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1.
Cells ; 11(20)2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-36291113

RESUMO

Among the factors involved in diabetic retinopathy (DR), nerve growth factor (NGF) and vascular endothelial growth factor A (VEGFA) have been shown to affect both neuronal survival and vascular function, suggesting that their crosstalk might influence DR outcomes. To address this question, the administration of eye drops containing NGF (ed-NGF) to adult Sprague Dawley rats receiving streptozotocin (STZ) intraperitoneal injection was used as an experimental paradigm to investigate NGF modulation of VEGFA and its receptor VEGFR2 expression. We show that ed-NGF treatment prevents the histological and vascular alterations in STZ retina, VEGFR2 expression decreased in GCL and INL, and preserved the co-expression of VEGFR2 and NGF-tropomyosin-related kinase A (TrkA) receptor in retinal ganglion cells (RGCs). The WB analysis confirmed the NGF effect on VEGFR2 expression and activation, and showed a recovery of VEGF isoform dysregulation by suppressing STZ-induced VEGFA121 expression. Reduction in inflammatory and pro-apoptotic intracellular signals were also found in STZ+NGF retina. These findings suggest that ed-NGF administration might favor neuroretina protection, and in turn counteract the vascular impairment by regulating VEGFR2 and/or VEGFA isoform expression during the early stages of the disease. The possibility that an increase in the NGF availability might contribute to the switch from the proangiogenic/apoptotic to the neuroprotective action of VEGF is discussed.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Fator de Crescimento Neural , Soluções Oftálmicas , Receptor trkA , Fator A de Crescimento do Endotélio Vascular , Animais , Ratos , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/etiologia , Retinopatia Diabética/prevenção & controle , Fator de Crescimento Neural/farmacologia , Fator de Crescimento Neural/uso terapêutico , Soluções Oftálmicas/farmacologia , Soluções Oftálmicas/uso terapêutico , Isoformas de Proteínas/metabolismo , Ratos Sprague-Dawley , Receptor trkA/metabolismo , Retina/metabolismo , Estreptozocina , Tropomiosina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
2.
Cancers (Basel) ; 14(11)2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35681602

RESUMO

We investigated the p75 Neurotrophin Receptor (p75NTR) expression and cleavage product p75NTR Intracellular Domain (p75ICD) as potential oncogenic and metastatic markers in human Laryngeal Squamous Cell Carcinoma (LSCC). p75NTR is highly expressed in Cancer Stem Cells (CSCs) of the laryngeal epithelia and it has been proposed as a marker for stemness, cell migration, and chemo-resistance in different squamous carcinomas. To investigate the clinical significance of p75NTR cleavage products in solid tumors, full-length and cleaved p75NTR expression was analyzed in laryngeal primary tumors from different-stage LSCC patients, diagnosed at the Policlinico Umberto I Hospital. Molecular and histological techniques were used to detect the expressions of p75NTR and p75ICD, and ATP Binding Cassette Subfamily G Member 2 (ABCG2), a CSC marker. We found regulated p75NTR cleavage during squamous epithelial tumor progression and tissue invasion. Our preliminary investigation suggests p75ICD expression and localization as possible features of tumorigenesis and metastaticity. Its co-localization with ABCG2 in squamous cells in the parenchyma invaded by the tumor formation allows us to hypothesize p75NTR and p75ICD roles in tumor invasion and CSC spreading in LSCC patients. These data might represent a starting point for a comprehensive analysis of p75NTR cleavage and of its clinical relevance as a potential molecular LSCC signature, possibly helping diagnosis, and improving prognosis and personalized therapy.

3.
Eur J Obstet Gynecol Reprod Biol ; 247: 32-41, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32058187

RESUMO

Neurotrophins (NTs) are a family of polypeptides whose functions have been extensively studied in the past two decades. In particular, Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) play a major role in the development, nutrition and growth of the central and peripheral nervous system and in the pathogenesis of neurodegenerative, cardiometabolic and (auto)immune diseases. However, NGF and BDNF have subtle functions for follicular development, implantation, and placentation. This short narrative review summarizes the existing evidence, published between 2000 and 2019, about the role of NTs in many different conditions that might affect women during and after pregnancy such as preeclampsia, gestational diabetes, obesity, depression, anxiety, smoking and alcohol abuse. Literature suggests that the dysregulation of synthesis and release of NTs may lead to decisive effects on both maternal and fetal health. Some piece of evidences was found about a possible association between NGF/BDNF and breastfeeding. Additional studies on human models are necessary to further characterize the role of NTs in life-changing experiences like labor and delivery.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator de Crescimento Neural/metabolismo , Complicações na Gravidez/metabolismo , Animais , Parto Obstétrico , Feminino , Humanos , Lactação/metabolismo , Sistema Nervoso Periférico/crescimento & desenvolvimento , Placentação , Período Pós-Parto/metabolismo , Gravidez
4.
Riv Psichiatr ; 55(1): 4-15, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32051620

RESUMO

The nerve growth factor (NGF) belongs to a family of proteins named neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. NGF regulates a large number of physiological mechanisms that result in neurotrophic, metabotrophic and/or immunotrophic effects. Neurodegenerative diseases, including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of changing the brain levels of neurotrophins, in particular NGF. The contribution of both NGF and its receptor TrkA in such events and the recent promising results of NGF based therapies are here presented and discussed.


Assuntos
Fator de Crescimento Neural/fisiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Doença de Alzheimer/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Infecções Parasitárias do Sistema Nervoso Central/metabolismo , Depressão/metabolismo , Humanos , Camundongos , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/metabolismo , Plasticidade Neuronal , Neurotrofina 3/metabolismo , Prognóstico , Ratos , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Esquizofrenia/metabolismo , Comportamento Social
5.
Aging (Albany NY) ; 11(23): 11770-11792, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31812953

RESUMO

Cancer Stem Cells (CSCs) are self-renewing cancer cells responsible for expansion of the malignant mass in a dynamic process shaping the tumor microenvironment. CSCs may hijack the host immune surveillance resulting in typically aggressive tumors with poor prognosis.In this review, we focus on neurotrophic control of cellular substrates and molecular mechanisms involved in CSC-driven tumor growth as well as in host immune surveillance. Neurotrophins have been demonstrated to be key tumor promoting signaling platforms. Particularly, Nerve Growth Factor (NGF) and its specific receptor Tropomyosin related kinase A (TrkA) have been implicated in initiation and progression of many aggressive cancers. On the other hand, an active NGF pathway has been recently proven to be critical to oncogenic inflammation control and in promoting immune response against cancer, pinpointing possible pro-tumoral effects of NGF/TrkA-inhibitory therapy.A better understanding of the molecular mechanisms involved in the control of tumor growth/immunoediting is essential to identify new predictive and prognostic intervention and to design more effective therapies. Fine and timely modulation of CSCs-driven tumor growth and of peripheral lymph nodes activation by the immune system will possibly open the way to precision medicine in neurotrophic therapy and improve patient's prognosis in both TrkA- dependent and independent cancers.


Assuntos
Neoplasias/metabolismo , Células-Tronco Neoplásicas/fisiologia , Fatores de Crescimento Neural/metabolismo , Humanos , Neoplasias/imunologia
6.
J Cell Physiol ; 234(10): 18297-18307, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30891770

RESUMO

This study sought to evaluate the prospective role exerted by vascular endothelial growth factor (VEGF) in the modulation of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) signalling pathways in the rabbit retina. To reach this aim, the anti-VEGF agents aflibercept and ranibizumab were used as a pharmacological approach to evaluate the putative consequences elicited by VEGF inhibition on neurotrophin signalling. VEGF inhibition determined a marked imbalance in proneurotrophin expression, a significant reduction in TrkA and TrkB phosphorylation states and a decrease in the pan-neurotrophin receptor p75. Importantly, VEGF blockade also caused a strong increase in cleaved caspase-3, beclin-1 and lipidated LC3. The effects were more pronounced in the aflibercept group when compared with ranibizumab-treated rabbits, particularly 1 week after injection. This study demonstrates that VEGF exerts pivotal physiological roles in regulating NGF and BDNF pathways in the retina, as its inhibition by anti-VEGF agents deeply impacts neurotrophin homeostasis. These events are accompanied by a sustained induction of apoptotic and autophagic markers, suggesting that anti-VEGF-dependent impairments in neurotrophin signalling could be responsible for the activation of retinal cell death pathways.


Assuntos
Autofagia/fisiologia , Caspase 3/metabolismo , Fatores de Crescimento Neural/metabolismo , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estudos Prospectivos , Coelhos , Ranibizumab/farmacologia , Receptor de Fator de Crescimento Neural/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão/farmacologia , Retina/efeitos dos fármacos , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Curr Neuropharmacol ; 17(1): 59-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28676012

RESUMO

BACKGROUND: Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-ßhydroxy 3ß-methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essential in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statins are able to induce pleiotropic actions, and acquire increased interest as potential and novel modulators in brain processes, especially during pathological conditions. OBJECTIVE: The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and pharmacodynamic properties of statins in the brain. In addition, effects of statin on brain diseases are discussed providing the most up-to-date information. METHODS: Relevant scientific information was identified from PubMed database using the following keywords: statins and brain, central nervous system, neurological diseases, neurodegeneration, brain tumors, mood, stroke. RESULTS: 315 scientific articles were selected and analyzed for the writing of this review article. Several papers highlighted that statin treatment is effective in preventing or ameliorating the symptomatology of a number of brain pathologies. However, other studies failed to demonstrate a neuroprotective effect. CONCLUSION: Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, additional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies.


Assuntos
Encefalopatias/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Animais , Encéfalo/metabolismo , Encefalopatias/metabolismo , Encefalopatias/prevenção & controle , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
J Cell Physiol ; 233(11): 8874-8883, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29856479

RESUMO

Intravitreal injection (IVT) of antivascular endothelial growth factor (anti-VEGF) agents is widely used for the treatment of retinal vascular diseases. Recently, the injection of anti-VEGF agents in the ocular anterior chamber has been proposed for the treatment of neovascular glaucoma and potential side effects on the corneal structures have been investigated with contrasting results. Increasing evidence has demonstrated that VEGF inhibition is associated with cellular apoptotic changes and that this effect may be mediated by alterations in nerve growth factor (NGF) pathway. In this study, we demonstrated that anterior chamber injection (IC), but not IVT injection of two different anti-VEGF agents, aflibercept and ranibizumab, affects rabbit corneal endothelium in terms of survival and apoptosis and is associated with changes in endothelial expression of NGF precursor (proNGF) and p75 neurotrophin receptor (p75NTR) receptor. We observed an increase in corneal endothelial cell incorporation of trypan blue and expression of cleaved-caspase 3 (c-Casp3), p75NTR, and RhoA after IC injection of both anti-VEGF drugs when compared with the vehicle. Our results showed that apoptosis induction by aflibercept was more pronounced when compared with that of ranibizumab. Aflibercept also mediated a significant increase in endothelial expression of proNGF when compared with the vehicle. In line with these data, IC administration of both anti-VEGF agents induced the activation of apoptotic signals in endothelial cells, including an increase in c-Casp3, decrease in Bad Ser 112 phosphorylation, and unbalance of AKT phosphorylation. These results demonstrated that administration of anti-VEGF in the anterior chamber of rabbit affects endothelial cell survival by inducing apoptosis through alteration of NGF pathway.


Assuntos
Glaucoma Neovascular/tratamento farmacológico , Fator de Crescimento Neural/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Animais , Câmara Anterior/efeitos dos fármacos , Câmara Anterior/patologia , Apoptose/genética , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Endotélio Corneano/efeitos dos fármacos , Endotélio Corneano/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glaucoma Neovascular/genética , Glaucoma Neovascular/patologia , Humanos , Injeções Intravítreas , Coelhos , Ranibizumab/administração & dosagem , Receptor de Fator de Crescimento Neural/genética , Fator A de Crescimento do Endotélio Vascular/genética , Proteína rhoA de Ligação ao GTP/genética
9.
Int J Mol Sci ; 18(1)2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28067793

RESUMO

Nerve growth factor (NGF) is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC) degenerate following optic-nerve crush (ONC), even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was performed to evaluate the effects of unilateral ONC on NGF expression and signaling in the adult retina. Visually evoked potential and immunofluorescence staining were used to assess axonal damage and RGC loss. The levels of NGF, proNGF, p75NTR, TrkA and GFAP and the activation of several intracellular pathways were analyzed at 1, 3, 7 and 14 days after crush (dac) by ELISA/Western Blot and PathScan intracellular signaling array. The progressive RGC loss and nerve impairment featured an early and sustained activation of apoptotic pathways; and GFAP and p75NTR enhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75NTR contribute to exacerbate retinal degeneration by further stimulating apoptosis during the second week after injury, and thus hamper the neuroprotective effect of the endogenous NGF. These findings might aid in identifying effective treatment windows for NGF-based strategies to counteract retinal and/or optic-nerve degeneration.


Assuntos
Fator de Crescimento Neural/metabolismo , Traumatismos do Nervo Óptico/complicações , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/metabolismo , Transdução de Sinais , Animais , Apoptose , Western Blotting , Potenciais Evocados Visuais/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Microscopia de Fluorescência , Compressão Nervosa , Fatores de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Precursores de Proteínas/metabolismo , Ratos , Ratos Long-Evans , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Retina/metabolismo , Retina/fisiopatologia , Degeneração Retiniana/etiologia , Degeneração Retiniana/fisiopatologia , Fatores de Tempo
10.
Growth Factors ; 33(5-6): 401-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26728403

RESUMO

Nerve growth factor (NGF) exerts protective actions in the healthy and diseased nervous system. Intranasal administration is a suitable and safe strategy to deliver NGF to CNS neurons. We investigated whether nasal anti-NGF-antibody (ANA) administration affects neuronal autophagy, in view of its putative regulatory role in this process. We focused on olfactory bulbs (OB), neocortex (Cx), hippocampus (HF) and septal complex (SC), known to be NGF-responsive and autophagically active. Our combined molecular/morphological results demonstrate that intranasally administered ANA reaches brain NGF-target neurons and lowers the levels of endogenous NGF and its receptors. Treatment also affects - in a brain region-dependent manner - the expression of the autophagic proteins Beclin-1 and Ambra1, as well as that of proteins belonging to the Bcl2 family, namely Bax and Bcl-2, reflecting apoptotic dysregulation. This study provides a nongenetically modified, NGF-defective animal model, representing a suitable tool to investigate novel properties of the neurotrophin, especially in relation to autophagy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Anticorpos/imunologia , Proteínas Reguladoras de Apoptose/biossíntese , Autofagia/fisiologia , Fator de Crescimento Neural/metabolismo , Administração Intranasal , Animais , Anticorpos/administração & dosagem , Proteína Beclina-1 , Linhagem Celular Tumoral , Hipocampo/metabolismo , Neocórtex/metabolismo , Fator de Crescimento Neural/imunologia , Bulbo Olfatório/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Receptores de Fator de Crescimento Neural/metabolismo , Proteína X Associada a bcl-2/biossíntese
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