelination at both the distal and proximal ends in another animal model of nerve trauma (3). Vitamin D has been shown to increase neurite outgrowth when added to cultured hippocampal cells. However, when removed from the diet of pregnant rats, decreased expression of NGF (neuron growth factor (NGF) was observed in the brains of newborns and adults. Recently, vitamin D has been shown to increase the expression of microtubule‐associated protein‐2 (MAP2), axonal growth‐associated protein‐43 (GAP43), and synapsin‐1 protein in rat cortical neurons (4). Based on this knowledge, we sought to determine whether vitamin D treatment during development might affect neurite length, and elongation velocity.MethodIn our study, primary cortical neuron culture was performed using 16‐day‐old rat embryos. 10−8 M 1,25‐dihydroxyvitamin D3 was applied 24 hours after the culture. Following vitamin D administration, neurite length measurements were made at 30‐second intervals for 30 min and at half‐hour intervals for 12 h under a live cell imaging microscope at 20X magnification.ResultThe results of our study showed that 30 min after vitamin D administration, neurite length and elongation velocity significantly increased in the vitamin D group compared to the control group (p = 0.0029 and p = 0.0310, respectively). In addition, the neurite outgrowth rate and neurite length increased in the vitamin D group 12 h after vitamin D administration compared to the control group (p = 0.0275, p = 0.0398, respectively).ConclusionOnly a few research have examined at how vitamin D affects neurite outgrowth. As a result of vitamin D administration in primary cortical neurons during the developmental phase, our study’s results demonstrated that neurite length and velocity increase in the first 12 hours.

Lessons learned in translating pain knowledge into practice.

During the past 2 decades, basic research deciphering the underlying mechanisms of nociception and chronic pain was thought to finally step beyond opioids and nonsteroidals and provide patients with new analgesics. But apart from calcitonin gene-related peptide antagonists, nothing arrived in hands of clinicians. To present existing evidence of 3 representative target molecules in the development of novel pain treatment that, so far, did not result in approved drugs. This Clinical Update aligns with the 2022 IASP Global Year Translating Pain Knowledge into Practice and selectively reviews best available evidence and practice. We highlight 3 targets: a ion channel, a neuronal growth factor, and a neuropeptide to explore why these drug targets have been dropped in clinical phase II-III trials. Antibodies to nerve growth factor had very good effects in musculoskeletal pain but resulted into more patients requiring joint replacements. Blockers of NaV1.7 were often not effective enough-at least if patients were not stratified. Blockers of neurokinin receptor were similarly not successful enough. In general, failure was most often to the result of a lack of effect and to a lesser extend because of unexpected severe side effects. However, all studies and trials lead to an enormous move in the scientific community to better preclinical models and testing as well as revised methods to molecularly phenotype and stratify patients. All stakeholders in the process can help in the future: better preclinical studies, phenotyping and stratifying patients, and participation in clinical trials to move the discovery of analgesics forward.

29 The Role of Leptin and Its Regulation in the Hypothalamus of Neonatal Calves

Abstract The constant occurrence of increased feed intake in offspring exposed to intrauterine growth restriction has been noted across multiple species including ruminants. In ruminants, reduced circulating leptin concentrations from birth through the first week or two of life may influence the development of the appetite center of the hypothalamus. It should able be noted that increased circulating cortisol at birth has been associated with this decreased circulating leptin in the perinatal ruminants, yet information is limited as to any cause and effect relationship between the two hormones. The objectives of these studies were to test directly the effects of exogenous cortisol on leptin concentrations relative to development of the hypothalamus in perinatal calves and voluntary feed intake as yearling. In two experiments, Holstein bulls (n = 27) and calves (n = 32 males; n = 30 females) from commercial Angus cows were assigned to treatments at parturition (day 0). Calves were intravenously infused with either a low cortisol [LC; n = 9, 3.5 ug/kg of body weight (BW)], high cortisol (HC; n = 9, 7.0 ug/kg BW), or a control (CON; n = 9, saline). Calves were administered a half dose of their respective treatment 24h postpartum. Jugular vein blood samples were collected before infusion and daily until d 17 or necropsy. At 5 days of age Holstein bull calves were euthanized where cerebral-spinal fluid (CSF) and hypothalamic tissue were collected. Serum and CSF leptin concentrations were analyzed via RIA. Neuronal growth factors were analyzed in hypothalamus samples via qRT-PCR. In experiment 2, yearling calves entered a GROWSAFE System and daily feed intake (FI) measured. Animals were allowed a two-week adjustment period to a growing ration for heifers and a finishing ration for steers. Heifer body condition scores (BCS) were collected at the beginning and end of the trial. Heifers underwent the feeding trial for 70 days and steers until they obtained a back fat (BF) thickness of 1.15 cm. Blood samples were analyzed similar to experiment 1. All data were analyzed via repeated measures using appropriate models of SAS (SAS Institute Inc., Cary, NC). Perinatal dairy bull calves had decreased (P &amp;lt; 0.013) serum and CSF leptin concentrations of HC and LC calves compared with CON. Hypothalamic expression of BDNF, FGF1 and FGF2 were decreased (P &amp;lt; 0.006) in HC and LC compared with CON. During the feeding trial: BW gain, BCS change, and number of feed events were increased (P = 0.001) in LC compared with HC and CON heifers. However, LC observed greater daily FI (P = 0.047) and tended to have greater final BW (P = 0.080) compared with HC and CON steers. In summary, these data support that exogenous cortisol administered to perinatal calves affects leptin production and the appetite center of the hypothalamus when administered during the neonatal period.

GSDMD gene knockout alleviates hyperoxia-induced hippocampal brain injury in neonatal mice

BackgroundNeonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain’s inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury.MethodsNewborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes.ResultsHyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO.ConclusionsGSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.

Biomimetic IGA neuron growth modeling with neurite morphometric features and CNN-based prediction

Neuron growth is a complex, multi-stage process that neurons undergo to develop sophisticated morphologies and interwoven neurite networks. Recent experimental research advances have enabled us to examine the effects of various neuron growth factors and seek potential causes for neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. A computational tool that studies the neuron growth process could shed crucial insights on the effects of various factors and potentially help find a cure for neurodegeneration. However, there is a lack of computational tools to accurately and realistically simulate the neuron growth process within reasonable time frames. Bio-phenomenon-based models ignore potential neuron growth factors and cannot generate realistic results, and bio-physics-based models require extensive, high-order governing equations that are computationally expensive. In this paper, we incorporate experimental neurite features into a phase field method-based neuron growth model using an isogeometric analysis collocation (IGA-C) approach. Based on a semi-automated quantitative analysis of neurite morphology, we obtain relative turning angle, average tortuosity, neurite endpoints, average segment length, and the total length of neurites. We use the total neurite length to determine the evolving days in vitro (DIV) and select corresponding neurite features to drive and constrain the neuron growth. This approach archives biomimetic neuron growth patterns with automatic growth stage transitions by incorporating corresponding DIV neurite morphometric data based on the total neurite length of the evolving neurite morphology. Furthermore, we built a convolutional neural network (CNN) to significantly reduce associated computational costs for predicting complex neurite growth patterns. Our CNN model adopts a customized convolutional autoencoder as the backbone that takes neuron growth simulation initializations and target iteration as the input and predicts the corresponding neurite patterns. This approach achieves high prediction accuracy (97.77%) while taking 7 orders of magnitude less computational times when compared with our IGA-C neuron growth solver.

Sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.

The present study aimed to evaluate if sepsis sensitizes behavioural and biochemical responses induced by m-amphetamine. For this, Wistar rats were submitted to the cecal ligation and puncture. After 30 days of cecal ligation and puncture procedure, the animals were submitted to a single intraperitoneal injection of saline or m-amphetamine (.25, .50, or 1.0 mg/kg). Locomotor behaviour was assessed 2 h after the administration. Interleukin (IL)-1β, IL-6, IL-10, tumour necrosis factor-α, dopamine-cAMP-regulated phosphoprotein of 32,000 kDa (DARPP-32) and neuronal calcium sensor (NCS-1) levels were evaluated in the frontal cortex, hippocampus and striatum. Also, brain-derived neurotrophic factor (BDNF), neuronal growth factor and glial-derived neurotrophic factor levels were assessed in the hippocampus. M-amphetamine alone (.25 and 1.0 mg/kg) increased rats' locomotion and exploratory behaviour compared with the Sham + Sal. Animals from the cecal ligation and puncture + m-amphetamine (.5 and/or 1.0 mg/kg) group showed an increase in locomotion, exploratory and risk-like behaviour when compared with the Sham + Saline group and with its respective Sham groups. Cecal ligation and puncture increased interleukin levels compared with the Sham + Sal. However, cecal ligation and puncture animals that received m-amphetamine (1 mg/kg) increased even more, these inflammatory parameters compared with the Sham + Sal and the cecal ligation and puncture + saline group. M-amphetamine at lower doses increased neurotrophic factors, but higher doses decreased these parameters in the brain of cecal ligation and puncture rats. M-amphetamine dose-dependently increased DARPP-32 and NCS-1 levels in cecal ligation and puncture rats in some structures. In conclusion, these results demonstrate that sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.

Design Principles of a Novel Construct for HBB Gene-Editing and Investigation of Its Gene-Targeting Efficiency in HEK293 Cells.

Beta-thalassemia is one of the most common monogenic inherited disorders worldwide caused by different mutations in the hemoglobin subunit beta (HBB) gene. Genome-editing based on clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 system (CRISPR/Cas9) has raised the hope for life-long gene therapy of beta-thalassemia. In a proof-of-concept study, we describe the detailed design and assess the efficacy of a novel homology-directed repair (HDR)-based CRISPR construct for targeting the HBB locus. The selectedsgRNAs were designed and cloned into an optimized CRISPR plasmid. The HDR donor templates containing a reporter and a selection marker flanked by the piggyBac Inverted Tandem Repeat (ITRs), the homology arms and the delta thymidine kinase (ΔTK) gene for negative selection were constructed. The efficiency of on-target mutagenesis by the eSpCas9/sgRNAs was assessed by mismatch assays. HDR-positive cells were isolated by treatment with G418 or selection based on truncated Neuron Growth Factor Receptor (tNGFR) expression using the Magnetic Activated Cell Sorting (MACS) method followed by ganciclovir (GCV) treatment to eliminate cells with random genomic integration of the HDR donor template. In-out PCR and sanger sequencing confirmed HDR in the isolated cells. Our data showed ~ 50% efficiency forco-transfectionof CRISPR/donor template plasmids in HEK293 cells and following G418 treatment, the HDR efficiency was detected at ~ 37.5%. Moreover, using a clinically-relevant strategy, HDR events were validated after selection for tNGFR+ cells followed by negative selection for ΔTK by GCV treatment. Thus, our HDR-based gene-editingstrategy could efficiently target the HBB locus and enrich for HDR-positive cells.

Glia maturation factor beta deficiency protects against diabetic osteoporosis by suppressing osteoclast hyperactivity

Excessive osteoclast activation, which depends on dramatic changes in actin dynamics, causes osteoporosis (OP). The molecular mechanism of osteoclast activation in OP related to type 1 diabetes (T1D) remains unclear. Glia maturation factor beta (GMFB) is considered a growth and differentiation factor for both glia and neurons. Here, we demonstrated that Gmfb deficiency effectively ameliorated the phenotype of T1D-OP in rats by inhibiting osteoclast hyperactivity. In vitro assays showed that GMFB participated in osteoclast activation rather than proliferation. Gmfb deficiency did not affect osteoclast sealing zone (SZ) formation but effectively decreased the SZ area by decreasing actin depolymerization. When GMFB was overexpressed in Gmfb-deficient osteoclasts, the size of the SZ area was enlarged in a dose-dependent manner. Moreover, decreased actin depolymerization led to a decrease in nuclear G-actin, which activated MKL1/SRF-dependent gene transcription. We found that pro-osteoclastogenic factors (Mmp9 and Mmp14) were downregulated, while anti-osteoclastogenic factors (Cftr and Fhl2) were upregulated in Gmfb KO osteoclasts. A GMFB inhibitor, DS-30, targeting the binding site of GMFB and Arp2/3, was obtained. Biocore analysis revealed a high affinity between DS-30 and GMFB in a dose-dependent manner. As expected, DS-30 strongly suppressed osteoclast hyperactivity in vivo and in vitro. In conclusion, our work identified a new therapeutic strategy for T1D-OP treatment. The discovery of GMFB inhibitors will contribute to translational research on T1D-OP.

Effect of Melatonin on Alpha Synuclein and Autophagy in Dopaminergic Neuronal Differentiation of Adipose Mesenchymal Stem Cells.

The current work investigated the effect of melatonin on differentiation of adipose mesenchymal stem cells (AD-MSCs) into dopamine producing cells and its effect on autophagy process and alpha-Synuclein (α-Syn) secretion. AD-MSCs were characterized by flow cytometry and divided into 4 groups; i) control group (AD-MSCs without any treatment), ii) M+MSCs group (MSCs treated with 1 µM melatonin for 12 days), iii) DN group (MSCs cultured in neurobasal A medium and essential neuronal growth factors for 12 days) and iv) DN+M group (MSCs cultured in neurobasal A medium and 1µM melatonin for 12 days. By the end of experiments, the dopamine and α-Syn levels using ELISA, the expression of MAP-2, m-TOR and α-Syn genes at the level of mRNA and detection of autophagosomes formation using transmission electron microscope were performed. We found that the isolated cells were MSCs due to their positivity expression for CD105 and CD90 and negativity expression for CD34 and CD45. The concentration of dopamine was significantly higher and α-Syn concentration was significantly lower in DN+M group when compared to other groups (P< 0.005). Also, this group showed the highly expression for MAP-2 gene and less expression for m-TOR and α-Syn genes (P< 0.005). Moreover, there was significantly increase in autophagosomes formation in this group than another group (P< 0.005). It is concluded that the melatonin promotes the differentiation of rat AD-MSCs into dopaminergic cells via induction of autophagy process and reduction of α-Syn secretion.

ER proteostasis regulators cell-non-autonomously control sleep

Sleep is regulated by peripheral tissues under fatigue. The molecular pathways in peripheral cells that trigger systemic sleep-related signals, however, are unclear. Here, a forward genetic screen in C.elegans identifies 3 genes that strongly affect sleep amount: sel-1, sel-11, and mars-1. sel-1 and sel-11 encode endoplasmic reticulum (ER)-associated degradation components, whereas mars-1 encodes methionyl-tRNA synthetase. We find that these machineries function in non-neuronal tissues and that the ER unfolded protein response components inositol-requiring enzyme 1 (IRE1)/XBP1 and protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α)/activating transcription factor-4 (ATF4) participate in non-neuronal sleep regulation, partly by reducing global translation. Neuronal epidermal growth factor receptor (EGFR) signaling is also required. Mouse studies suggest that this mechanism is conserved in mammals. Considering that prolonged wakefulness increases ER proteostasis stress in peripheral tissues, our results suggest that peripheral ER proteostasis factors control sleep homeostasis. Moreover, based on our results, peripheral tissues likely cope with ER stress not only by the well-established cell-autonomous mechanisms but also by promoting the individual's sleep.

Pharmacokinetics and toxicology studies of new neuronal growth factor

Pharmacokinetics and toxicology studies of new neuronal growth factor

The Emerging Role of Pericyte-Derived Extracellular Vesicles in Vascular and Neurological Health.

Pericytes (PCs), as a central component of the neurovascular unit, contribute to the regenerative potential of the central nervous system (CNS) and peripheral nervous system (PNS) by virtue of their role in blood flow regulation, angiogenesis, maintenance of the BBB, neurogenesis, and neuroprotection. Emerging evidence indicates that PCs also have a role in mediating cell-to-cell communication through the secretion of extracellular vesicles (EVs). Extracellular vesicles are cell-derived, micro- to nano-sized vesicles that transport cell constituents such as proteins, nucleic acids, and lipids from a parent originating cell to a recipient cell. PC-derived EVs (PC-EVs) play a crucial homeostatic role in neurovascular disease, as they promote angiogenesis, maintain the integrity of the blood-tissue barrier, and provide neuroprotection. The cargo carried by PC-EVs includes growth factors such as endothelial growth factor (VEGF), connecting tissue growth factors (CTGFs), fibroblast growth factors, angiopoietin 1, and neurotrophic growth factors such as brain-derived neurotrophic growth factor (BDNF), neuron growth factor (NGF), and glial-derived neurotrophic factor (GDNF), as well as cytokines such as interleukin (IL)-6, IL-8, IL-10, and MCP-1. The PC-EVs also carry miRNA and circular RNA linked to neurovascular health and the progression of several vascular and neuronal diseases. Therapeutic strategies employing PC-EVs have potential in the treatment of vascular and neurodegenerative diseases. This review discusses current research on the characteristic features of EVs secreted by PCs and their role in neuronal and vascular health and disease.

Evaluation of the dynamics of changes in the quantitative content of neuron growth factor (Beta-NGF) in the blood serum of patients who have suffered an ischemic stroke under the influence of complex physical rehabilitation

The article is devoted to the study of dynamic of changes in the quantitative content of neuron growth factor (Beta-NGF) in the blood serum of patients who have suffered ischemic stroke under the influence of complex physical rehabilitation. 116 patients in the recovery period of ischemic stroke (IS) (from 3 to 6 months) were examined. The average age of the patients was 61.4±0.53 years. During the study all patients were divided into two groups depending on the type of rehabilitation treatment. Group 1 consisted of 66 patients who received standard drug therapy aimed at secondary prevention during the entire period of the study and undergoing a course of complex physical rehabilitation. Group 2 consisted of 50 patients who received only standard drug therapy as part of secondary IS prevention. The control group included 30 practically healthy persons of the appropriate age and subjects who, according to the anamnesis and neuroimaging data, had no signs of a previous IS. The average age of the control group was 61.07±0.75 years. Beta-NGF was determined in 22 patients of group 1 and group 2 before the beginning of inpatient treatment and after its completion. This study was also conducted once for 10 people from the control group. The analysis of the results showed a significant decrease in the content of Beta-NGF in blood serum in patients with IS in the recovery period, which, in our opinion, may be associated with hypoxic damage to the brain tissue. In favor of this, data indicate the presence of a strong correlation between the level of Beta-NGF content and MMSE indicators. Also, the obtained data suggest that a significant decrease in the level of Beta-NGF content can be an indicator of the presence of type 2 diabetes. Significantly higher quantitative content of Beta-NGF in blood serum and statistically significant differences in dynamic changes during the study in patients of the first group indicate that physical rehabilitation can contribute to an increase in the content of Beta-NGF and thus cause a positive effect on the restoration of functions impaired as a result of a brain catastrophe.

Methacrylic acid-based biomaterials promote peripheral innervation in the subcutaneous space of mice

Peripheral nerve innervation is essential for regulating tissue repair and regeneration. MAA-based biomaterials have been previously shown to promote angiogenesis. Here we show a new role for MAA-based biomaterials in promoting terminal axon nerve growth. Our results demonstrate that MAA-based biomaterials promote peripheral nerve growth in an Igf-1 and Shh dependent manner. The resulting nerves increased the sensitivity of treated mice paws to nociception. iDISCO clearing showed that MAA increased the presence of peripheral nerve structures in whole explants. MAA was also able to increase the expression of key neuronal markers and growth factors in a peripheral neuropathy model, the diabetic db/db mouse, suggesting that MAA-based biomaterials may be relevant to treatment of peripheral neuropathy. Moreover, in a peripheral neuropathy model, MAA was able to up-regulate the expression of growth factors for an extended duration suggesting MAA may prevent degeneration through an effect on factors that promote survival. As all tissues are innervated, MAA-based biomaterials could have broad applications in the promoting regeneration and preventing degeneration of peripheral nerves.

Application of chemical factors for acceleration of consolidation phase of the distraction osteogenesis: a scoping review.

This study aimed to analyze the effect of injecting chemical factors compared to conventional distraction osteogenesis (DO) treatment on the bone formation of the distracted area of the maxillofacial region in human and animal studies. Electronic search was done in PubMed, Scopus, Embase, and Cochrane database for studies published until September 2021. The studies' risk of bias (ROB) was assessed using the Cochrane Collaborations and NIH quality assessment tools. Meta-analyses were performed to assess the difference in the amount of bone formation and maximal load tolerance. Among a total of 58 included studies, eight studies analyzed the bone formation rate of the distracted area in human models and others in animal models. Results of the human studies showed acceptable outcomes in the case of using bone morphogenic protein-2 (BMP-2), autologous bone-platelet gel, and calcium sulfate. However, using platelet reach plasma does not increase the rate of bone formation significantly. Quantitative analyses showed that both BMP-2 (SMD = 26.57; 95% CI = 18.86 to 34.28) and neuron growth factor (NGF) (SMD = 16.19; 95% CI = 9.64 to 22.75) increase the amount of bone formation. Besides, NGF increased the amount of load tolerance significantly (SMD = 30.03; 95% CI = 19.91 to 40.16). Additionally, BMP-2 has no significant impact on the post-treatment maxillary length (SMD = 9.19; 95% CI = - 2.35 to 20.73). Limited number of human studies with low quality used chemical factors to enhance osteogenesis and showed acceptable results. However, more studies with higher quality are required.