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1.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502019

RESUMO

The lungs play a very important role in the human respiratory system. However, many factors can destroy the structure of the lung, causing several lung diseases and, often, serious damage to people's health. Nerve growth factor (NGF) is a polypeptide which is widely expressed in lung tissues. Under different microenvironments, NGF participates in the occurrence and development of lung diseases by changing protein expression levels and mediating cell function. In this review, we summarize the functions of NGF as well as some potential underlying mechanisms in pulmonary fibrosis (PF), coronavirus disease 2019 (COVID-19), pulmonary hypertension (PH), asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Furthermore, we highlight that anti-NGF may be used in future therapeutic strategies.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Pulmão/patologia , Fator de Crescimento Neural/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Asma/tratamento farmacológico , Asma/patologia , COVID-19/tratamento farmacológico , COVID-19/patologia , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Pulmão/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular/métodos , Fator de Crescimento Neural/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/patologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia
2.
Nanoscale ; 13(37): 15598-15610, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34529749

RESUMO

The facial nerve is a crucial nerve in the maxillofacial region and is vulnerable to damage. As a consequence of the complications during nerve restoration, existing remedies have certain limitations, thus the treatment of facial nerve injury is always a perplexing task for people. Regulation of Schwann cells is always the breakpoint of neurorestoration since Schwann cells count a great deal in injured nerve repair. In this study, we presented proof that tetrahedral framework nucleic acids (tFNAs), a kind of nucleic acid nanomaterial, were capable of regulating the neurorestorative pathway NGF/PI3 K/AKT, resulting in the activation of a series of cell behaviors related to injured nerve restoration such as proliferation and migration. In vivo experiments also proved that tFNAs enhanced the expressions of axon and myelin marker proteins, impelled histological recovery, promoted the efficient restoration of nerve conduction and muscle movement. Additionally, tFNAs possessed excellent biocompatibility and superior endocytosis ability. Thus, there is good potential for tFNAs to be applied in the therapy of facial nerve injury or even peripheral nerve injury.


Assuntos
Ácidos Nucleicos , Proteínas Proto-Oncogênicas c-akt , Nervo Facial , Humanos , Fator de Crescimento Neural , Fosfatidilinositol 3-Quinases
3.
Adv Exp Med Biol ; 1331: 3-10, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453288

RESUMO

Neurotrophins (NTs) are molecules regulating differentiation, maintenance, and functional plasticity of vertebrate nervous systems. Nerve growth factor (NGF) was the first to be identified in the neurotrophin family. The long scientific history of NTs provided not only advancement in the neuroscience field but opened new scenarios involving different body districts in physiological and pathological conditions, which include the immune, endocrine, and skeletal system, vascular districts, inflammation, etc. To date, many biological aspects of NTs have been clarified, but the new discoveries are still opening new insights on molecular and cellular mechanisms and systemic effects, also affecting the possible therapeutic application of NTs. This short review summarizes the main aspects of NGF biology and biochemistry, including the role of the NGF precursor molecule, high- and low-affinity receptors and related intracellular pathways, and target cells.


Assuntos
Receptores de Fator de Crescimento Neural , Transdução de Sinais , Diferenciação Celular , Fator de Crescimento Neural/genética , Neurogênese , Ligação Proteica , Receptores de Fator de Crescimento Neural/genética
4.
Adv Exp Med Biol ; 1331: 11-18, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453289

RESUMO

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 45 years, 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.


Assuntos
Fator de Crescimento Neural , Neurônios , Animais , Insetos , Camundongos , Neurobiologia , Fator de Crescimento Transformador beta
5.
Adv Exp Med Biol ; 1331: 19-29, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453290

RESUMO

During the development of the nervous system, neurons respond to diffusible cues secreted by target cells. Because such target-derived factors regulate development, maturation, and maintenance of axons as well as somatodendritic compartments, signals initiated at distal axons must be retrogradely transmitted toward cell bodies. Neurotrophins, including the nerve growth factor (NGF), provide one of the best-known examples of target-derived growth factors. The cell biological processes of endocytosis and retrograde trafficking of their Trk receptors from growth cones to cell bodies are key mechanisms by which target-derived neurotrophins influence neurons. Evidence accumulated over the past several decades has begun to uncover the molecular mechanisms of formation, transport, and biological functions of these specialized endosomes called "signaling endosomes."


Assuntos
Endossomos , Fator de Crescimento Neural , Axônios , Fator de Crescimento Neural/genética , Neurônios , Transdução de Sinais
6.
Adv Exp Med Biol ; 1331: 51-63, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453292

RESUMO

The self-repair ability of tissues and organs in case of injury and disease is a fundamental biological mechanism and an important therapeutic target. The tissue plasticity and the presence of adult stem cell niches open a new path in the development of pharmacological and non-pharmacological treatments finalized to improve the intrinsic regeneration.In this context, nerve growth factor (NGF) is widely studied for its capability of driving endogenous regeneration of ectoderm-derived tissues, directly acting on the cell targets and through the regulation of the stem cell niches. In fact, this growth factor is very promising for its key role in the development and multiplicity of the cellular targets.In this chapter, we have traveled across the recent history of NGF pleiotropic role in ectodermal tissue generation and repair, from embryonic development to skin wound healing, axonal regrowth, and remyelination.The better understanding of both the biological mechanisms underlying regeneration and the physiological role of NGF in development and injury response will open new therapeutic strategies, driven by the potential applications of this growth factor as an agent for improving endogenous regeneration processes.


Assuntos
Fator de Crescimento Neural , Regeneração Nervosa , Axônios , Cicatrização
7.
Adv Exp Med Biol ; 1331: 31-48, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453291

RESUMO

Recent research has demonstrated that degeneration of the basal forebrain cholinergic system, far from being a mere downstream mediator of Alzheimer's disease (AD) symptoms, may play a disease-aggravating role in the continuum of AD pathology. The search for novel biomarkers of the cholinergic deficit in AD and novel therapeutic targets for the sustenance of the basal forebrain cholinergic system has therefore taken on more urgency. A novel model that explains the preferential vulnerability of basal forebrain cholinergic neurons in AD as the result of pathological alterations to nerve growth factor (NGF) metabolism offers an integrated investigative platform for the development of such biomarkers and therapeutics. By positing a reciprocal trophic interaction between the basal forebrain and its target tissues, this model can also explain the disease-modifying nature of the cholinergic deficit in AD and can incorporate other key factors in basal forebrain cholinergic degeneration, including NGF receptor changes and retrograde transport deficits in AD. This chapter will focus on the potential of NGF metabolic pathway biomarkers in AD as well as therapeutic targets to correct NGF metabolic deficits, aiding the development of novel pro-cholinergic therapeutics.


Assuntos
Doença de Alzheimer , Preparações Farmacêuticas , Doença de Alzheimer/tratamento farmacológico , Biomarcadores , Humanos , Redes e Vias Metabólicas , Fator de Crescimento Neural/metabolismo
8.
Adv Exp Med Biol ; 1331: 65-75, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453293

RESUMO

Nerve growth factor (NGF) is an important molecule for the development and differentiation of neuronal and non-neuronal cells. Here we analyze by immunohistochemistry the distribution of NGF in the dental pulp mesenchyme of embryonic and functional human teeth. In the dental pulp of both embryonic and healthy functional teeth, NGF is mainly expressed in the odontoblasts that are responsible for dentine formation, while in functional teeth NGF is also expressed in nerve fibers innervating the dental pulp. In injured teeth, NGF is expressed in the newly formed odontoblastic-like cells, which replace the dying odontoblasts. In these teeth, NGF expression is also upregulated in the intact odontoblasts, suggesting a role for this molecule in dental tissue repair. Similarly, in cultures of human dental pulp cells, NGF expression is strongly upregulated during their differentiation into odontoblasts as well as during the mineralization process. In microfluidic devices, release of NGF from cultured human dental pulp cells induced neuronal growth from trigeminal ganglia toward the NGF secreting cells. These results show that NGF is closely linked to the various functions of odontoblasts, including secretory and neuronal attraction processes.


Assuntos
Odontoblastos , Dente , Diferenciação Celular , Polpa Dentária , Humanos , Minerais , Fator de Crescimento Neural/genética
9.
Adv Exp Med Biol ; 1331: 119-144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453296

RESUMO

This chapter relates biographic personal and scientific interactions with Rita Levi-Montalcini. It highlights research from our laboratory inspired by Rita's fundamental discovery. This work from studies on potentially neuro-reparative gangliosides, their interactions with NGF, the role of exogenous NGF in the recovery of degenerating cholinergic neurons of the basal forebrain to the evidence that endogenous NGF maintains the "day-to-day" cortical synaptic phenotype and the discovery of a novel CNS "NGF metabolic pathway." This brain pathway's conceptual platform allowed the investigation of its status during the Alzheimer's disease (AD) pathology. This revealed a major compromise of the conversion of the NGF precursor molecule (proNGF) into the most biologically active molecule, mature NGF (mNGF). Furthermore, in this pathology, we found enhanced protein levels and enzymatic activity of the proteases responsible for the proteolytic degradation of mNGF. A biochemical prospect explaining the tropic factor vulnerability of the NGF-dependent basal forebrain cholinergic neurons and of their synaptic terminals. The NGF deregulation of this metabolic pathway is evident at preclinical stages and reflected in body fluid particularly in the cerebrospinal fluid (CSF). The findings of a deregulation of the NGF metabolic pathway and its reflection in plasma and CSF are opening doors for the development of novel biomarkers for preclinical detection of AD pathology both in Alzheimer's and in Down syndrome (DS) with "silent" AD pathology.


Assuntos
Doença de Alzheimer , Síndrome de Down , Encéfalo/metabolismo , Neurônios Colinérgicos/metabolismo , Humanos , Fator de Crescimento Neural/metabolismo
10.
Adv Exp Med Biol ; 1331: 193-202, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453299

RESUMO

Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain characterized by extracellular beta-amyloid plaques, intraneuronal tau inclusions, vascular impairment, inflammation, neurodegeneration, and memory loss. Acetylcholine is the most important neurotransmitter for memory, and cholinergic neurons selectively degenerate in AD, and a loss of acetylcholine directly correlates with cognitive decline. Nerve growth factor (NGF) is the most potent growth factor to support the survival of these cholinergic neurons. Thus, researchers are interested to deliver NGF directly into the brain to the cholinergic neurons. As the brain is isolated by the blood-brain barrier, the large protein NGF cannot easily pass into the brain, and peripheral administration of NGF also causes severe side effects. Blood cells may represent a potent therapeutic strategy to deliver NGF into the brain. Monocytes can be isolated and loaded with NGF and may transmigrate into the brain. As monocytes are precursors of microglia, they may differentiate and release NGF but also phagocyte and eliminate toxic plaques. Platelets are small anuclear cells and become rapidly activated during vascular lesions, and they may migrate to lesion sites and repair blood vessels and also eliminate toxic beta-amyloid depositions in vessels. In order to guarantee a stable and slow release, the use of biomaterials is of interest, especially collagen hydrogels that may be useful to protect these transmigrating blood cells. In this review, I summarize advantages and challenges of using transmigrating cells to deliver NGF directly into the brain.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Colágeno , Humanos , Hidrogéis , Monócitos , Fator de Crescimento Neural
11.
Adv Exp Med Biol ; 1331: 205-214, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453300

RESUMO

Since its first characterization in the early 1950s, the role of the polypeptidic nerve growth factor (NGF) in controlling behavior remained elusive. Since the mid-1980s, we undertook a series of experiments aimed at elucidating the biological role(s) played by neurotrophins, particularly NGF, in adult rodents. At the beginning, we concentrated on the submandibular salivary gland of the male mouse, which was known to store massive amount of NGF. We found that under specific stress conditions, the salivary NGF is released in the bloodstream: intermale fighting between isolated males was the first reported context in which salivary NGF was released, thus providing a physiological significance for its presence in the adult, territorial males. We also found that dominant males release less NGF than subordinates and provided a loop-type model which includes intermale social confrontation, adrenal gland size, and functional status, corticosterone release, a model resulting in likelihood to be stabilized in a "dominant" or a "subordinate" social status. A variety of social anxiety contexts of mammals, humans included, has been described since then, and further studies carried out on humans showed that NGF is released in the bloodstream of parachutists at their first skydiving experience and in the case of ranking high on the Passionate Love Scale (amour fou). Ethological data from lab rodents helped in understanding NGF function in subtly controlling social "status" of male mice: the considerations about the interplay among neurobiological, physiological, and behavioral factors in structuring the dominant vs subordinate phenotypes may well apply to other vertebrate species, specifically addressing the underlying role of neurotrophins in relating behavior and brain neuroplasticity.


Assuntos
Ansiedade , Fator de Crescimento Neural , Animais , Encéfalo , Masculino , Camundongos , Plasticidade Neuronal , Vertebrados
12.
Adv Exp Med Biol ; 1331: 145-165, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453297

RESUMO

Alzheimer's disease (AD), one of the most common causes of dementia in elderly people, is characterized by progressive impairment in cognitive function, early degeneration of basal forebrain cholinergic neurons (BFCNs), abnormal metabolism of the amyloid precursor protein (APP), amyloid beta-peptide (Aß) depositions, and neurofibrillary tangles. According to the cholinergic hypothesis, dysfunction of acetylcholine-containing neurons in the basal forebrain contributes markedly to the cognitive decline observed in AD. In addition, the neurotrophic factor hypothesis posits that the loss nerve growth factor (NGF) signalling in AD may account for the vulnerability to atrophy of BFCNs and consequent impairment of cholinergic functions. Though acetylcholinesterase inhibitors provide only partial and symptomatic relief to AD patients, emerging data from in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) studies in mild cognitive impairment (MCI) and AD patients highlight the early involvement of BFCNs in MCI and the early phase of AD. These data support the cholinergic and neurotrophic hypotheses of AD and suggest new targets for AD therapy.Different mechanisms account for selective vulnerability of BFCNs to AD pathology, with regard to altered metabolism of APP and tau. In this review, we provide a general overview of the current knowledge of NGF and APP interplay, focusing on the role of APP in regulating NGF receptors trafficking/signalling and on the involvement of NGF in modulating phosphorylation of APP, which in turn controls APP intracellular trafficking and processing. Moreover, we highlight the consequences of APP interaction with p75NTR and TrkA receptor, which share the same binding site within the APP juxta-membrane domain. We underline the importance of insulin dysmetabolism in AD pathology, in the light of our recent data showing that overlapping intracellular signalling pathways stimulated by NGF or insulin can be compensatory. In particular, NGF-based signalling is able to ameliorates deficiencies in insulin signalling in the medial septum of 3×Tg-AD mice. Finally, we present an overview of NGF-regulated microRNAs (miRNAs). These small non-coding RNAs are involved in post-transcriptional regulation of gene expression , and we focus on a subset that are specifically deregulated in AD and thus potentially contribute to its pathology.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Idoso , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Humanos , Camundongos , Fator de Crescimento Neural , Neurônios
13.
Adv Exp Med Biol ; 1331: 167-191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453298

RESUMO

Age-dependent progressive neurodegeneration and associated cognitive dysfunction represent a serious concern worldwide. Currently, dementia accounts for the fifth highest cause of death, among which Alzheimer's disease (AD) represents more than 60% of the cases. AD is associated with progressive cognitive dysfunction which affects daily life of the affected individual and associated family. The cognitive dysfunctions are at least partially due to the degeneration of a specific set of neurons (cholinergic neurons) whose cell bodies are situated in the basal forebrain region (basal forebrain cholinergic neurons, BFCNs) but innervate wide areas of the brain. It has been explicitly shown that the delivery of the neurotrophic protein nerve growth factor (NGF) can rescue BFCNs and restore cognitive dysfunction, making NGF interesting as a potential therapeutic substance for AD. Unfortunately, NGF cannot pass through the blood-brain barrier (BBB) and thus peripheral administration of NGF protein is not viable therapeutically. NGF must be delivered in a way which will allow its brain penetration and availability to the BFCNs to modulate BFCN activity and viability. Over the past few decades, various methodologies have been developed to deliver NGF to the brain tissue. In this chapter, NGF delivery methods are discussed in the context of AD.


Assuntos
Doença de Alzheimer , Prosencéfalo Basal , Doença de Alzheimer/tratamento farmacológico , Humanos , Fator de Crescimento Neural/metabolismo , Neurônios/metabolismo
14.
Adv Exp Med Biol ; 1331: 255-263, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453304

RESUMO

Nerve growth factor (NGF) is a neuroprotective molecule performing not only on central and peripheral neurons but also on cells of the visual system. Human retinitis pigmentosa (RP) is a major cause of blindness worldwide, and a resolute therapy is still lacking. Recent studies have shown that ocular NGF administration exerts a protective action on damaged retinal cells of mammalians, including human beings, although whether NGF also protects photoreceptors is not clear.We used the Royal College of Surgeons (RCS) strain in this study. The RCS is a rodent affected by inherited retinitis pigmentosa (RP) during postnatal life. For this study, we investigated whether ocular NGF treatment reduces/stops the progression of photoreceptor degeneration of rats with RP.This study was carried out in vitro on isolated photoreceptors to further investigate the action on these cells and whether the action is direct or mediated.The results indicate that ocular NGF administration can protect photoreceptors from degeneration into a model developing inherited RP and that the NGF action is direct. In this regard, we observed that binding of NGF to its receptor modulates expression of rhodopsin, a specific biological marker for photoreceptor survival and functionality.Part of the data reported in this chapter has been published in a previous study.


Assuntos
Degeneração Retiniana , Retinite Pigmentosa , Animais , Modelos Animais de Doenças , Fator de Crescimento Neural/genética , Células Fotorreceptoras , Ratos , Retinite Pigmentosa/tratamento farmacológico , Retinite Pigmentosa/genética , Rodopsina/genética
15.
Adv Exp Med Biol ; 1331: 265-273, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453305

RESUMO

Nerve growth factor (NGF) plays a crucial role in retinal disorders, as suggested by in vitro/in vivo models. The major effect embraces the neuroprotective activity on retinal ganglion cells (RGCs) undergoing degeneration, as observed in experimental diabetic retinopathy, age-related and diabetic macular degeneration, and some vitreoretinal diseases. Focused experiments suggested that locally applied NGF (intravitreal delivery) not only allowed the counteraction of RGC degeneration but also provided data for a whole retina restoration. The currently available retinal microsurgery allows the collection of human aqueous and more interesting vitreous (vitreal reflux) humors. The recent biomolecular analysis highlights the possibility to identify disease-associated biomarkers and allow the monitoring of retinal impairments with sustain to the retinal imaging. Coupled to other soluble mediators, NGF has been quantified in aqueous (slightly expressed) from diabetic retinopathy-suffering patients (cataract surgery) and vitreal reflux (significantly impaired) of diabetic macular degeneration-suffering patients (intravitreal surgery). Although the reasons of these NGF impairments are not fully comprehended, some retinal cells (glial cells, bipolar neurons, and RGCs) have been recognized partially responsible for these local changes.Taken together, the recent progress in the ocular microsurgeries might be associated with sampling of small amount of ocular humors, allowing the collection of biochemical information about diseased retina and the monitoring of treatment. The chance to detect NGF and likewise other neuroprotective or pro-/anti-inflammatory factors in these fluids would open to the possibility to identify biomarkers of early diagnosis or monitoring of retinal disease evolution/therapy (precision medicine).


Assuntos
Fator de Crescimento Neural , Doenças Neurodegenerativas , Humanos , Neuroproteção , Retina , Células Ganglionares da Retina
16.
Adv Exp Med Biol ; 1331: 277-287, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453306

RESUMO

Stimuli that lead to the release of gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins and, consequently, ovulation in mammals fall into two broad categories. In the first, high plasma oestrogen concentrations induce the events that trigger ovulation, a characteristic of spontaneous ovulators. In the second, nerve stimuli occurring during mating reach the hypothalamus and trigger the release of GnRH and ovulation with a neuroendocrine reflex that characterizes induced ovulators.In this review, we will give an overview of the distribution of NGF and its expression in the different tissues of the male accessory sex glands, the main sites of NGF production. Next, we will highlight the role of NGF in sperm function and its potential cryopreserving role in artificial insemination techniques. Finally, we will evaluate the functions of NGF in ovulation, particularly in induced ovulators. Overall, the information obtained so far indicates that NGF is widely distributed in organs that regulate the reproductive activity, in both males and females. In spontaneous ovulators, NGF exerts mainly a luteotrophic action, while, in induced ovulators it is the main ovulation-inducing factor. A better understanding of the role of NGF in reproduction would be of great interest, since it could help finding innovative therapeutic aids to improve mammalian fertility.


Assuntos
Fator de Crescimento Neural , Sêmen , Animais , Feminino , Hormônio Liberador de Gonadotropina , Masculino , Ovulação , Reprodução
17.
Nat Commun ; 12(1): 4939, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400627

RESUMO

Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. Here, the role of sensory nerve fibers in this abnormal cell fate decision is investigated using a severe extremity injury model in mice. Soft tissue trauma results in NGF (Nerve growth factor) expression, particularly within perivascular cell types. Consequently, NGF-responsive axonal invasion occurs which precedes osteocartilaginous differentiation. Surgical denervation impedes axonal ingrowth, with significant delays in cartilage and bone formation. Likewise, either deletion of Ngf or two complementary methods to inhibit its receptor TrkA (Tropomyosin receptor kinase A) lead to similar delays in axonal invasion and osteochondral differentiation. Mechanistically, single-cell sequencing suggests a shift from TGFß to FGF signaling activation among pre-chondrogenic cells after denervation. Finally, analysis of human pathologic specimens and databases confirms the relevance of NGF-TrkA signaling in human disease. In sum, NGF-mediated TrkA-expressing axonal ingrowth drives abnormal osteochondral differentiation after soft tissue trauma. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation.


Assuntos
Diferenciação Celular , Fator de Crescimento Neural/metabolismo , Receptor trkA/metabolismo , Transdução de Sinais , Ferimentos e Lesões/metabolismo , Animais , Axônios/metabolismo , Cartilagem/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/genética , Osteogênese , Células-Tronco/metabolismo , Ferimentos e Lesões/patologia
18.
BMC Musculoskelet Disord ; 22(1): 634, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301215

RESUMO

BACKGROUND: Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP). Following disc injury, nerve growth factor (NGF) concentrations rise in IVDs, and anti-NGF therapy has been shown to attenuate LBP in humans. Increased levels of tumor necrosis factor-α (TNF-α) and transforming growth factor-ß (TGF-ß) in degenerative IVDs and in in vitro studies suggest that these factors promote NGF production. However, whether these factors regulate NGF in vivo remains unclear. Thus, we studied NGF regulation in a mouse model of IVD injury. METHODS: After inducing IVD injury, we examined mRNA levels of Tnfa, Tgfb, and Ngf in IVDs from control and IVD-injured mice across 7 days. To do this, we used magnetic cell separation to isolate CD11b ( +) (macrophage-rich) and CD11b (-) (IVD cell-rich) cell fractions from injured IVDs. To study the effect of TNF-α on Ngf expression, we examined Ngf expression in injured IVDs from C57BL/6 J and Tnfa-knockout (KO) mice (C57BL/6 J background). To study the effect of TGF-ß on Ngf expression, C57/BL6J mice were given an intraperitoneal injection of either the TGF-ß inhibitor SB431542 or DMSO solution (vehicle) one and two days before harvesting IVDs. RESULTS: mRNA expression of Tnfa, Tgfb, and Ngf was significantly increased in injured IVDs. Tnfa was predominantly expressed in the CD11b ( +) fraction, and Tgfb in the CD11b (-) fraction. Ngf expression was comparable between CD11b ( +) and CD11b (-) fractions, and between wild-type and Tnfa-KO mice at post-injury day (PID) 1, 3, and 7. SB431542 suppressed TGF-ß-mediated Ngf expression and NGF production in vitro. Further, administration of SB431542 significantly reduced Ngf expression in IVDs such that levels were below those observed in vehicle-treated animals at PID3 and PID7. CONCLUSION: A TGF-ß inhibitor reduced Ngf expression in a mouse model of IVD injury, suggesting that TGF-ß may regulate NGF expression in vivo.


Assuntos
Degeneração do Disco Intervertebral , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Disco Intervertebral , Degeneração do Disco Intervertebral/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta/antagonistas & inibidores
19.
Handb Clin Neurol ; 179: 219-229, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34225964

RESUMO

There is currently no effective treatment for the most common of the dementia disorders, Alzheimer's disease (AD). It has been known for decades that the central cholinergic system is important for memory. The cholinergic neurons in the basal forebrain with its cortical and hippocampal projections degenerate in AD and thus contribute to the cognitive decline characteristic of AD. This knowledge led to the development of the currently approved treatment for AD, with inhibitors of acetylcholine-esterase targeting the cholinergic system with beneficial but mild effects. In recent years, other approaches to influence the degenerating cholinergic system in AD focusing on nerve growth factor (NGF) have been undertaken. NGF is required for the survival and function of the basal forebrain cholinergic neurons, the most important being the nucleus basalis of Meynert (nbM). Since there is a lack of NGF and its receptors in the AD forebrain, the hypothesis is that local delivery of NGF to the nbM could revive the cholinergic circuitry and thereby restore cognitive functions. Since NGF does not pass through the blood-brain barrier, approaches involving cerebral injections of genetically modified cells or viral vectors or implantation of encapsulated cells in the nbM in AD patients have been used. These attempts have been partially successful but also have limitations, which are presented and discussed here. In conclusion, these trials point to the importance of further development of NGF-related therapies in AD.


Assuntos
Doença de Alzheimer , Núcleo Basal de Meynert , Doença de Alzheimer/terapia , Terapia Baseada em Transplante de Células e Tecidos , Neurônios Colinérgicos , Terapia Genética , Humanos , Fator de Crescimento Neural
20.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209299

RESUMO

Alzheimer's disease (AD)-associated neurodegeneration is triggered by different fragments of amyloid beta (Aß). Among them, Aß (25-35) fragment plays a critical role in the development of neurodegeneration-it reduces synaptic integrity by disruption of excitatory/inhibitory ratio across networks and alters the growth factors synthesis. Thus, in this study, we aimed to identify the involvement of neurotrophic factors-the insulin-like growth factor 1 (IGF-1) and nerve growth factor (NGF)-of AD-like neurodegeneration induced by Aß (25-35). Taking into account our previous findings on the neuroprotective effects of the mix of proteoglycans of embryonic genesis (PEG), it was suggested to test its regulatory effect on IGF-1 and NGF levels. To evaluate the progress of neurodegeneration, in vivo electrophysiological investigation of synaptic activity disruption of the entorhinal cortex-hippocampus circuit at AD was performed and the potential recovery effects of PEG with relative structural changes were provided. To reveal the direct effects of PEG on brain functional activity, the electrophysiological pattern of the single cells from nucleus supraopticus, sensomotor cortex and hippocampus after acute injection of PEG was examined. Our results demonstrated that after i.c.v. injection of Aß (25-35), the level of NGF decreased in cerebral cortex and hypothalamus, and, in contrast, increased in hippocampus, prompting its multidirectional role in case of brain damage. The concentration of IGF-1 significantly increased in all investigated brain structures. The administration of PEG balanced the growth factor levels accompanied by substantial restoration of neural tissue architecture and synaptic activity. Acute injection of PEG activated the hypothalamic nucleus supraopticus and hippocampal neurons. IGF-1 and NGF levels were found to be elevated in animals receiving PEG in an absence of amyloid exposure. We suggest that IGF-1 and NGF play a critical role in the development of AD. At the same time, it becomes clear that the neuroprotective effects of PEG are likely mediated via the regulation of neurotrophins.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Encéfalo , Eletrocardiografia , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Neural/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley
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