Search Results (18)

The bidirectional transfer of biological information between insulin and neurotrophin-3 (NT-3) in hemodialysis patients (end-stage renal disease—ESRD) with type 2 diabetes mellitus (T2DM) is extremely poorly studied. Why was NT-3 chosen? Because, of all the nerve growth factors, this one also exhibits specific actions at the nephron level. The authors of this manuscript also conducted the first study on the serum behavior of NT-3 in this category of patients. Even though the results have already been published, the way in which an endocrine compound (insulin) interacts at the renal level with a growth factor with predominantly autocrine and paracrine action (NT-3), under both normal and pathological conditions, has not been thoroughly studied. This paper will address the following topics: 1. that insulin synthesis and release involve the same molecules that also exert important actions at the renal level; 2. involvement of insulin deficiency/resistance in the development of diabetic nephropathy and end-stage renal disease vs. kidney influences on serum glucose and insulin levels; 3. actions of NT-3 under normal conditions vs. diabetes mellitus; 4. aspects highlighted by personal studies performed on hemodialysis patients with T2DM. Taking an original approach, the functional link between insulin and NT-3 in hemodialysis patients, especially those with T2DM, will be presented. Finally, new therapeutic possibilities and directions for patient monitoring will be proposed, as well as topics for further research. Full article

Background and Objectives: Angiographic no-reflow (NRF) after percutaneous coronary intervention (PCI) reflects impaired microvascular reperfusion despite successful treatment of the epicardial culprit lesion. Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in endothelial signaling, platelet biology, inflammation, and angiogenesis. Its relationship with NRF in non-ST-segment elevation myocardial infarction (NSTEMI) remains insufficiently characterized. Materials and Methods: This single-center prospective observational cohort study included 700 consecutive NSTEMI patients undergoing culprit-lesion PCI. Admission serum total BDNF was measured before PCI using a standardized enzyme-linked immunosorbent assay protocol. Angiographic NRF was defined as final thrombolysis in myocardial infarction (TIMI) flow <3 and/or TIMI 3 flow with myocardial blush grade (MBG) 0–1 in the absence of residual stenosis, dissection, severe spasm, or other mechanical obstruction. Four sequential logistic regression models were used to evaluate the stability of the association between BDNF and NRF: Model 1 adjusted for clinical variables; Model 2 further adjusted for laboratory and inflammatory variables; Model 3 further adjusted for cardiac injury and functional variables; and Model 4 further adjusted for angiographic and procedural variables. Discrimination, calibration, reclassification, decision-curve analysis, and internal validation were assessed. Results: NRF occurred in 114 of 700 patients (16.3%). Serum total BDNF was higher in the NRF group than in the reflow group [555 (465–688) vs. 386 (292–496) pg/mL, p < 0.001]. BDNF remained independently associated with NRF across sequential models: Model 1 OR 1.67 per 100 pg/mL (95% CI 1.43–1.96), Model 2 OR 1.49 (95% CI 1.24–1.79), Model 3 OR 1.41 (95% CI 1.16–1.72), and Model 4 OR 1.31 (95% CI 1.07–1.60). The BDNF-only AUC was 0.787, while the final BDNF-enriched Model 4 reached an AUC of 0.866. The optimism-corrected bootstrap AUC was 0.852 and the 10-fold cross-validated AUC was 0.845. Conclusions: Higher admission serum total BDNF was independently associated with angiographic NRF in NSTEMI patients undergoing PCI and improved risk discrimination when added to clinical, biochemical, cardiac, and angiographic predictors. These findings suggest that serum total BDNF may reflect a context-dependent biomarker signal related to acute thrombo-inflammatory, platelet-associated, and microvascular injury pathways; however, the observed incremental value was modest and requires external validation. Full article

(1) Insulin-like growth factor-1 (IGF-1) is a neurotrophin with anti-inflammatory properties. Neuroinflammation and stress activate peripheral immune mechanisms, which may contribute to the development of depression and anxiety in sporadic Alzheimer’s disease (sAD). This study aims to evaluate whether intracerebroventricular (ICV) premedication with IGF-1 in a rat model of streptozotocin (STZ)-induced neuroinflammation can prevent the emergence of anhedonia and anxiety-like behavior by impacting the peripheral inflammatory responses. (2) Male Wistar rats were subjected to double ICVSTZ (total dose: 3 mg/kg) and ICVIGF-1 injections (total dose: 2 µg). We analyzed the level of anhedonia (sucrose preference), anxiety (elevated plus maze), peripheral inflammation (hematological and cytometric measurement of leukocyte populations, interleukin (IL)-6), and corticosterone concentration at 7 (very early stage, VES), 45 (early stage, ES), and 90 days after STZ injections (late stage, LS). (3) We found that ICVIGF-1 administration reduces behavioral symptoms: anhedonia (ES and LS) and anxiety (VES, ES), and peripheral inflammation: number of leukocytes, lymphocytes, T lymphocytes, monocytes, granulocytes, IL-6, and corticosterone concentration (LS) in the rat model of sAD. (4) The obtained results demonstrate beneficial effects of central IGF-1 administration on neuropsychiatric symptoms and peripheral immune system activation during disease progression in the rat model of sAD. Full article

Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurosteroids, including allopregnanolone (ALLO), play critical roles in modulating neuronal activity in the brain. Levels of these compounds dynamically fluctuate in response to physiological and environmental conditions, particularly stress, suggesting complex regulatory interactions. This study aimed to explore the effects of acute stress and ALLO (individually and combined) on hippocampal expression of BDNF, its TrkB receptor, and other neurotrophins in sheep, a translational large animal model. Adult, luteal-phase sheep (n = 24), implanted with a guide cannula into the third brain ventricle, were divided into four experimental groups: (i) 3 days of Ringer–Locke solution (RL) infusion as the control; (ii) 3 days of RL infusion with 4 h acute stress on day three; (iii) 3 days of ALLO infusion (4 × 15 µg/60 µL/30 min) with 4 h acute stress on day three; and (iv) 3 days of ALLO infusion alone (n = 6 per group). Both acute stress and ALLO alone significantly reduced BDNF concentration and BDNF transcript abundance in the hippocampal CA1 and CA3 fields compared to the control group. The combined application of both stress and ALLO resulted in decreased levels of these parameters, except for BDNF concentration in the CA3 region. Additionally, TrkB mRNA expression in both hippocampal fields was significantly reduced in all treatment groups. Changes in mRNA levels for other neurotrophins, including nerve growth factor (NGF) and neurotrophin 3 (NT3) and 4 (NT4), varied under experimental conditions. While an inhibitory effect was predominant, NGF expression in the CA1 region remained unaffected by stress or ALLO. Interestingly, stress alone induced a significant increase in NT4 mRNA expression in the CA3 field compared to the control. In conclusion, the study demonstrated that a 4 h acute stress exposure inhibited the synthesis of BDNF, TrkB, and several other neurotrophins in the sheep hippocampus. Furthermore, ALLO, whose increased levels are highly correlated with the initial stress response, may serve as a mediator of this stress effect, temporarily preventing over-stimulation of hippocampal BDNF release and signaling. Full article

Background/Objectives: Brain insulin resistance is a potential causal factor for dementia in Alzheimer’s disease (AD). Insulin-like growth factor-1 (IGF-1), a neurotrophin, plays a key role in central insulin signaling and neuroprotection. Intracerebrovenitricular (ICV) administration of streptozotocin (STZ) disrupts insulin signal transduction, leading to brain insulin resistance, which may mimic the early pathophysiological changes in sporadic AD (sAD). In this study, we investigated whether restoring insulin signaling through ICV injection of IGF-1 could ameliorate spatial memory deficits during sAD progression in a rat model induced by ICV STZ injection. Methods: Male Wistar rats (n = 40) were subjected to double ICV injections of STZ (0.75 mg/kg/ventricle, days 2 and 4) and IGF-1 (1 μg/single injection, days 1 and 3), and placed at the Morris water maze (MWM) at baseline, 7, 45 and 90 days after injections. Reference (days 1–3 and day 4 MWM)) and working (days 5–8 MWM) memory, microglia activation (CD68⁺ cells), and amyloid β (Aβ) deposition (immunohistochemistry) were measured. Results: We found that ICVIGF-1 administration protected working memory demonstrated as (1) reduced latency to reach the platform, and reduced swimming distance in trials 3 (p < 0.05) and 4 (p < 0.01) on days 45 and 90 post-injection and (2) a short-term (up to 45 days post-injection) enhancement of reference memory, manifested by a reduction in swimming distance and latency (p < 0.05). Furthermore, IGF-1 treatment reduced neuroinflammation in CA2 (p < 0.05) and Aβ deposition in CA1(p < 0.01) of the hippocampus. Conclusions: Central IGF-1 attenuates spatial memory deficits in the ICVSTZ-induced sAD model by reducing neuroinflammation and Aβ accumulation in the hippocampus. Full article

Background: In recent years, the role of neurotrophins and their receptors in peripheral tissues has been of great interest. At a metabolic level, the brain-derived neurotrophic factor (BDNF) and its receptor trkB have been reported to participate in insulin secretion from the pancreas in response to increases in circulating blood glucose. Objetive: To determines the role of the BDNF-trkB pathway in insulin secretion and pancreatic morphology in rats fed a cafeteria-style diet for 16 weeks. Methods: For the study, male rats of the Wistar strain were divided into three groups as follows: (1) control group (standard diet), (2) CAF group (cafeteria-style diet) and (3) CAF group treated with ANA-12 (TrkB receptor antagonist). After 4 months of intervention, the glucose and insulin tolerance curves, serum insulin levels, body fat and hematoxylin-eosin staining pancreas were evaluated. Results: The results showed that the cafeteria-style diet induced an increase in the amount of body fat, alterations in the glucose tolerance curve, increased insulin circulation levels, increased HOMA indices and increased pancreatic islet size. The antagonism of the trkB receptor in the rats fed a cafeteria-style diet enhanced some effects such as the accumulation of body fat and insulin secretion and induced a greater increase in the pancreas islet size. Conclusions: Under conditions of cafeteria-style diet-induced obesity, the antagonism of the BDNF-trkB pathway had no enhanced effect on the increase in insulin secretion or pancreatic islet size. Full article

In the etiology of discogenic pain, attention is paid to the role of neurotrophic factors, which include classic neurotrophins (NTs). This study aimed to assess changes in the concentrations of NT-3 and NT-4 in the intervertebral discs (IVDs) of the lumbosacral (L/S) spine depending on the advancement of degenerative changes, pain severity, habits, and comorbidities. The study group included 113 patients who underwent microdiscectomy due to degenerative IVD disease of the L/S spine. The severity of degenerative IVD changes was assessed using the five-point Pfirrmann scale, and the pain intensity was assessed according to the visual analog scale (VAS). In turn, the control group included 81 participants from whom IVDs of the L/S section of the spine were collected post-mortem during forensic autopsy or organ donation. At the mRNA level, we noted NT-3 overexpression in the test samples compared with the controls (fold change (FC) = 9.12 ± 0.56; p < 0.05), while NT-4 transcriptional activity was decreased in the test samples compared with the controls (FC = 0.33 ± 0.07; p < 0.05). However, at the protein level, the concentrations of NT-3 (134 ± 5.78 pg/mL vs. 6.78 ± 1.17 pg/mL; p < 0.05) and NT-4 (316.77 ± 8.19 pg/mL vs. 76.92 ± 4.82 pg/mL; p < 0.05) were significantly higher in the test samples compared with the control samples. Nevertheless, the concentration of both proteins did not statistically significantly change depending on the advancement of degenerative changes and the pain intensity (p > 0.05). In addition, higher levels of NT-3 and NT-4 were noted in IVD samples from patients who consumed alcohol, smoked tobacco, were overweight/obese, or had comorbid diabetes compared with patients without these risk factors (p < 0.05). Our analysis confirmed that differences in the degenerative process of IVD, energy metabolism, and lifestyle are related to changes in the concentration profiles of NT-3 and NT-4. Full article

(1) Background: Stroke is the leading cause of serious long-term disability. Walking dysfunction and paresis of the upper extremities occurs in more than 80% of people who have had a stroke. (2) Methods: We studied post-genomic markers in biosamples of muscle and brain tissue from animals that underwent intracerebral hematoma and recovered after 42 days. Our purpose was to understand the biological mechanisms associated with recovery from hemorrhagic stroke. We analyzed the peptides formed after trypsinolysis of samples by HPLC-MS, and the results were processed by bioinformatics methods, including the establishment of biochemical relationships (gene to gene) using topological omics databases such as Reactome and KEGG. (3) Results: In the pig brain, unique compounds were identified which are expressed during the recovery period after traumatic injury. These are molecular factors of activated microglia, and they contribute to the functional recovery of neurons and reduce instances of hematoma, edema, and oxidative stress. Complexes of the main binding factors of the neurotrophins involved in the differentiation and survival of nerve cells were found in muscles. (4) Conclusions: A network of gene interactions has been constructed for proteins involved in the regulation of synaptic transmission, in particular presynaptic vesicular and endocytic processes. The presence of transmitters and transporters associated with stimulation of NMDA receptors at neuromuscular junctions shows the relationship between upper motor neurons and neuromuscular junctions. Full article

Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are currently treated with non-specific immunosuppressive agents based on non-randomized, uncontrolled studies. Therefore, relapses and prolongated courses are common and remain challenging. For a more specific therapy, a better understanding of the underlying pathophysiology is crucial. Therefore, we aimed to analyze signaling pathways to expand the knowledge on the pathophysiology and possibly identify specific targets in the future, as occurred recently in Graves’ orbitopathy with the IGF-1 receptor. Furthermore, we analyzed potential mechanisms for the described potential progression to orbital MALT (mucosa-associated lymphoid tissue) lymphoma. The investigation cohort for this screening study comprised of 12 patients with either typical NSOI (n = 6), IgG4-ROD or MALT lymphoma (n = 3 each). Mean age was 56.4 ± 17 years. MALT samples, in contrast with IgG4-ROD and NSOI, showed overall upregulation for extracellular matrix receptor interaction (ECM) and adipocytokine signaling. Investigating signaling compounds for MALT samples, differentially expressed genes were re-identified as targets with relevant expression. Even though pathway analysis showed differentially altered products when comparing IgG4-ROD with MALT, main conductors of differentiation in B- and T-cell signaling were commonly altered when observing the microenvironment of examined tissues. Our data reveal the characteristic differences and similarities in genetic-expression-based pathway profiles between MALT lymphoma, IgG4-ROD and NSOI, which may be useful for elucidating the associated pathogenic mechanisms and developing specific treatments for these orbital diseases. Full article

(1) Background: Pulmonary embolism (PE) is a severe condition, representing the third most important cardiovascular cause of death after myocardial infarction and stroke. Despite the use of clinical pre-test probability scores, D-dimer measuring, and computer tomography pulmonary angiography (CTPA), PE diagnosis remains a challenge. Brain-derived neurotrophic factor (BDNF) is the most important member of the neurotrophin family, which has also been shown to be involved in the physiopathology of cardiovascular conditions such as heart failure and myocardial infarction. In this study, we aimed to assess the BDNF expression in patients with acute PE compared to the general population, and to also investigate its diagnostic and prognostic role. (2) Methods: We conducted a single center prospective study, which included 90 patients with PE and 55 healthy volunteers. Clinical and paraclinical parameters, together with plasma levels of BDNF, were evaluated in all patients after admission. (3) Results: The plasma levels of BDNF were significantly lower in the PE patients compared with the control group (403 vs. 644 pg/mL, p < 0.001). ROC analysis revealed an AUC of 0.806 (95% CI 0.738–0.876, p < 0.001) and a cut-off value of 564 pg/mL, which associated a sensitivity of 74.4% and a specificity of 78.2% for PE. Low BDNF levels also correlated with prognostic markers of PE, such as PESI score (p = 0.023), NT-proBNP (p < 0.01), right ventricular diameter (p = 0.029), and tricuspid annular plane systolic elevation (p = 0.016). Moreover, we identified a decreased BDNF expression in patients with high-risk PE (p < 0.01), thrombolytic treatment (p = 0.01), and patients who died within 30 days (p = 0.05). (4) Conclusions: Our study revealed that plasma BNDF is significantly lower in patients with PE when compared with the general population, and may be considered as a promising biomarker in complementing the current diagnostic tools for PE. Furthermore, low levels of BDNF might also be used to predict a poor outcome of this condition. Full article

The neurotrophin family is composed of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), Neurotrophin 3 (NT3) and NT4. These neurotrophins regulate several crucial functions through the activation of two types of transmembrane receptors, namely p75, which binds all neurotrophins with a similar affinity, and tyrosine kinase (Trk) receptors. Neurotrophins, besides their well-known pivotal role in the development and maintenance of the nervous system, also display the ability to regulate the development of taste buds in mammals. Therefore, the aim of this study is to investigate if NGF, BDNF, NT3 and NT4 are also present in the taste buds of zebrafish (Danio rerio), a powerful vertebrate model organism. Morphological analyses carried out on adult zebrafish showed the presence of neurotrophins in taste bud cells of the oropharyngeal cavity, also suggesting that BDNF positive cells are the prevalent cell population in the posterior part of the oropharyngeal region. In conclusion, by suggesting that all tested neurotrophins are present in zebrafish sensory cells, our results lead to the assumption that taste bud cells in this fish species contain the same homologous neurotrophins reported in mammals, further confirming the high impact of the zebrafish model in translational research. Full article

(1) Background: Neuroblastomas (NBs) are the most common extracranial solid tumors of children. The amplification of the Myc-N proto-oncogene (MYCN) is a major driver of NB aggressiveness, while high expression of the neurotrophin receptor NTRK1/TrkA is associated with mild disease courses. The molecular effects of NTRK1 signaling in MYCN-amplified NB, however, are still poorly understood and require elucidation. (2) Methods: Inducible NTRK1 expression was realized in four NB cell lines with (IMR5, NGP) or without MYCN amplification (SKNAS, SH-SY5Y). Proteome and phosphoproteome dynamics upon NTRK1 activation by its ligand, NGF, were analyzed in a time-dependent manner in IMR5 cells. Target validation by immunofluorescence staining and automated image processing was performed using the three other NB cell lines. (3) Results: In total, 230 proteins and 134 single phosphorylated class I phosphosites were found to be significantly regulated upon NTRK1 activation. Among known NTRK1 targets, Stathmin and the neurosecretory protein VGF were recovered. Additionally, we observed the upregulation and phosphorylation of Lamin A/C (LMNA) that accumulated inside nuclear foci. (4) Conclusions: We provide a comprehensive picture of NTRK1-induced proteome and phosphoproteome dynamics. The phosphorylation of LMNA within nucleic aggregates was identified as a prominent feature of NTRK1 signaling independent of the MYCN status of NB cells. Full article

(1) Background: One mechanism through which physical activity (PA) provides benefits is by triggering activity at a molecular level, where neurotrophins (NTs) are known to play an important role. However, the expression of the circulating levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4/5), in response to exercise, is not fully understood. Therefore, the aim was to provide an updated overview on the neurotrophin (NT) variation levels of BDNF and NT-4/5 as a consequence of a long-term aerobic exercise intervention, and to understand and describe whether the upregulation of circulating NT levels is a result of neurotrophic factors produced and released from the brain, and/or from neurotrophic secreting peripheral organs. (2) Methods: The articles were collected from PubMed, SPORTDiscus, Web of Science, MEDLINE, and Embase. Data were analyzed through a narrative synthesis. (3) Results: 30 articles studied humans who performed training protocols that ranged from 4 to 48 weeks; 22 articles studied rodents with an intervention period that ranged from 4 to 64 weeks. (4) Conclusions: There is no unanimity between the upregulation of BDNF in humans; conversely, concerning both BDNF and NT-4/5 in animal models, the results are heterogeneous. Whilst BDNF upregulation appears to be in relative agreement, NT-4/5 seems to display contradictory and inconsistent conclusions. Full article

Type 2 diabetes mellitus (T2DM) is known to be associated with an increased risk of dementia, specifically Alzheimer’s disease and vascular dementia. Intermittent fasting (IF) has been proposed to produce neuroprotective effects through the activation of several signaling pathways. In this study, we investigated the effect of IF on rat behavior in type 2 diabetic rats. Forty male Wistar Kyoto rats were divided into four groups (n = 10 for each): the ad libitum (Ad) group, the intermittent fasting group (IF), the streptozotocin-induced diabetic 2 group (T2DM) fed a high-fat diet for 4 weeks followed by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) 25 mg kg⁻¹, and the diabetic group with intermittent fasting (T2DM+IF). We evaluated the impact of 3 months of IF (16 h of food deprivation daily) on the levels of brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), serotonin, dopamine, and glutamate in the hippocampus, and rat behavior was assessed by the forced swim test and elevated plus maze. IF for 12 weeks significantly increased (p < 0.05) the levels of NT3 and BDNF in both control and T2DM rats. Additionally, it increased serotonin, dopamine, and glutamic acid in diabetic rats. Moreover, IF modulated glucose homeostasis parameters, with a significant decrease (p < 0.05) in insulin resistance and downregulation of serum corticosterone level. Interestingly, T2DM rats showed a significant increase in anxiety and depression behaviors, which were ameliorated by IF. These findings suggest that IF could produce a potentially protective effect by increasing the levels of BDNF and NT3 in both control and T2DM rats. IF could be considered as an additional therapy for depression, anxiety, and neurodegenerative diseases. Full article

Bone marrow-derived mast cells (BMMCs) are often used as a model system for studies of the role of MCs in health and disease. These cells are relatively easy to obtain from total bone marrow cells by culturing under the influence of IL-3 or stem cell factor (SCF). After 3 to 4 weeks in culture, a nearly homogenous cell population of toluidine blue-positive cells are often obtained. However, the question is how relevant equivalents these cells are to normal tissue MCs. By comparing the total transcriptome of purified peritoneal MCs with BMMCs, here we obtained a comparative view of these cells. We found several important transcripts that were expressed at very high levels in peritoneal MCs, but were almost totally absent from the BMMCs, including the major chymotryptic granule protease Mcpt4, the neurotrophin receptor Gfra2, the substance P receptor Mrgprb2, the metalloprotease Adamts9 and the complement factor 2 (C2). In addition, there were a number of other molecules that were expressed at much higher levels in peritoneal MCs than in BMMCs, including the transcription factors Myb and Meis2, the MilR1 (Allergin), Hdc (Histidine decarboxylase), Tarm1 and the IL-3 receptor alpha chain. We also found many transcripts that were highly expressed in BMMCs but were absent or expressed at low levels in the peritoneal MCs. However, there were also numerous MC-related transcripts that were expressed at similar levels in the two populations of cells, but almost absent in peritoneal macrophages and B cells. These results reveal that the transcriptome of BMMCs shows many similarities, but also many differences to that of tissue MCs. BMMCs can thereby serve as suitable models in many settings concerning the biology of MCs, but our findings also emphasize that great care should be taken when extrapolating findings from BMMCs to the in vivo function of tissue-resident MCs. Full article