Neurotrophic Factor Growth Research Articles

Serum brain-derived neurotrophic factor in the diagnosis of febrile seizure.

Brain-derived neurotrophic factor (BDNF) is a noncovalently linked homodimer protein from the neurotrophic growth factor family. Although it is expressed throughout the brain, it is produced more intensively in the entorhinal cortex and hippocampus and can cross the blood-brain barrier in two directions easily. The aim of this study is to understand, for the first time, whether there is a relationship between febrile seizure (FS) and BDNF. The study included cases diagnosed with FS and febrile illness, of similar age, weight, and height, between 6months and 6years. Samples for serum BDNF measurement were taken within the first 24-48h of admission at the hospital and levels were measured using the commercial enzyme-linked immunosorbent assay kit and expressed in ng/mL. Eighty cases (40 FS, 40 febrile illness) were included in the study. The mean serum BDNF was found to be 6.7±2.4ng/mL in the FS group and 4.5±2.6ng/mL in the febrile illness group (P=0.001). No relation was found between gender, age, body weight, length, and platelet counts and serum BDNF levels. The optimal cut-off value for serum BDNF was found to be 5.2ng/mL (75% sensitivity, 62.5% specificity, AUC: 0.723) to distinguish between FS and febrile illness. Excluding demographic variables such as gender, age, weight, length, and platelet counts serum BDNF levels have increased in children with FS. Considering the hippocampal origin of FS, we can suggest that the pathophysiology of FS may be related to the BDNF.

Altered levels of interleukins and neurotrophic growth factors in mood disorders and suicidality: an analysis from periphery to central nervous system

Interleukins and neurotrophins levels are altered in the periphery of patients with major depression and suicidal behavior, however it is not clear if similar abnormalities occur in the central nervous system. Our objective was to examine the association of IL-6, IL-1β, BDNF, and GDNF levels between postmortem plasma, cerebrospinal fluid (CSF), and brain tissue in a heterogeneous diagnostic subject groups including normal controls, mood disorders only, mood disorders with AUD/SUD (alcohol abuse disorder, substance abuse disorder), and AUD/SUD without mood disorders. To address these questions we collected postmortem plasma (n = 29), CSF (n = 28), and brain (BA10) (n = 57) samples from individuals with mood disorder, mood disorder with AUD/SUD, AUD/SUD and normal controls. These samples were analyzed using a multiplex based luminex assay with a customized 4-plex cytokine/interleukins- IL-6, IL-1β, BDNF, and GDNF human acute phase based on xMAP technology platform. Protein levels were determined using a Luminex 200 instrument equipped with Xponent-analyzing software. We observed IL-6 (p = 2.1e-07), and GDNF (p = 0.046) were significantly correlated between brain and CSF. In addition, IL-6 (p = 0.031), were significantly correlated between brain and plasma. Overall diagnostic group analysis showed a significant difference with brain GDNF, p = 0.0106. Pairwise comparisons showed that GDNF level is—39.9 ± 12 pg/ml, p = 0.0106, was significantly higher than in the brains derived from mood disorders compared to normal controls, —23.8 ± 5.5 pg/ml, p = 0.034. Brain BDNF was higher in suicide (p = 0.0023), males compared to females (p = 0.017), and psychiatric medication treated vs. non-treated (p = 0.005) individuals. Overall, we demonstrate that blood IL-6, GDNF and BDNF could be informative peripheral biomarkers of brain biology associated with mood disorders, substance disorders, and suicide.

Tungsten accumulates in the intervertebral disc and vertebrae stimulating disc degeneration and upregulating markers of inflammation and pain.

Tungsten is incorporated in many industrial goods, military applications and medical devices due to its ability to impart flexibility, strength and conductance to materials. Emerging evidence has questioned the safety of tungsten exposure as studies have demonstrated it can promote tumour formation, induce pulmonary disease and alter immune function. Although tungsten is excreted from the body it can accumulate in certain organs such as the brain, colon, liver, kidneys, spleen and bones, where most of the bioaccumulation occurs. Whether prolonged tungsten exposure leads to accumulation in other tissues is unknown. The present study demonstrated that mice exposed to 15 ppm sodium tungstate for 4 weeks in their drinking water showed comparable accumulation in both the bony vertebrae and intervertebral discs (IVDs). Lumbar IVD height was significantly reduced in tungsten-exposed mice and accompanied by decreased proteoglycan content and increased fibrosis. In addition to catabolic enzymes, tungsten also increased the expression of the inflammatory cytokines IL-1β and tumour necrosis factor (TNF)-α as well as the neurotrophic factors nerve growth factor (NGF) and brain-derived nerve factor (BDNF) in IVD cells. Tungsten significantly increased the presence of nociceptive neurons at the endplates of IVDs as observed by the expression of calcitonin gene-related peptide (CGRP) and anti-protein gene product 9.5 (PGP9.5) in endplate vessels. The present study provided evidence that tungsten may enhance disc degeneration and fibrosis as well as increase the expression of markers for pain. Therefore, tungsten toxicity may play a role in disc degeneration disease.

The role of neurotrophic growth factors in the pathophysiology of bronchial asthma associated with obesity

Bronchial asthma (BA) and obesity are common diseases with a tendency towards a steady and progressive increase in the number of patients. A combination of these diseases is one of the major problems of modern medicine, requiring close attention due to a decrease in the quality of life, poor control over the course of the primary disease, and an increase in the frequency and duration of hospitalization. The association between asthma and obesity is obvious. However, detailed mechanisms underlying it require further investigation. In the last decade, in the formation of the phenotype of BA combined with obesity, much attention has been paid not only to the immune, but also to the neurogenic mechanisms of inflammatory response. It is known that the functioning of all parts of the nervous system can be controlled by neurotrophic growth factors due to their ability to influence many signalling mechanisms. Currently, there is evidence that neurotrophic factors are involved in the pathogenesis of bronchopulmonary and metabolic diseases. The review is devoted to detailed investigation of the mechanisms of neurogenic inflammation in obesity and asthma with participation of neurotrophic factors that may play a significant role in the formation of the BA phenotype associated with obesity. The study of new mechanisms involved in the pathogenesis of asthma and obesity will make it possible to find common therapeutic targets for this asthma phenotype.

Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism

AbstractPatients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line–derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.

Stem Cells: Insights into Niche, Classification, Identification, Characterization, Mechanisms of Regeneration by Using Stem Cells, and Applications in Joint Disease Remedy

Background: Stem cell therapy has attracted much interest in the 21st century, not only because of the controversy surrounding the ethics involving pluripotent stem cells, but their potential for clinical use. Objectives: The present review highlights the stem cells niche, types, identification, and characterization, mechanisms of regeneration by using stem cells, and applications in joint disease remedy. Stem cells could be well differentiated cells with the potential to display different cell types depending on the host niche. Niche is defined as the cellular microenvironment providing support and stimuli to control the properties of stem cells. It consists of signaling molecules, inter-cell contacts and interaction between stem cells and their extracellular matrix neighbors. Stem cells are classified according to their sources into two main types, the embryonic and non-embryonic. Embryonic stem cells are pluripotent and can differentiate into all germ layers. Non-embryonic stem cells can be sub-classified into fetal stem cells and adult stem cells. Cultured cells can be made to differentiate into exclusive lineages by providing selective media components that can be identified by histochemical staining and quantified by quantitative Real-time polymerase chain reaction. Mesenchymal stem cells (MSCs) can be identified based on the expression of specific proteins called surface antigen phenotype of mesenchymal stem cell markers. MSCs secrete a variety of interleukins, several neurotrophic factors, many cytokines, and growth factors. These secreted bioactive factors have both paracrine and autocrine effects, which are anti-fibrotic and anti-apoptotic, as well as enhance angiogenesis. Furthermore, they stimulate mitosis and differentiation of tissue-intrinsic reparative stem cells. Systemic MSC transplantation can engraft to an injured tissue and promote wound healing through differentiation, and proliferation in synergy with hematopoietic stem cells. MSCs have been shown to express a variety of chemokines and chemokine receptors and can home to sites of inflammation by migrating towards injury or inflammatory chemokines and cytokines. MSCs are proven to have immunomodulatory properties that are among the most intriguing aspects of their biology. The immunosuppressive properties of MSCs inhibit the immune response of naive and memory T cells in a mixed lymphocyte culture and induce mitogen. The systemic infusion of MSCs can be used in immunosuppressive therapy of various disorders. MSCs have become an alternative source of cells that can be drawn from several these cells have been used as treatment to repair cartilage defects at early stages sources. Using the MSCs and directing them into chondrogenic differentiation might lead to the formation of higher quality cartilage, which has a great composition of hyaline, adequate structural reorganization and therefore improved biomechanical properties. Conclusion: It can be concluded that stem cells are classified according to their sources into two main types, the embryonic and non-embryonic. Embryonic stem cells are pluripotent and can differentiate into all germ layers. Non-embryonic stem cells can be sub-classified into fetal stem cells and adult stem cells. MSCs secrete bioactive factors that are anti-fibrotic and anti-apoptotic, as well as enhance angiogenesis. The systemic infusion of MSCs can be used in immunosuppressive therapy of various disorders. These cells have been used as treatment to repair cartilage defects at early stages.

Mini-review: Trophic interactions between cancer cells and primary afferent neurons

Cancer neurobiology is an emerging discipline that inevitably unfurls new perspectives in oncology. The role that nerves play in cancer progression resonates with the long-reported dependency of tumors on neuro-molecular mechanisms that remain insufficiently elucidated. Whereas interactions between neurotrophic growth factors and receptors have been heavily studied in the nervous system, their expression in cancers and their impact on tumor cell growth and metastasis through their corresponding signaling pathways has been undervalued. Accumulating evidence suggests that trophic factors released by nerves strongly influence tumor development and that this neural contribution appears to not only play a stimulatory role but also function as an essential part of the tumor’s microenvironment. This bidirectional communication between proliferating cells and tumor-infiltrating nerves drives axonogenesis and tumor growth and migration. Acquiring a better understanding of the trophic interactions between primary afferent neurons and invading tumors will guide clinically actionable strategies to prevent tumor-associated axonogenesis, disrupting the chemical crosstalk between neurons and tumors and ultimately decreasing tumor growth and spread.

Recombinant Human Growth Hormone Activates Neuroprotective Growth Factors in Hypoxic Brain Injury in Neonatal Mice.

Perinatal hypoxia severely disrupts cerebral metabolic and maturational programs beyond apoptotic cell death. Antiapoptotic treatments such as erythropoietin are suggested to improve outcomes in hypoxic brain injury; however, the results are controversial. We analyzed the neuroprotective effects of recombinant human growth hormone (rhGH) on regenerative mechanisms in the hypoxic developing mouse brain in comparison to controls. Using an established model of neonatal acute hypoxia (8% O2, 6 hours), P7 mice were treated intraperitoneally with rhGH (4000 µg/kg) 0, 12, and 24 hours after hypoxic exposure. After a regeneration period of 48 hours, expression of hypoxia-inducible neurotrophic factors (erythropoietin [EPO], vascular endothelial growth factor A [VEGF-A], insulin-like growth factors 1 and 2 [IGF-1/-2], IGF binding proteins) and proinflammatory markers was analyzed. In vitro experiments were performed using primary mouse cortical neurons (E14, DIV6). rhGH increased neuronal gene expression of EPO, IGF-1, and VEGF (P < .05) in vitro and diminished apoptosis of hypoxic neurons in a dose-dependent manner. In the developing brain, rhGH treatment led to a notable reduction of apoptosis in the subventricular zone and hippocampus (P < .05), abolished hypoxia-induced downregulation of IGF-1/IGF-2 expression (P < .05), and led to a significant accumulation of endogenous EPO protein and anti-inflammatory effects through modulation of interleukin-1β and tumor necrosis factor α signaling as well as upregulation of cerebral phosphorylated extracellularly regulated kinase 1/2 levels (ERK1/2). Indicating stabilizing effects on the blood-brain barrier (BBB), rhGH significantly modified cerebrovascular occludin expression. Thus, we conclude that rhGH mediates neuroprotective effects by the activation of endogenous neurotrophic growth factors and BBB stabilization. In addition, the modification of ERK1/2 pathways is involved in neuroprotective actions of rhGH. The present study adds further evidence that pharmacologic activation of neurotrophic growth factors may be a promising target for neonatal neuroprotection.

Nanofibrous bicomponent scaffolds for the dual delivery of NGF and GDNF: controlled release of growth factors and their biological effects

Electrospun fibrous scaffolds capable of providing dual growth factor delivery in a controlled manner have distinctive advantages for tissue engineering. In this study, we have investigated the formation, structure, and characteristics/properties of fibrous bicomponent scaffolds for the dual delivery of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) for peripheral nerve tissue regeneration. GDNF and NGF were incorporated into core-shell structured poly(lactic-co-glycolic acid) (PLGA) and poly (d,l-lactic acid) (PDLLA) nanofibers, respectively, through emulsion electrospinning. Using dual-source dual-power electrospinning, bicomponent scaffolds composed of GDNF/PLGA fibers and NGF/PDLLA fibers with different fiber component ratios were produced. The structure, properties, and in vitro release behavior of mono- and bicomponent scaffolds were systematically investigated. Concurrent and sustained release of GDNF and NGF from bicomponent scaffolds was achieved and their release profiles could be tuned. In vitro biological investigations were conducted. Rat pheochromocytoma cells were found to attach, spread, and proliferate on all scaffolds. The release of growth factors from scaffolds could induce much improved neurite outgrowth and neural differentiation. GDNF and NGF released from GDNF/PLGA scaffolds and NGF/PDLLA scaffolds, respectively, could induce dose-dependent neural differentiation separately. GDNF and NGF released from bicomponent scaffolds exerted a synergistic effect on promoting neural differentiation.

The First and Last Time I Met Rita Levi-Montalcini: From the Insect Neurotrophic Factor to the Nerve Growth Factor Clinical Application : RLM and the Discovery of Two Neurotrophic Factors.

The neurotrophic factor nerve growth factor (NGF) has been discovered in the 1950s by Rita Levi-Montalcini, first in a neoplastic tissue and, later, in the mouse salivary gland (see 1A). Levi-Montalcini characterized its action in the sensory and sympathetic neurons (1B) and, a few years later, in central nervous, endocrine, and immune systems. Nerve growth factor plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. The aim of the present overview is to describe my personal scientific and human experiences working with Rita Levi-Montalcini for over 45years, first at Washington University in St. Louis, Missouri, USA, searching (1) the invertebrate neurotrophic factor in the cockroaches and, later, at the Institute of Neurobiology of the National Research Council (CNR) in Rome studying (2) the role of NGF for various neuronal and non-neuronal functions; (3) the potential involvement of NGF in the pathobiology of human cutaneous, ocular, neurodegenerative, and cardiometabolic diseases; and finally (4) NGF potential clinical application.

The Role of Neurotrophic Factors in Pathophysiology of Major Depressive Disorder.

According to the neurotrophic hypothesis of major depressive disorder (MDD), impairment in growth factor signaling might be associated with the pathology of this illness. Current evidence demonstrates that impaired neuroplasticity induced by alterations of neurotrophic growth factors and related signaling pathways may be underlying to the pathophysiology of MDD. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic factor involved in the neurobiology of MDD. Nevertheless, developing evidence has implicated other neurotrophic factors, including neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), glial cell-derived neurotrophic factor (GDNF), and fibroblast growth factor (FGF) in the MDD pathophysiology. Here, we summarize the current literature on the involvement of neurotrophic factors and related signaling pathways in the pathophysiology of MDD.

Combined training of aerobic exercise and 3D video game to improve hippocampal and memory functions in older adults: An RCT trial

AbstractBackgroundWith the proportion of older adults rising, the progressive cognitive decline and dementia have become one of the most serious public health issues worldwide. As a result, there is a pressing need for developing effective non‐pharmaceutical intervention programs to counteract age‐related cognitive decline. Animal models robustly support that aerobic exercise can effectively improve neurogenesis and memory, whereas most of the current findings from human studies are in contrast. We speculated that two reasons may contribute to these inconsistent findings in human research. One is that hippocampal neurogenesis induced by the aerobic exercise is more likely to survive when simultaneously accompanied by cognitive stimulations, particularly when the cognitive goals are challenging. Another is that the beneficial effects from aerobic exercise are specific to hippocampal dependent memory tasks. Therefore, we designed a training program by combining aerobic cycling with 3D video game.MethodWe conducted a randomized controlled trial with healthy older adults randomly assigned to combined aerobic cycling and 3D video game training group (n=22), aerobic cycling group (n=23), 3D video games group (n=25), or control group (n=28). The effects of combined training on neuroplasticity (including plasma brain‐derived neurotrophic growth factor, hippocampal gray matter volume, and hippocampal‐cortical functional connectivity) and cognitive plasticity (focusing on hippocampal‐dependent memory, tested via Mnemonic Similarity Task) were examined compared with all three other groups. The training lasted four months with a frequency of twice per week, 1hour per session.ResultThe combined and video game training groups reported equivalent game experiences and reached similar game levels. The average and maximum heart rates were being monitored to ensure a medium exercise intensity in both combined and cycling groups. In addition self‐reported fatigue levels were equivalent in these two groups. The preliminary behavioral data analysis revealed that combined group performed better on immediate and delayed memory recall. More importantly, there was a larger effect size in pattern separation task in combined group (Cohen’s d =1.12) than in cycling (Cohen’s d =0.49) and video game (Cohen’s d =0.55) groups.ConclusionCombined aerobic exercise ‐ video game training could improve hippocampal‐dependent memory functions, which waits the MRI data analysis to further prove.

Melatonin ameliorates spatial memory and motor deficits via preserving the integrity of cortical and hippocampal dendritic spine morphology in mice with neurotrauma.

We aimed to elucidate the role of cortical and hippocampal dendritic spines on neurological deficits associated with hippocampal microgliosis, hippocampal neurogenesis, and neuroinflammation in mice with cortical compact impact (CCI) injury. In the present study, we found that CCI reduced spatial memory mean latency (10s. vs 50s) and motor dysfunction (130s. vs 150s.) in mice, as determined by Morris water maze and rotarod test, respectively. Golgi staining of cortical pyramidal neurons revealed that, compared to the controls, the CCI group treated with vehicle solution had significantly lower values of dendritic order (or dendritic branch number) (4.0 vs 6.2), total spine length (400μm vs 620μm) and spine density (40spines/μm vs 60spines/μm), but had significantly higher values of dendritic beading (40beadings/mm vs 20beadings/mm). Additionally, Sholl analysis showed that, compared to controls, the CCI + NS group mice had significantly lower values of dendritic intersections (1.0 vs 2.0). Immunofluorescence assay also revealed that, compared to controls, the CCI + NS group mice had significantly higher values of the newly formed hippocampal cells (1250/mm2 vs 1000/mm2) but significantly lower values of dendritic order (2.0 branch # vs 4.2 branch #), total spine length (180μm vs 320μm) and intersection (1.0 vs 3.0). The CCI + NS group mice further showed significantly higher numbers of microglia in the dentate gyrus of the hippocampus and higher concentrations of pro-inflammatory cytokines in the cerebrospinal fluids. All the CCI-induced spatial memory (40s) and motor (150s) dysfunction, deranged dendritic and spine morphology of cortical pyramidal neurons or hippocampal newly formed cells, hippocampal microgliosis, and central neuroinflammation were all significantly reduced by melatonin administration during post-CCI. Simultaneously, melatonin therapy caused an enhancement in the compensatory hippocampal neurogenesis and neurotrophic growth factors (e.g., doublecortin-1) and compensatory central anti-inflammatory cytokines. Our results indicate that melatonin attenuates the spatial memory and motor deficits via the modification of cortical and hippocampal dendritic spine morphology, hippocampal microgliosis and neurogenesis, and neuroinflammation in mice with traumatic brain injury.

Central nervous system damage markers in children: current state of the problem

Pathology of the central nervous system (CNS) occupies one of the leading places in the structure of childhood morbidity and mortality. In the modern world the diagnosis of central nervous system diseases is based not only on the a thorough history, identification of certain neurological symptoms during an objective medical examination of the child and data from various neuroimaging methods, but also on the use of laboratory research methods with the identification of specific markers which indicate a pathological process occurring in the tissues of the brain and spinal cord. The article presents modern data on the biochemical parameters indicating damage to the nervous tissue, as well as their role in conditions of homeostasis and the prospects for further research. We analyzed the latest domestic and foreign literature on the properties and role of such indicators as neurotrophic growth factor, vascular endothelial growth factor, monocytic chemotactic protein, trigger receptor expressed on myeloid cells-1, trigger receptor expressed on myeloid cells-2, transforming growth factor, fractalkin, a nerve growth factor, which is a promising direction in the study of damage to nerve tissue. We can conclude that а study of the level of these markers will help diagnose the presence of damage to the nerve tissue, its severity, and therefore, select the right individual therapy for each specific child, thereby preventing the development of severe neurological consequences.

Effects of an alpha-1d adrenoreceptor antagonist (naftopidil) on bladder dysfunction after radiotherapy in female rats.

Storage-phase bladder dysfunction can develop after pelvic radiotherapy. As the alpha-1d adrenoreceptor (a1d-AR) is dominant in the human detrusor, we aimed to investigate the effect of an a1d-AR antagonist on bladder dysfunction after pelvic radiotherapy in a rat model. Twenty-four female Wistar rats were used. Eight rats (14-15weeks, 250-300g) were randomized to three groups (normal reference group, radiation alone group and radiation plus naftopidil group). An 18-Gy dose of radiotherapy was applied to the radiation alone and radiation plus naftopidil groups. Naftopidil (20mg/kg) was administered daily to the radiation plus naftopidil group. Four weeks after radiation, all rats underwent cystometry and were killed for reverse transcription polymerase chain reaction to detect mRNAs [a1d-AR, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF)], Western blot to detect proteins (a1d-AR, extracellular-signal-regulated kinase, BDNF and VEGF) and immunohistochemistry. Compared to the radiation alone group, (1) the decrease in the mRNA and protein expression of a1d-AR and VEGF was ameliorated, (2) the increase in the expression of BDNF mRNA and proteins such as extracellular-signal-regulated kinase and BDNF was suppressed, (3) submucosal thickness and vascularity on immunohistochemistry were improved, and (4) the baseline intravesical pressure and intercontraction interval in cystometry were ameliorated in the radiation plus naftopidil group. Administration of an a1d-AR antagonist could improve storage-phase bladder dysfunction after radiotherapy not only by upregulating a1d-AR, which might decrease bladder compliance, but also by enhancing vascularity, which might protect the urinary bladder from chronic ischemic inflammation.

Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model.

PurposeDiabetes mellitus (DM)-induced brain damage is characterized by cellular, molecular and functional changes. The mechanisms include oxidative stress, neuroinflammation, reduction of neurotrophic factors, insulin resistance, excessive amyloid beta (Aβ) deposition and Tau phosphorylation. Both antidiabetic and neuroprotective effects of the phytoestrogen genistein have been reported. However, the beneficial effect of genistein in brain of the ob/ob mouse model of severe obesity and diabetes remains to be determined.MethodsIn this study, female ob/ob mice and lean control mice were fed with either a standard diet or a diet containing genistein (600mg/kg) for a period of 4 weeks. Body weight was monitored weekly. Blood was collected for the measurement of glucose, insulin and common cytokines. Mice brains were isolated for Western immunoblotting analyses.ResultsTreatment with genistein reduced weight gain of ob/ob mice and decreased hyperglycemia compared to ob/ob mice fed the standard diet. The main findings show that genistein treatment increased insulin sensitivity and the expression levels of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factors (BDNF). In these mice, genistein also reduced Aβ deposition and the level of hyper-phosphorylated Tau protein.ConclusionThe results of our study indicate the beneficial effects of genistein in the obese diabetic mouse brain, including improving brain insulin signaling, increasing neurotrophic support, and alleviating Alzheimer’s disease-related pathology.

Chasing Protection in Parkinson's Disease: Does Exercise Reduce Risk and Progression?

Exercise may be the most commonly offered yet least consistently followed therapeutic advice for people with Parkinson’s disease (PD). Epidemiological studies of prospectively followed cohorts have shown a lower risk for later developing PD in healthy people who report moderate to high levels of physical activity, and slower rates of motor and non-motor symptom progression in people with PD who report higher baseline physical activity. In animal models of PD, exercise can reduce inflammation, decrease α-synuclein expression, reduce mitochondrial dysfunction, and increase neurotrophic growth factor expression. Randomized controlled trials of exercise in PD have provided clear evidence for short-term benefits on many PD measurements scales, ranging from disease severity to quality of life. In this review, we present these convergent epidemiological and laboratory data with particular attention to translationally relevant features of exercise (e.g., intensity requirements, gender differences, and associated biomarkers). In the context of these findings we will discuss clinical trial experience, design challenges, and emerging opportunities for determining whether exercise can prevent PD or slow its long-term progression.

Distinct effects of acute exercise and breaks in sitting on working memory and executive function in older adults: a three-arm, randomised cross-over trial to evaluate the effects of exercise with and without breaks in sitting on cognition

BackgroundSedentary behaviour is associated with impaired cognition, whereas exercise can acutely improve cognition.ObjectiveWe compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks...

Premacular Cells as Source of Neurotrophic Factors in Idiopathic Macular Holes

ABSTRACT Purpose: To describe the presence of neurotrophic growth factors and histopathologic characteristics of internal limiting membrane (ILM) specimens obtained from large idiopathic full-thickness macular holes (FTMH). Methods: In 24 eyes of 24 patients with FTMH of diameter >400 µm, ILM specimens were harvested directly at the edge surrounding the macular hole during vitrectomy with peeling. We performed interference and phase contrast microscopy of flat mounts followed by immunostaining and transmission electron microscopy. Primary antigens directed against neurotrophic growth factors as well as antigens to glial and ganglion cells were used. Topographic relationship of cells and collagen was demonstrated by serial ultrathin sectioning. Results: Immunofluorescence microscopy demonstrated the presence of glial-derived neurotrophic factor and ciliary neurotrophic factor. Expression of vimentin, glial fibrillary acidic protein (GFAP), neurofilament, calretinin, and melanopsin was seen positive too. Cellular retinaldehyde-binding protein was seen positive in half of the specimens. Co-localisation of anti-GFAP as well as anti-vimentin with neurotrophic factors was found. Electron microscopy revealed cells exclusively on the vitreal side of the ILM. Cell fragments on the retinal side were rarely seen. Conclusion: In large FTMH, ILM specimens present positive immunolabelling of neurotrophic factors. The co-localization with macroglial cell markers suggests a premacular cell composition as a source of the neurotrophic factors. Ultrastructurally, premacular cells were found on the vitreal side of the ILM and not within the collagen network of the ILM itself.

Circulating Diabetic Candidate Neurotrophic Factors, Brain-Derived Neurotrophic Factor and Fibroblast Growth Factor 21, in Sleeve Gastrectomy

Recent studies show brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 21 (FGF21) are neurotrophic factors associated with obesity and diabetes mellitus (DM). Laparoscopic sleeve gastrectomy (LSG) can significantly reduce weight and improve DM. In this study, we enrolled 78 patients with obesity and evaluated the change of BDNF and FGF21 6 months after LSG. At baseline, the BDNF level was similar between the preoperative DM (n = 30) (17.1 ± 7.7 ng/ml) and non-DM (n = 48) (17.0 ± 6.9 ng/ml) patients with obesity, but FGF21 was significantly higher in the DM patients (201.5 ± 204.3 versus 107.6 ± 63.8 pg/ml). At 6 months after LSG, most of the preoperative DM patients (96.7%) had DM either resolved (66.7%) or improved (30%). BDNF increased and FGF21 decreased significantly regardless of the preoperative DM status, while FGF21 decreased more prominently in the preoperative DM patients (−92.6 ± 179.8 versus −4.6 ± 63.4 pg/ml). After adjusted for age, sex, and preoperative DM status, FGF21 became significantly and positively related to C-peptide (β = 18.887), insulin (β = 2.399), and homeostasis model assessment of insulin resistance index (β = 8.566) after surgery. In conclusion, diabetic patients with obesity had higher FGF21 and similar BDNF levels compared to non-diabetic obese patients. BDNF increased and FGF21 decreased significantly after LSG. FGF21 became positively associated with several insulin-related profiles after surgery.