Genetic predisposition of BDNF (rs6265) gene is susceptible to Schizophrenia: A prospective study and updated meta-analysis / Asociación entre el gen BDNF (rs6265) y predisposición a la esquizofrenia: estudio prospectivo y metaanálisis actualizado

Introduction: Genetic polymorphism in the BDNF gene has been found to cause neuronal alterations and has been identified as a causal factor for many neuropsychiatric disorders. Therefore, various neurological case–control studies and meta-analyses have been conducted to find the possible link between BDNF and susceptibility to schizophrenia. Method: This meta-analysis gathered data from 25 case–control studies including a total of 8384 patients with schizophrenia and 8821 controls in order to identify the relationship between the rs6265 single nucleotide polymorphism and the disease, evaluating the combined odds ratio and 95% confidence intervals under 5 different genetic models. Validation followed the “Leave one out” method, and we used the Egger test and Begg's funnel plot to identify publication bias. Results: Research into the rs6265 (G/A) polymorphism revealed a non-significant association with schizophrenia in all 5 genetic models; in the subgroup analysis, no association was found between white and Asian populations, with a p value > .05. Conclusions: Overall, the updated meta-analysis revealed that rs6265 exonic polymorphisms do not increase susceptibility to this disease. However, to better understand the pathogenesis of the disease, there is a need for further case–control studies into the BDNF polymorphism including larger sample sizes and different ethnic groups.(AU)

Introducción: Se sabe que los polimorfismos del gen BDNF provocan alteraciones neuronales y parecen ser un factor causal en muchos trastornos neuropsiquiátricos. Es por ello que se han llevado a cabo varios metaanálisis y estudios de casos y controles con el objetivo de evaluar la posible relación entre BDNF y la esquizofrenia. Método: Realizamos un metaanálisis de 25 estudios de casos y controles, que incluyó un total de 8.384 pacientes con esquizofrenia y 8.821 controles. Se analizó la relación entre el polimorfismo de nucleótido simple rs6265 y la esquizofrenia mediante odds ratios combinados y sus intervalos de confianza del 95% con 5 modelos genéticos diferentes. Utilizamos el método de validación cruzada dejando uno fuera («leave one out»), la prueba de Egger y el gráfico en embudo de Begg para identificar posibles sesgos de publicación. Resultados: Los estudios sobre el polimorfismo rs6265 (G/A) muestran una asociación no significativa con la esquizofrenia en los 5 modelos genéticos. En el análisis por subgrupos, no se encontró relación con las poblaciones caucásica y asiática (p > 0,05). Conclusiones: La presencia de polimorfismos rs6265 no aumenta la predisposición a desarrollar esquizofrenia. Sin embargo, se deben realizar más estudios de casos y controles sobre polimorfismos de BDNF, con muestras más numerosas y con individuos de diferentes grupos étnicos, para comprender mejor los mecanismos patogénicos de la enfermedad.(AU)

Association between Parkinson's Disease and Cancer: New Findings and Possible Mediators.

Epidemiological evidence points to an inverse association between Parkinson's disease (PD) and almost all cancers except melanoma, for which this association is positive. The results of multiple studies have demonstrated that patients with PD are at reduced risk for the majority of neoplasms. Several potential biological explanations exist for the inverse relationship between cancer and PD. Recent results identified several PD-associated proteins and factors mediating cancer development and cancer-associated factors affecting PD. Accumulating data point to the role of genetic traits, members of the synuclein family, neurotrophic factors, the ubiquitin-proteasome system, circulating melatonin, and transcription factors as mediators. Here, we present recent data about shared pathogenetic factors and mediators that might be involved in the association between these two diseases. We discuss how these factors, individually or in combination, may be involved in pathology, serve as links between PD and cancer, and affect the prevalence of these disorders. Identification of these factors and investigation of their mechanisms of action would lead to the discovery of new targets for the treatment of both diseases.

Cognitive dysfunction, depression and serum level of brain-derived neurotrophic factor (BDNF) in Egyptian patients with rheumatoid arthritis / Disfunción cognitiva, depresión y nivel sérico del factor neurotrófico derivado del cerebro (BDNF) en pacientes egipcios con artritis reumatoide

Aim of the work: To evaluate serum brain-derived neurotrophic factor (BDNF) in Egyptian patients with rheumatoid arthritis (RA) and its relation with cognitive dysfunction. Patients and methods: The study was carried out on 60 RA patients; 30 were active (group A) and 30 were non active (group B); and 30 controls (group C). RA disease activity was assessed via DAS28 tool, cognitive function via The Montreal Cognitive Assessment and depression via the PHQ depression scale. Serum BDNF levels were measured. Results: The mean age in group A was 37.8 (±9.37) years with 83.3% females, in group B was 39.97 (±8.04) years with 86.7% females and in group C was 33.17 (±3.6) years with 93.3% females. Abnormal cognitive functions test was detected in 66.7% of group A, 66.7% of group B, and in 23.3% of group C. There was a statistically significant difference in BDNF serum level between both groups of patients (1.58±0.9ng/ml for group A, 1.81±1.17ng/ml for group B) compared with the control group (3.01±1.25ng/ml, p<0.001). There was no statistically significant difference between BDNF and both disease duration and cognitive function, also no statistically significant difference regarding cognitive function, depression, and BNDF levels in patients with and without fibromyalgia. At a cut-off value of <2ng/ml, BDNF detected RA patients with cognitive dysfunction with a sensitivity of 80%, specificity of 96.67%. Conclusion: BDNF can be a potential biomarker of cognitive dysfunction in RA patients.(AU)

Objetivo: Evaluar el factor neurotrófico derivado del cerebro (BDNF) en suero en pacientes egipcios con artritis reumatoide (AR) y su relación con la disfunción cognitiva. Pacientes y métodos: El estudio se realizó en 60 pacientes con AR; 30 eran activos (grupo A) y 30 no activos (grupo B); y 30 controles (grupo C). La actividad de la enfermedad de AR se evaluó a través de la herramienta DAS28, la función cognitiva a través de la Evaluación Cognitiva de Montreal y la depresión a través de la escala de depresión PHQ. Se midieron los niveles de BDNF en suero. Resultados: La edad media en el grupo A fue de 37,8 (±9,37) años con 83,3% de mujeres, en el grupo B de 39,97 (±8,04) años con 86,7% de mujeres y en el grupo C de 33,17 (±3,6) años con 93,3% de mujeres. La prueba de funciones cognitivas anormales se detectó en 66,7% del grupo A, 66,7% del grupo B y 23,3% del grupo C. Hubo una diferencia estadísticamente significativa en el nivel sérico de BDNF entre ambos grupos de pacientes (1,58±0,9ng/mL para grupo A, 1,81±1,17ng/mL para el grupo B) en comparación con el grupo control (3,01±1,25ng/mL, p<0,001). No hubo diferencias estadísticamente significativas entre el BDNF y la duración de la enfermedad y la función cognitiva, tampoco hubo diferencias estadísticamente significativas con respecto a la función cognitiva, la depresión y los niveles de BDNF en pacientes con y sin fibromialgia. A un valor de corte de <2ng/mL, BDNF detectó pacientes con AR con disfunción cognitiva con una sensibilidad de 80% y una especificidad de 96,67%. Conclusión: BDNF puede ser un biomarcador potencial de disfunción cognitiva en pacientes con AR.(AU)

Encontro com Especialistas - Estratégias de neuroproteção no recém-nascido pré-termo

Encontro com os Especialistas Sérgio Marba, médico neonatologista do Hospital da Mulher Caism/Unicamp, professor do Departamento de Pediatria da FCM/Unicamp, consultor neonatal e do Método Canguru/MS e membro do Grupo Executivo do Programa de Reanimação Neonatal (PRN/SBP); Mônica Aparecida Pessoto, médica neonatologista do Hospital da Mulher Caism/Unicamp, professora do Departamento de Pediatria da FCM/Unicamp e consultora do Método Canguru/MS; José Paulo de Siqueira Guida, médico obstetra, professor doutor do departamento de tocoginecologia da FCM/Unicamp; Nicole Gianini, médica neonatologista, consultora do Método Canguru/MS, membro do Departamento de Perinatologia da SBP e SOPERJ.

Pigment epithelium­derived factor inhibits proliferation, invasion and angiogenesis, and induces ferroptosis of extravillous trophoblasts by targeting Wnt­ß­catenin/VEGF signaling in placenta accreta spectrum.

Placenta accreta spectrum (PAS) is one of the most dangerous complications in obstetrics, which can lead to severe postpartum bleeding and shock, and even necessitate uterine removal. The abnormal migration and invasion of extravillous trophoblast cells (EVTs) and enhanced neovascularization occurring in an uncontrolled manner in time and space are closely related to the abnormal expression of pro­angiogenic and anti­angiogenic factors. The pigment epithelium­derived factor (PEDF) is a multifunctional regulatory factor that participates in several important biological processes and is recognized as the most efficient inhibitor of angiogenesis. The present study aimed to explore the effects of PEDF on EVT phenotypes and the underlying mechanisms in PAS. HTR­8/SVneo cells were transfected to overexpress or knock down PEDF. Cell proliferation and invasion were assessed using Cell Counting Kit­8, 5­ethynyl­2'­deoxyuridine and Transwell assays. In vitro angiogenesis was analyzed using tube formation assays. The degree of ferroptosis was assessed by evaluating the levels of lipid reactive oxygen species, total iron, Fe2+, malondialdehyde and reduced glutathione using commercial kits. The expression levels of biomarkers of ferroptosis, angiogenesis, cell proliferation and Wnt signaling were examined by western blotting. PEDF overexpression decreased the proliferation, invasion and angiogenesis, and induced ferroptosis of EVTs. Activation of Wnt signaling with BML­284 and overexpression of vascular endothelial growth factor (VEGF) reversed the PEDF overexpression­induced suppression of cell proliferation, invasion and tube formation. PEDF overexpression­induced ferroptosis was also decreased by Wnt agonist treatment and VEGF overexpression. It was predicted that PEDF suppressed the proliferation, invasion and angiogenesis, and increased ferroptosis in EVTs by decreasing Wnt­ß­catenin/VEGF signaling. The findings of the present study suggested a novel regulatory mechanism of the phenotypes of EVTs and PAS.

Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain.

BACKGROUND: Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify the associated signaling pathway for the strategy of BCP management. METHODS: The rat BCP model was established by intratibial implantation of Walker 256 cells. Von Frey filaments measured the mechanical pain threshold. Movement-induced pain was assessed using limb use scores. Expressions of associated molecules in the affected tibias or dorsal root ganglia (DRG) were measured by immunofluorescence, immunohistochemistry, real-time quantitative polymerase chain reaction, or western blotting. Transduction of deleted in colorectal cancer (DCC) signaling was inhibited by intrathecal injection of DCC-siRNA. RESULTS: In BCP rats, the presence of calcitonin gene-related peptide (CGRP)-positive nerve fibers increased in the metastatic bone lesions. The metastatic site showed enrichment of well-differentiated osteoclasts and expressions of netrin-1 and its attractive receptor DCC. Upregulation of DCC and increased phosphorylation levels of focal adhesion kinase (FAK) and Rac family small GTPase 1/Cell division cycle 42 (Rac1/Cdc42) were found in the DRG. Intrathecal administration of DCC-siRNA led to a significant reduction in FAK and Rac1/Cdc42 phosphorylation levels in the DRG, decreased nociceptive nerve innervation, and improved pain behaviors. CONCLUSIONS: Netrin-1 may contribute to the activation of the BCP by inducing nociceptive nerve innervation and improving pain behaviors.

Neurotrophins and Trk Neurotrophin Receptors in the Retina of Adult Killifish (Nothobranchius guentheri).

Specific subpopulations of neurons in nerve and sensory systems must be developed and maintained, and this is accomplished in significant part by neurotrophins (NTs) and the signaling receptors on which they act, called tyrosine protein kinase receptors (Trks). The neurotrophins-tyrosine protein kinase receptors (NTs/Trks) system is involved in sensory organ regulation, including the visual system. An NTs/Trks system alteration is associated with neurodegeneration related to aging and diseases, including retinal pathologies. An emergent model in the field of translational medicine, for instance, in aging study, is the annual killifish belonging to the Nothobranchius genus, thanks to its short lifespan. Members of this genus, such as Nothobranchius guentheri, and humans share a similar retinal stratigraphy. Nevertheless, according to the authors' knowledge, the occurrence and distribution of the NTs/Trks system in the retina of N. guentheri has never been investigated before. Therefore, the present study aimed to localize neurotrophin BDNF, NGF, and NT-3 and TrkA, TrkB, and TrkC receptors in the N. guentheri retina using the immunofluorescence method. The present investigation demonstrates, for the first time, the occurrence of the NTs/Trks system in N. guentheri retina and, consequently, the potential key role of these proteins in the biology and survival of the retinal cells.

Synergy between PEDF and Doxorubicin in Breast Cancer Cells: Effects on Metastatic and Metabolic Pathways.

Pigment epithelium-derived factor (PEDF), a serine protease inhibitor (Serpin) family member, shows promise in inhibiting tumour growth. In our study, we explored the effects of PEDF on the efficacy of the frontline chemotherapy agent doxorubicin (Dox) in BC cells. We found that Dox+PEDF treatment significantly reduced glucose uptake in MDA-MB-231 cells compared to the control (p = 0.0005), PEDF (p = 0.0137), and Dox (p = 0.0171) alone but paradoxically increased it in MCF-7 cells. Our findings further revealed that PEDF, Dox, and Dox+PEDF substantially hindered tumour cell migration from tumour spheroids, with Dox+PEDF showing the most significant impact (p < 0.0001). We also observed notable decreases in the expression of metastatic markers (uPAR, uPA, CXCR4, MT1-MMP, TNF-α) across all treatment groups (p < 0.0001) in both cell lines. When it comes to metabolic pathways, PEDF increased phosphorylated IRS-1 (p-IRS1) levels in MDA-MB-231 and MCF-7 (p < 0.0001), while Dox decreased it, and the combination led to an increase. In MDA-MB-231 cells, treatment with PEDF, Dox, and the combination led to a notable decrease in both phosphorylated AKT (p-AKT) and total AKT levels. In MCF-7, while PEDF, Dox, and their combination led to a reduction in p-AKT, total levels of AKT increased in the presence of Dox and Dox+PEDF. Combining PEDF with Dox enhances the targeting of metastatic and metabolic pathways in breast cancer cell lines. This synergy, marked by PEDF's increasing roles in cancer control, may pave the way for more effective cancer treatments.

Clinical value and mechanistic analysis of HIIT on modulating risk and symptoms of depression: A systematic review / Valor clínico y análisis mecanicista del HIIT sobre la modulación del riesgo y los síntomas de la depresión: una revisión sistemática

Background: The exact causal mechanisms of depression remain unclear due to the complexity of the triggers, which has led to limitations in treating depression using modern drugs. High-intensity interval training (HIIT) is as effective as medication in treating depression without toxic side effects. Typically, HIIT requires less time commitment (i.e., shorter exercise duration) and exhibits pronounced benefits on depressive symptoms than other forms of physical exercise. This review summarizes the risk reduction and clinical effects of HIIT for depression and discusses the underlying mechanisms, providing a theoretical basis for utilizing HIIT in treating depression. Methods: A database search was conducted in PubMed, Embase, Web of Science, and Scopus from inception up to October 2022. The methodological quality of the included literature was evaluated by the physiotherapy evidence database (PEDro) scale criteria. The review focused on evaluating the changes in depression risk or symptoms of HIIT interventions in healthy individuals, patients with depression, and patients with other disorders co-morbid with depression. Consequently, the mechanisms associated with depression related HIIT were summarized. Results: A total of 586 participants (52 % female; mean age: 43.58±8.93 years) from 22 studies were included. Implementing HIIT using different exercise types alleviates depressive symptoms in individuals with depression and in individuals with depression who have exhibited comorbidities and reduced depression scale scores in subjects immediately after acute exercise. In addition, the long-interval HIIT and short-interval HIIT in the treatment of patients with cardiovascular or psychiatric disorders may reduce depressive symptoms via complex exercise-related changes on several levels, including by effecting the following measures: releasing monoamines, reducing neuronal death, inducing neurogenesis, modulating the functional...(AU)

Survival and maturation of human induced pluripotent stem cell-derived dopaminergic progenitors in the parkinsonian rat brain is enhanced by transplantation in a neurotrophin-enriched hydrogel.

Objective.Although human induced pluripotent stem cell (iPSC)-derived cell replacement for Parkinson's disease has considerable reparative potential, its full therapeutic benefit is limited by poor graft survival and dopaminergic maturation. Injectable biomaterial scaffolds, such as collagen hydrogels, have the potential to address these issues via a plethora of supportive benefits including acting as a structural scaffold for cell adherence, shielding from the host immune response and providing a reservoir of neurotrophic factors to aid survival and differentiation. Thus, the aim of this study was to determine if a neurotrophin-enriched collagen hydrogel could improve the survival and maturation of iPSC-derived dopaminergic progenitors (iPSC-DAPs) after transplantation into the rat parkinsonian brain.Approach.Human iPSC-DAPs were transplanted into the 6-hydroxydopamine-lesioned striatum either alone, with the neurotrophins GDNF and BDNF, in an unloaded collagen hydrogel, or in a neurotrophin-loaded collagen hydrogel.Post-mortem, human nuclear immunostaining was used to identify surviving iPSC-DAPs while tyrosine hydroxylase immunostaining was used to identify iPSC-DAPs that had differentiated into mature dopaminergic neurons.Main results.We found that iPSC-DAPs transplanted in the neurotrophin-enriched collagen hydrogel survived and matured significantly better than cells implanted without the biomaterial (8 fold improvement in survival and 16 fold improvement in dopaminergic differentiation). This study shows that transplantation of human iPSC-DAPs in a neurotrophin-enriched collagen hydrogel improves graft survival and maturation in the parkinsonian rat brain.Significance.The data strongly supports further investigation of supportive hydrogels for improving the outcome of iPSC-derived brain repair in Parkinson's disease.

Mechanism of electroconvulsive therapy in schizophrenia: a bioinformatics analysis study of RNA-seq data.

OBJECTIVE: The molecular mechanism of electroconvulsive therapy (ECT) for schizophrenia remains unclear. The aim of this study was to uncover the underlying biological mechanisms of ECT in the treatment of schizophrenia using a transcriptional dataset. METHODS: The peripheral blood mRNA sequencing data of eight patients (before and after ECT) and eight healthy controls were analyzed by integrated co-expression network analysis and the differentially expressed genes were analyzed by cluster analysis. Gene set overlap analysis was performed using the hypergeometric distribution of phypfunction in R. Associations of these gene sets with psychiatric disorders were explored. Tissue-specific enrichment analysis, gene ontology enrichment analysis, and protein-protein interaction enrichment analysis were used for gene set organization localization and pathway analysis. RESULTS: We found the genes of the green-yellow module were significantly associated with the effect of ECT treatment and the common gene variants of schizophrenia ( P  = 0.0061; family-wise error correction). The genes of the green-yellow module are mainly enriched in brain tissue and mainly involved in the pathways of neurotrophin, mitogen-activated protein kinase and long-term potentiation. CONCLUSION: Genes associated with the efficacy of ECT were predominantly enriched in neurotrophin, mitogen-activated protein kinase and long-term potentiation signaling pathways.

Mesencephalic astrocyte-derived neurotrophic factor ameliorates inflammatory response in polycystic ovary syndrome via inhibiting TLR4-NF-κB-NLRP3 pathway.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder in women of reproductive age, which often leads to female infertility. Chronic inflammation is a significant factor in the development of PCOS. Our study aimed to explore the impact of mesencephalic astrocyte-derived neurotrophic factor (MANF), a scientifically validated anti-inflammatory factor, on 99 diagnosed PCOS patients. We also investigated its effects on PCOS mice induced with dehydroepiandrosterone (DHEA) and KGN cells induced with dihydrotestosterone (DHT). Our findings revealed a decrease in serum MANF levels in PCOS patients, which were negatively associated with serum tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) levels. The administration of recombinant human MANF (rhMANF) in PCOS mice demonstrated a decrease in pro-inflammatory cytokines and monocytes/macrophages in both peripheral blood and ovarian tissues. Furthermore, the inclusion of rhMANF notably ameliorated DHEA-induced ovarian dysfunction and fibrosis by negatively regulating the toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB)-NLR family, pyrin domain containing protein 3 (NLRP3) pathway. Additionally, in vitro experiments showed that the up-regulation of MANF offset DHT-induced inhibition of viability and apoptosis in KGN cells. Collectively, this study highlights the anti-inflammatory properties of MANF in PCOS and suggests its potential as a therapeutic approach for the management of PCOS.

Synergistic Effect of Electrical and Biochemical Stimulation on Human iPSC-Derived Neural Differentiation in a Microfluidic Electrode Array Chip.

Neural differentiation is crucial for advancing our understanding of the nervous system and developing treatments for neurological disorders. The advanced methods and the ability to manipulate the alignment, proliferation, and differentiation of stem cells are essential for studying neuronal development and synaptic interactions. However, the utilization of human induced pluripotent stem cells (iPSCs) for disease modeling of neurodegenerative conditions may be constrained by the prolonged duration and uncontrolled cell differentiation required for functional neural cell differentiation. Here, we developed a microfluidic chip to enhance the differentiation and maturation of specific neural lineages by placing aligned microelectrodes on the glass surface to regulate the neural differentiation of human iPSCs. The utilization of electrical stimulation (ES) in conjunction with neurotrophic factors (NF) significantly enhanced the efficiency in generating functional neurons from human iPSCs. We also observed that the simultaneous application of NF and ES to human iPSCs promoted their differentiation and maturation into functional neurons while increasing synaptic interactions. Our research demonstrated the effect of combining NF and ES on human iPSC-derived neural differentiation.

Combined laser-activated SVF and PRP remodeled spinal sclerosis via activation of Olig-2, MBP, and neurotrophic factors and inhibition of BAX and GFAP.

A single injection of platelet-rich plasma (PRP) or stromal vascular fraction (SVF) in treating neurological ailments suggests promise; however, there is limited evidence of the efficacy of combination therapy. This trial aimed to determine whether combining SVF and PRP could provide further therapeutic effects in treating multiple sclerosis (MS). Fifteen Persian cats were separated into three groups (n = 5): group I (control negative), and group II (control positive); EB was injected intrathecally into the spinal cord and then treated 14 days later with intrathecal phosphate buffered saline injection, and group III (SVF + PRP), cats were injected intrathecally with EB through the spinal cord, followed by a combination of SVF and PRP 14 days after induction. Therapeutic effects were evaluated using the Basso-Beattie-Bresnahan scale throughout the treatment timeline and at the end. Together with morphological, MRI scan, immunohistochemical, transmission electron microscopy, and gene expression investigations. The results demonstrated that combining SVF and PRP successfully reduced lesion intensity on gross inspection and MRI. In addition to increased immunoreactivity to Olig2 and MBP and decreased immunoreactivity to Bax and GFAP, there was a significant improvement in BBB scores and an increase in neurotrophic factor (BDNF, NGF, and SDF) expression when compared to the positive control group. Finally, intrathecal SVF + PRP is the most promising and safe therapy for multiple sclerosis, resulting in clinical advantages such as functional recovery, MRI enhancement, and axonal remyelination.

NINJ1 induces plasma membrane rupture and release of damage-associated molecular pattern molecules during ferroptosis.

Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent accumulation of oxidized phospholipids in cellular membranes, culminating in plasma membrane rupture (PMR) and cell lysis. PMR is also a hallmark of other types of programmed necrosis, such as pyroptosis and necroptosis, where it is initiated by dedicated pore-forming cell death-executing factors. However, whether ferroptosis-associated PMR is also actively executed by proteins or driven by osmotic pressure remains unknown. Here, we investigate a potential ferroptosis role of ninjurin-1 (NINJ1), a recently identified executor of pyroptosis-associated PMR. We report that NINJ1 oligomerizes during ferroptosis, and that Ninj1-deficiency protects macrophages and fibroblasts from ferroptosis-associated PMR. Mechanistically, we find that NINJ1 is dispensable for the initial steps of ferroptosis, such as lipid peroxidation, channel-mediated calcium influx, and cell swelling. In contrast, NINJ1 is required for early loss of plasma membrane integrity, which precedes complete PMR. Furthermore, NINJ1 mediates the release of cytosolic proteins and danger-associated molecular pattern (DAMP) molecules from ferroptotic cells, suggesting that targeting NINJ1 could be a therapeutic option to reduce ferroptosis-associated inflammation.

3-Amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carbonitrile: A fluorescent molecule that induces differentiation in PC12 cells.

Neural differentiation is triggered by the activation of multiple signaling pathways initiated by various neurotrophic factors. An elucidation of these mechanisms is anticipated to facilitate the prevention of diseases and the development of novel therapeutic approaches. Alternative small-molecule inducers for neuroscience studies are required instead of protein-based reagents for more efficient and convenient experiments. We demonstrated that small molecules of thieno[2,3-b]pyridine derivatives that induce neural differentiation, compounds 3a and 9a in particular, exhibited significant neuritogenic activity in rat pheochromocytoma (PC12) cells. Moreover, 3a displayed pronounced fluorescence and a discernible Stokes shift. Furthermore, the outcome of the experiment conducted on the NGF-insensitive clones of rat PC12 cells, and the results of the intercellular uptake analyses suggested that the 3a-mediated activation of neural differentiation occurred independently of the TrkA receptor. Therefore, 3a portrays potential applicability both as a small molecule reagent to replace novel neurotrophic factors and as a potent fluorescent reagent for various techniques, including bioimaging.

Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple organs, has been shown to demonstrate anti-EndoMT activity in cardiovascular diseases. In the present study, the role of PEDF in PH was investigated. METHODS: For PEDF overexpression, Sprague Dawley rats were infected with an adeno-associated virus through injection via the internal jugular vein. To establish PH models, the animals were subjected to monocrotaline or Sugen/hypoxia. Four weeks later, pulmonary artery angiography was performed, and hemodynamic parameters, right ventricular function, and vascular remodeling were evaluated. EndoMT and cell proliferation in the pulmonary arteries were assessed via immunofluorescence staining. Moreover, pulmonary artery endothelial cells (PAECs) isolated from experimental PH rats were cultured to investigate the underlying molecular mechanisms involved. RESULTS: PEDF expression was significantly downregulated in PAECs from PH patients and PH model rats. Overexpressed PEDF alleviated the development of PH by improving pulmonary artery morphology and perfusion, reducing pulmonary artery pressure, improving right ventricular function, and alleviating vascular remodeling. PEDF inhibits EndoMT and reduces excessive PAEC proliferation. Moreover, PEDF overexpression reduced EndoMT in cultured PAECs by competitively inhibiting the binding of wnt to LRP6 and downregulating phosphorylation at the 1490 site of LRP6. CONCLUSIONS: Our findings suggest that PEDF may be a potential therapeutic target for PH. We also found that PEDF can inhibit EndoMT in PAECs and may exert these effects by inhibiting the Wnt/LRP6/ß-catenin pathway.

Acute-Phase Plasma Pigment Epithelium-Derived Factor Predicting Outcomes after Aneurysmal Subarachnoid Hemorrhage in the Elderly.

Aneurysmal subarachnoid hemorrhage (SAH) has increased with the aging of the population, but the outcome for elderly SAH patients is very poor. Therefore, predicting the outcome is important for determining whether to pursue aggressive treatment. Pigment epithelium-derived factor (PEDF) is a matricellular protein that is induced in the brain, and the plasma levels could be used as a biomarker for the severity of metabolic diseases. This study investigated whether acute-phase plasma PEDF levels could predict outcomes after aneurysmal SAH in the elderly. Plasma samples and clinical variables were collected over 1-3 days, post-SAH, from 56 consecutive elderly SAH patients ≥75 years of age registered in nine regional stroke centers in Japan between September 2013 and December 2016. The samples and variables were analyzed in terms of 3-month outcomes. Acute-phase plasma PEDF levels were significantly elevated in patients with ultimately poor outcomes, and the cutoff value of 12.6 µg/mL differentiated 3-month outcomes with high sensitivity (75.6%) and specificity (80.0%). Acute-phase plasma PEDF levels of ≥12.6 µg/mL were an independent and possibly better predictor of poor outcome than previously reported clinical variables. Acute-phase plasma PEDF levels may serve as the first biomarker to predict 3-month outcomes and to select elderly SAH patients who should be actively treated.

Neurotrophic Natural Products.

Neurotrophins (NGF, BDNF, NT3, NT4) can decrease cell death, induce differentiation, as well as sustain the structure and function of neurons, which make them promising therapeutic agents for the treatment of neurodegenerative disorders. However, neurotrophins have not been very effective in clinical trials mostly because they cannot pass through the blood-brain barrier owing to being high-molecular-weight proteins. Thus, neurotrophin-mimic small molecules, which stimulate the synthesis of endogenous neurotrophins or enhance neurotrophic actions, may serve as promising alternatives to neurotrophins. Small-molecular-weight natural products, which have been used in dietary functional foods or in traditional medicines over the course of human history, have a great potential for the development of new therapeutic agents against neurodegenerative diseases such as Alzheimer's disease. In this contribution, a variety of natural products possessing neurotrophic properties such as neurogenesis, neurite outgrowth promotion (neuritogenesis), and neuroprotection are described, and a focus is made on the chemistry and biology of several neurotrophic natural products.

Repair effect of neurotrophic factor III (NT-3) on rats with spinal injury model and its mechanism.

The present study aimed to study the repair effect of neurotrophic factor III (NT-3) on spinal injury model rats and its mechanism. Wistar rats with spinal injury were established by accelerated compression stroke after the operation and divided into control group, model group, and NT-3 intervention group. The motor function of rats in each group was evaluated at different postoperative time points (3, 7, 14 d). HE staining was used to detect the changes in tissue structure and morphology of the injured spinal column in each group. The changes of SOD, MDA and GSH in serum of rats were detected. The concentrations of inflammatory cytokines IL-1ß, IL-6, IL-17 and TNF-α in serum were detected by enzyme-linked immunosorbent assay (ELISA). Western blot was used to detect the expression changes of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax) in injured spinal tissue of rats in each group. Compared with model group, motor function score of NT-3 intervention group increased gradually, and had statistical significance at 7 and 14 days (5.29±1.62 vs 9.33±2.16, 5.92±1.44 vs 14.56±2.45, T =7.386, 9.294, P =0.004, 0.000). The levels of SOD and GSH in serum of NT-3 intervention group were significantly increased (t=9.117, 12.207, P=0.000, 0.000), while the level of MDA was significantly decreased (t=5.089, P=0.011). Serum levels of inflammatory cytokines IL-1ß, IL-6, IL-17 and TNF-α in NT-3 intervention group were significantly decreased (T =6.157, 7.958, 6.339, 6.288, P=0.008, 0.005, 0.005, 0.007). In the NT-3 treatment group, Bax protein was significantly decreased (0.24±0.05 vs 0.89±0.12, T =8.579, P=0.001), and the relative expression of Bcl-2 protein was significantly increased (0.75±0.06 vs 0.13±0.05, T =9.367, P=0.001). Neurotrophic factor III can promote spinal injury repair in spinal injury model rats, and play a role by enhancing antioxidant stress ability, inhibiting inflammatory factors, promoting Bcl-2 and decreasing Bax expression.