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BACKGROUND: The emergence of the Nerve Growth Factor (NGF) has promoted the development of neuroprotective therapy; however, it has little effect on cerebral ischemia because of its poor Blood-Brain Barrier (BBB) permeability. Specific Mode Electroacupuncture Stimulation (SMES) can open BBB safely and effectively; however, it has shown inconclusive clinical effects and indirect clinical evidence in the recovery phase. Hence, the authors conducted a multicentre, randomized, placebo-controlled, assessor-blinded clinical trial to assess the effectiveness and safety of SMES combined with NGF treatment used during ischaemic stroke recovery. METHODS: A total of 288 stroke patients from three hospitals will be recruited and randomly allocated to four groups: acupuncture + placebo, acupuncture + NGF, SMES + placebo, and SMES + NGF, in a 1:1:1:1 ratio. Assessment data will be collected at baseline, 2-weeks, and 4-weeks during the treatment period, as well as at the 4-week and 8-week follow-up after treatment completion. The primary outcome measure will be the basic cure rate. The secondary outcome measures include the simplified Modified Barthel Index, Timed Up and Go Test, Fugl-Meyer Assessment of Motor Function Score, Tinetti Performance Oriented Mobility Assessment, Montreal Cognitive Assessment, and Loewenstein Occupational Therapy Cognitive Assessment. Moreover, resting-state functional magnetic resonance imaging and Functional near-infrared spectroscopy can detect changes in cerebral blood flow and brain function and investigate the relationship between the clinical efficacy and mechanism of the prescribed interventions. CONCLUSION: This study will provide clinical evidence for the efficacy and safety of SMES combined with NGF in the treatment of stroke patients.

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BACKGROUND: Neurotrophins (NTs) and their precursors (pro-NTs) are polypeptides with important roles in neuronal development, differentiation, growth, survival and plasticity, as well as apoptosis and neuronal death. Imbalance in NT levels were observed in schizophrenia spectrum disorders, but evidence in ultra-high risk for psychosis (UHR) samples is scarce. METHODS: A naturalistic sample of 87 non-help-seeking UHR subjects and 55 healthy controls was drawn from the general population. Blood samples were collected and NT-3, NT-4/5, BDNF, pro-BDNF, NGF, pro-NGF were analyzed through enzyme linked immunosorbent assay (ELISA). Information on cannabis and tobacco use was also collected. Logistic regression models and path analysis were used to control for confounders (tobacco, age, cannabis use). RESULTS: NT-4/5 was significantly decreased, and pro-BDNF was significantly increased in UHR individuals compared to controls. Cannabis use and higher NGF levels were significantly related to transition to psychiatric disorders among UHR subjects. Increased pro-BDNF and decreased NT-4/5 influenced transition by the mediation of perceptual abnormalities. CONCLUSIONS: Our study shows for the first time that NTs are altered in UHR compared to healthy control individuals, and that they can be a predictor of transition to psychiatric illnesses in this population. Future studies should employ larger naturalistic samples to confirm the findings.

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The perception of noxious environmental stimuli by nociceptive sensory neurons is an essential mechanism for the prevention of tissue damage. Etv4 is a transcriptional factor expressed in most nociceptors in dorsal root ganglia (DRG) during the embryonic development. However, its physiological role remains unclear. Here, we show that Etv4 ablation results in defects in the development of the peripheral peptidergic projections in vivo, and in deficits in axonal elongation and growth cone morphology in cultured sensory neurons in response to NGF. From a mechanistic point of view, our findings reveal that NGF regulates Etv4-dependent gene expression of molecules involved in extracellular matrix (ECM) remodeling. Etv4-null mice were less sensitive to noxious heat stimuli and chemical pain, and this behavioral phenotype correlates with a significant reduction in the expression of the pain-transducing ion channel TRPV1 in mutant mice. Together, our data demonstrate that Etv4 is required for the correct innervation and function of peptidergic sensory neurons, regulating a transcriptional program that involves molecules associated with axonal growth and pain transduction.

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Genetic variations in components of the immune response seem to be an important factor that contributes to the manifestation of symptoms of some diseases related to HTLV-1 infection. Nerve growth factor (NGF) and the p75 neurotrophin receptor (p75NTR) are related to the maintenance of neurons and the activation of the immune response. In this study, we evaluated the association of the NGF -198C/T, NGF Ala35Val, and p75NTR Ser205Leu polymorphisms with HTLV-1 infection and plasma cytokine levels in 166 samples from individuals infected with HTLV-1 (59 symptomatic and 107 asymptomatic). The genotyping and quantification of the proviral load were performed by real-time PCR, and cytokine levels were measured by ELISA. The NGF -198C/T and NGF Ala35Val polymorphisms were not associated with HTLV-1 infection. The frequency of the Ser/Leu genotype of p75NTR Ser205Leu was more frequent in the control group (p = 0.0385), and the Ser/Leu genotype and allele Leu were more frequent among the asymptomatic (p < 0.05), especially with respect to the HTLV-1-associated myelopathy (HAM) group (p < 0.05). The symptomatic showed a higher proviral load and higher TNF-α and IL-10 levels (p < 0.05). Asymptomatic carriers of the Ser/Leu genotype (p = 0.0797) had lower levels of proviral load and higher levels of TNF-α (p = 0.0507). Based on the results obtained, we conclude that the p75NTR Ser205Leu polymorphism may be associated with reduced susceptibility to HTLV-1 infection, a lower risk of developing symptoms, including HAM, and better infection control.

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Astrocytes preserve the brain microenvironment homeostasis in order to protect other brain cells, mainly neurons, against damages. Glial cells have specific functions that are important in the context of neuronal survival in different models of central nervous system (CNS) diseases. Microglia are among these cells, secreting several molecules that can modulate astrocyte functions. Although 1,2-dihydroxybenzene (catechol) is a neurotoxic monoaromatic compound of exogenous origin, several endogenous molecules also present the catechol group. This study compared two methods to obtain astrocyte-enriched cultures from newborn Wistar rats of both sexes. In the first technique (P1), microglial cells began to be removed early 48 h after primary mixed glial cultures were plated. In the second one (P2), microglial cells were late removed 7 to 10 days after plating. Both cultures were exposed to catechol for 72 h. Catechol was more cytotoxic to P1 cultures than to P2, decreasing cellularity and changing the cell morphology. Microglial-conditioned medium (MCM) protected P1 cultures and inhibited the catechol autoxidation. P2 cultures, as well as P1 in the presence of 20% MCM, presented long, dense, and fibrillary processes positive for glial fibrillary acidic protein, which retracted the cytoplasm when exposed to catechol. The Ngf and Il1beta transcription increased in P1, meanwhile astrocytes expressed more Il10 in P2. Catechol decreased Bdnf and Il10 in P2 cultures, and it decreased the expression of Il1beta in both conditions. A prolonged contact with microglia before isolation of astrocyte-enriched cultures modifies astrocyte functions and morphology, protecting these cells against catechol-induced cytotoxicity.

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Nerve growth factor (NGF) and its high-affinity receptor TRKA are overexpressed in epithelial ovarian cancer (EOC) displaying a crucial role in the disease progression. Otherwise, NGF interacts with its low-affinity receptor P75, activating pro-apoptotic pathways. In neurons, P75 could be cleaved by metalloproteinases (α and γ-secretases), leading to a decrease in P75 signaling. Therefore, this study aimed to evaluate whether the shedding of P75 occurs in EOC cells and whether NGF/TRKA could promote the cleavage of the P75 receptor. The immunodetection of the α-secretase, ADAM17, TRKA, P75, and P75 fragments was assessed by immunohisto/cytochemistry and Western blot in biopsies and ovarian cell lines. The TRKA and secretases' inhibition was performed using specific inhibitors. The results show that P75 immunodetection decreased during EOC progression and was negatively correlated with the presence of TRKA in EOC biopsies. NGF/TRKA increases ADAM17 levels and the fragments of P75 in ovarian cells. This effect is abolished when cells are previously treated with ADAM17, γ-secretase, and TRKA inhibitors. These results indicate that NGF/TRKA promotes the shedding of P75, involving the activation of secretases such as ADAM17. Since ADAM17 has been proposed as a screening marker for early detection of EOC, our results contribute to understanding better the role of ADAM17 and NGF/TRKA in EOC pathogenesis, which includes the NGF/TRKA-mediated cleavage of P75.

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Leprosy, also known as Hansen's disease, continues to have a substantial impact on infectious diseases throughout the world. Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae and shows a wide clinical and immunopathological spectrum related to the immune response of the host. This disease affects the skin and other internal organs with a predilection to infect Schwann cells, which play an active role during axonal degeneration, affecting peripheral nerves and promoting neurological damage. This chronic inflammation influences immune function, leading to neuroimmune disorders. Leprosy is also associated with neuroimmune reactions, including type 1 (reverse) and type 2 (erythema nodosum leprosum) reactions, which are immune-mediated inflammatory complications that can occur during the disease and appear to worsen dramatically; these complications are the main concerns of patients. The reactions may induce neuritis and neuropathic pain that progressively worsen with irreversible deformity and disabilities responsible for the immunopathological damage and glial/neuronal death. However, the neuronal damage is not always associated with the reactional episode. Also, the efficacy in the treatment of reactions remains low because of the nonexistence of a specific treatment and missing informations about the immunopathogenesis of the reactional episode. There is increasing evidence that peripheral neuron dysfunction strongly depends on the activity of neurotrophins. The most important neurotrophin in leprosy is nerve growth factor (NGF), which is decreased in the course of leprosy, as well as the presence of autoantibodies against NGF in all clinical forms of leprosy and neuroimmune reactions. The levels of autoantibodies against NGF are decreased by the immunomodulatory activity of cyclosporin A, which mainly controls pain and improves motor function and sensitivity. Therefore, the suppression of anti-NGF and the regulation of NGF levels can be attractive targets for immunomodulatory treatment and for controlling the neuroimmune reactions of leprosy, although further studies are needed to clarify this point.

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Abstract Diabetic Neuropathy (DN) is one of the prevailing micro vascular complications of diabetes which can be characterized by neuropathic pain. Streptozotocin (STZ) induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy. STZ injection leads to neurotoxicity of peripheral nerves that leads to development of Peripheral Diabetic Neuropathy in rat model. The present study was aimed at exploring the protective role of Tinospora cordifolia extract in STZ induced neurotoxicity and evaluating mechanisms responsible for attenuating neuropathic pain. Neuropathic pain markers like hyperalgesia, allodynia and motor deficits were assessed before STZ injection and after the treatment with 250 mg/kg and 500 mg/kg dose of Tinospora cordifolia. Oxidative stress markers, NGF expression in sciatic nerve were observed after seven weeks treatment. Our results demonstrated that seven weeks treatment with Tinospora cordifolia leaf extract significantly relieved thermal hyperalgesia and allodynia by increasing the antioxidant enzyme levels, decreasing the lipid peroxidation and by increasing the Nerve growth factor (NGF) expression in diabetic rat sciatic nerves. Our findings highlighted the beneficial effects of oral administration of Tinospora cordifolia extract in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and by inducing NGF m RNA in sciatic nerves.

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Liver fibrosis results from many chronic injuries and may often progress to cirrhosis and hepatocellular carcinoma (HCC). In fact, up to 90% of HCC arise in a cirrhotic liver. Conversely, stress is implicated in liver damage, worsening disease outcome. Hence, stress could play a role in disrupting liver homeostasis, a concept that has not been fully explored. Here, in a murine model of TAA-induced liver fibrosis we identified nerve growth factor (NGF) to be a crucial regulator of the stress-induced fibrogenesis signaling pathway as it activates its receptor p75 neurotrophin receptor (p75NTR), increasing liver damage. Additionally, blocking the NGF decreased liver fibrosis whereas treatment with recombinant NGF accelerated the fibrotic process to a similar extent than stress challenge. We further show that the fibrogenesis induced by stress is characterized by specific changes in the hepatoglycocode (increased ß1,6GlcNAc-branched complex N-glycans and decreased core 1 O-glycans expression) which are also observed in patients with advanced fibrosis compared to patients with a low level of fibrosis. Our study facilitates an understanding of stress-induced liver injury and identify NGF signaling pathway in early stages of the disease, which contributes to the established fibrogenesis.

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Ovarian cancer is the most lethal gynecological neoplasm, and epithelial ovarian cancer (EOC) accounts for 90% of ovarian malignancies. The 5-year survival is less than 45%, and, unlike other types of cancer, the proportion of women who die from this disease has not improved in recent decades. Nerve growth factor (NGF) and tropomyosin kinase A (TRKA), its high-affinity receptor, play a crucial role in pathogenesis through cell proliferation, angiogenesis, invasion, and migration. NGF/TRKA increase their expression during the progression of EOC by upregulation of oncogenic proteins as vascular endothelial growth factor (VEGF) and c-Myc. Otherwise, the expression of most oncoproteins is regulated by microRNAs (miRs). Our laboratory group reported that the tumoral effect of NGF/TRKA depends on the regulation of miR-145 levels in EOC. Currently, mitochondria have been proposed as new therapeutic targets to activate the apoptotic pathway in the cancer cell. The mitochondria are involved in a myriad of functions as energy production, redox control, homeostasis of Ca+2, and cell death. We demonstrated that NGF stimulation produces an augment in the Bcl-2/BAX ratio, which supports the anti-apoptotic effects of NGF in EOC cells. The review aimed to discuss the role of mitochondria in the interplay between NGF/TRKA and miR-145 and possible therapeutic strategies that may decrease mortality due to EOC.

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The aim of the present study was to evaluate the effects of 2 different intensities of resistance training (RT) bouts, performed with the equated total load lifted (TLL), on the acute responses of neurotrophic factors (NFs) (brain-derived neurotrophic factor [BDNF]; and nerve growth factor [NGF]), as well as on metabolic (lactate concentration) and hormonal (salivary cortisol concentration) responses. Thirty participants (males, 22.8 ± 2.3 years old, 177 ± 6.8 cm, 75.5 ± 7.9 kg, n = 15; and females, 22.2 ± 1.7 years, 163.7 ± 6.5 cm, 57 ± 7.6 kg, n = 15) performed 2 separate acute RT bouts with one week between trials. One bout consisted of 4 sets of 5 submaximal repetitions at 70% of 1RM and the other of 4 sets of 10 submaximal repetitions at 35% of 1RM for each exercise. Both RT bouts were conducted using the bench press and squat exercises. The TLL in each bout (determined by sets x repetitions x load [kg]) was equated. Serum BDNF, serum NGF, salivary cortisol, and blood lactate concentration were determined pre- and post-RT. No significant pre- to post-exercise increase in neurotrophic factors (p > 0.05; BDNF; effect size = 0.46 and NGF; effect size = 0.48) was observed for either of the RT bouts. A similar increase in blood lactate concentration was observed pre- to post-exercise for both RT bouts (p < 0.05). Cortisol increased similarly for both RT bouts, when compared to the resting day condition (p < 0.05). In conclusion, the results suggest that, despite differences in RT schemes, a similar acute neurotrophic, metabolic and hormonal response was observed when the TLL is equated.

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Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, ß-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and ß-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.

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Nerve Growth Factor (NGF) and its high-affinity receptor tropomyosin receptor kinase A (TRKA) increase their expression during the progression of epithelial ovarian cancer (EOC), promoting cell proliferation and angiogenesis through several oncogenic proteins, such as c-MYC and vascular endothelial growth factor (VEGF). The expression of these proteins is controlled by microRNAs (miRs), such as miR-145, whose dysregulation has been related to cancer. The aims of this work were to evaluate in EOC cells whether NGF/TRKA decreases miR-145 levels, and the effect of miR-145 upregulation. The levels of miR-145-5p were assessed by qPCR in ovarian biopsies and ovarian cell lines (human ovarian surface epithelial cells (HOSE), A2780 and SKOV3) stimulated with NGF. Overexpression of miR-145 in ovarian cells was used to evaluate cell proliferation, migration, invasion, c-MYC and VEGF protein levels, as well as tumor formation and metastasis in vivo. In EOC samples, miR-145-5p levels were lower than in epithelial ovarian tumors. Overexpression of miR-145 decreased cell proliferation, migration and invasion of EOC cells, changes that were concomitant with the decrease in c-MYC and VEGF protein levels. We observed decreased tumor formation and suppressed metastasis behavior in mice injected with EOC cells that overexpressed miR-145. As expected, ovarian cell lines stimulated with NGF diminished miR-145-5p transcription and abundance. These results suggest that the tumoral effects of NGF/TRKA depend on the regulation of miR-145-5p levels in EOC cells, and that its upregulation could be used as a possible therapeutic strategy for EOC.

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Allopregnanolone (3α,5α-tetrahydroprogesterone; pharmaceutical formulation: brexanolone) is a neurosteroid that has recently been approved for the treatment of postpartum depression, promising to fill part of a long-lasting gap in the effectiveness of pharmacotherapies for depressive disorders. In this review, we explore the experimental research that characterized the antidepressant-like effects of allopregnanolone, with a particular focus on the neurotrophic adaptations induced by this neurosteroid in preclinical studies. We demonstrate that there is a consistent decrease in allopregnanolone levels in limbic brain areas in rodents submitted to stress-induced models of depression, such as social isolation and chronic unpredictable stress. Further, both the drug-induced upregulation of allopregnanolone or its direct administration reduce depressive-like behaviors in models such as the forced swim test. The main drugs of interest that upregulate allopregnanolone levels are selective serotonin reuptake inhibitors (SSRIs), which present the neurosteroidogenic property even in lower, non-SSRI doses. Finally, we explore how these antidepressant-like behaviors are related to neurogenesis, particularly in the hippocampus. The protagonist in this mechanism is likely the brain-derived neurotrophic factor (BFNF), which is decreased in animal models of depression and may be restored by the normalization of allopregnanolone levels. The role of an interaction between GABA and the neurotrophic mechanisms needs to be further investigated.

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Traumatic brain injury (TBI) is a critical health problem worldwide, with a high incidence rate and potentially severe long-term consequences. Depending on the level of mechanical stress, astrocytes react with complex morphological and functional changes known as reactive astrogliosis. In cases of severe tissue injury, astrocytes proliferate in the area immediately adjacent to the lesion to form the glial scar, which is a major barrier to neuronal regeneration in the central nervous system. The flavonoid agathisflavone has been shown to have neuroprotective, neurogenic, and immunomodulatory effects and could have beneficial effects in situations of TBI. In this study, we investigated the effects of agathisflavone on modulating the responses of astrocytes and neurons to injury, using the in vitro scratch wound model of TBI in primary cultures of rat cerebral cortex. In control conditions, the scratch wound induced an astroglial injury response, characterized by upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy, together with the reduction in proportion of neurons within the lesion site. Treatment with agathisflavone (1 µM) decreased astroglial GFAP expression and hypertrophy and induced an increase in the number of neurons and neurite outgrowth into the lesion site. Agathisflavone also induced increased expression of the neurotrophic factors NGF and GDNF, which are associated with the neuroprotective profile of glial cells. These results demonstrate that in an in vitro model of TBI, the flavonoid agathisflavone modulates the astrocytic injury response and glial scar formation, stimulating neural recomposition.

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The ovulation-inducing effect of seminal plasma was first suggested in Bactrian camels over 30 years ago, initiating a long search to identify the 'ovulation-inducing factor' (OIF) present in camelids semen. During the last decade, primarily in llamas and alpacas, this molecule has been intensively studied characterizing its biological and chemical properties and ultimately identifying it as ß-Nerve Growth Factor (ß-NGF). The high concentration of OIF/ß-NGF in seminal plasma of llamas and alpacas, and the striking effects of seminal fluid on ovarian function strongly support the notion of an endocrine mode of action. Also, have challenged the dogma of mating induced ovulation in camelid species, questioning the classical definition of reflex ovulators, which at the light of new evidence should be revised and updated. On the other hand, the presence of OIF/ß-NGF and its ovulatory effect in camelids confirm the notion that seminal plasma is not only a transport and survival medium for sperm but also, a signaling agent targeting female tissues after insemination, generating relevant physiological and reproductive consequences. The presence of this molecule, conserved among induced as well as spontaneous ovulating species, clearly suggests that the potential impacts of this reproductive feature extend beyond the camelid species and may have broad implications in mammalian fertility. The aim of the present review is to provide a brief summary of all research efforts undertaken to isolate and identify the ovulation inducing factor present in the seminal plasma of camelids. Also to give an update of the current understanding of the mechanism of action of seminal ß-NGF, at central and ovarian level; finally suggesting possible brain targets for this molecule.

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Saliva plays an important role in swallowing, chewing and speaking, and is essential for maintaining proper oral health. The aging process leaves to decrease of saliva production causing a condition called xerostomia, which is a big problem for the elderly. Literature shows that during aging the parenchyma of the salivary glands is replaced by fat and connective tissue. Neural growth factor NGF and NGF receptor TrkA are synthesized and secreted by salivary glands SG; however, the physiological role of these proteins in saliva and maintenance of SG has not been fully elucidated. The aim of this study was evaluate alterations in NGF and TrkA expression in sublingual SG SL during the aging process. The cases were divided into two groups for comparison: adult group, individuals between 30 and 60 years old; and elderly group, individuals over 60 years. NGF and TrkA expression were evaluated by immunohistochemistry. Quantitative analysis was measured by Image J software, Mann Whitney”s Test and Pearson’s Correlation Test. Qualitative data were analyzed by Fisher's Exact Test. Analyzing the SL samples, we observed that NGF expression occurred in serous, mucous and ducts cells. The NGF expression in serous acini was diffuse, granular and cytoplasmatic. In both striated and excretory ducts, NGF was quite expressed in the cytoplasm and had a more diffuse than granular pattern. The NGF expression in mucosal cells was smaller and was predominantly in the cytoplasm, the staining pattern was both diffuse and granular. Fisher's Exact Test showed that there was higher labeling in striatal and excretory duct cell cytoplasm in the adult group compared to the elderly one p 0,037. In addition, the granular expression was higher in the striatal duct cells of adults compared to the elderly p 0,043. Mann Whitney's test demonstrated that there was no difference in NGF expression in the adult group compared to the elderly one p≥0.05. Pearson’s correlation test did not show linear correlation between age and expression of NGF. The TrkA expression was more expressive in mucosal acini and ducts. In mucous cells, TrkA was expressed in the cytoplasm and in peribasal portion diffusely and granularly. In ductal cells, TrkA was expressed in almost all cases and the pattern was citoplasmatic and granular. In serous acini, the labeling was predominant cytoplasmatic and diffuse. Fisher's Exact Test showed that the granular labeling of striated duct cells was higher in the elderly group than in the adult one p 0,03. In contrast, the diffuse pattern was higher in striated duct cell of the adults if compared with the elderly p 0,008. Mann Whitney's test demonstrated that there was no difference in TrkA expression in the adult group compared to the elderly one p0.05. Pearson’s correlation test did not show linear correlation between age and expression of TrkA.

A saliva desempenha um papel importante na deglutição, mastigação e fala, e é essencial para manter a saúde bucal adequada. O processo de envelhecimento diminui a produção de saliva, causando uma condição chamada xerostomia, que é um grande problema para os idosos. A literatura mostra que durante o envelhecimento, o parênquima das glândulas salivares é substituído por gordura e tecido conjuntivo. O fator de crescimento neural (NGF) e o receptor para NGF (TrkA) são sintetizados e secretados pelas glândulas salivares (GS); no entanto, o papel fisiológico dessas proteínas na saliva e na manutenção das GS não foi totalmente elucidado. O objetivo deste estudo foi avaliar alterações na expressão de NGF e TrkA na GS sublingual (SL) durante o processo de envelhecimento. Os casos foram divididos em dois grupos para comparação: grupo de adultos, indivíduos entre 30 e 60 anos; e grupo de idosos, indivíduos acima de 60 anos. A expressão de NGF e TrkA foi avaliada por imunoistoquímica. A análise quantitativa foi mensurada pelo software Image J, pelo teste de Mann Whitney e pelo teste de correlação de Pearson. Os dados qualitativos foram analisados pelo teste exato de Fisher. Analisando as amostras de SL, observamos que a expressão de NGF ocorreu principalmente nas células serosas, nas células mucosas e nos ductos. A expressão de NGF nos ácinos serosos foi difusa, granular e citoplasmática. Nos ductos estriado e excretor, o NGF foi bastante expresso no citoplasma e apresentava um padrão mais difuso do que granular. A expressão de NGF nas células da mucosa foi menor quando comparada com as células serosas e ductais e predominantemente no citoplasma, o padrão de coloração foi difuso e granular. O teste exato de Fisher mostrou que houve maior número de casos marcados, no citoplasma dos ductos excretor e estriado, no grupo adulto em comparação com o idoso (p=0,037). Além disso, a expressão granular foi maior nas células do ducto estriado de adultos em comparação com os idosos (p=0,043). O teste de Mann Whitney demonstrou que não houve diferença na expressão de NGF no grupo adulto comparado ao grupo idoso (p≥0,05) e o teste de Correlação de Pearson, mostrou que não houve correlação linear entre a idade dos indivíduos e a expressão do NGF. A expressão de TrkA foi mais expressiva nos ácinos mucosos e nos ductos. Nas células mucosas, o TrkA foi expresso no citoplasma e na porção peribasal de forma difusa e granular. Nas células ductais, oTrkA foi expresso em quase todos os casos e o padrão foi citoplasmático e granular. Nos ácinos serosos, a marcação foi predominantemente citoplasmática e difusa. O teste exato de Fisher mostrou que a marcação granular das células do ducto estriado era maior no grupo de idosos do que no grupo de adultos (p=0,033). Por outro lado, o padrão difuso foi maior nas células do ducto estriado dos adultos se comparado aos idosos (p= 0,008). O teste de Mann Whitney demonstrou que não houve diferença na expressão de TrkA no grupo adulto comparado ao grupo idoso (p≥0,05) e o teste de Correlação de Pearson, mostrou que não houve correlação linear entre a idade dos indivíduos e a expressão do TrkA.

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Epithelial ovarian cancer (EOC) is a lethal gynecological neoplasia characterized by extensive angiogenesis and overexpression of nerve growth factor (NGF). Here, we investigated the mechanism by which NGF increases vascular endothelial growth factor (VEGF) expression and the vasculogenic potential of EOC cells, as well as the contribution of the cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) signaling axis to these events. EOC biopsies and ovarian cell lines were used to determine COX-2 and PGE2 levels, as well as those of the potentially pro-angiogenic proteins c-MYC (a member of the Myc transcription factors family), survivin, and ß-catenin. We observed that COX-2 and survivin protein levels increased during EOC progression. In the EOC cell lines, NGF increased the COX-2 and PGE2 levels. In addition, NGF increased survivin, c-MYC, and VEGF protein levels, as well as the transcriptional activity of c-MYC and ß-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef) in a Tropomyosin receptor kinase A (TRKA)-dependent manner. Also, COX-2 inhibition prevented the NGF-induced increases in these proteins and reduced the angiogenic score of endothelial cells stimulated with conditioned media from EOC cells. In summary, we show here that the pro-angiogenic effect of NGF in EOC depends on the COX-2/PGE2 signaling axis. Thus, inhibition COX-2/PGE2 signaling will likely be beneficial in the treatment of EOC.

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Angiogenesis, or generation of new blood vessels from other pre-existing, is a key process to maintain the supply of nutrients and oxygen in tissues. Unfortunately, this process is exacerbated in pathologies such as retinopathies and cancers with high angiogenesis as ovarian cancer. Angiogenesis is regulated by multiple systems including growth factors and neurotrophins. One of the most studied angiogenic growth factors is the vascular endothelial growth factor (VEGF), which is overexpressed in several cancers. It has been recently described that neurotrophins could regulate angiogenesis through direct and indirect mechanisms. Neurotrophins are a family of proteins that include nerve growth factor (NGF), brain-derived growth factor (BDNF), and neurotrophins 3 and 4/5 (NT 3, NT 4/5). These molecules and their high affinity receptors (TRKs) regulate the development, maintenance, and plasticity of the nervous system. Furthermore, it was recently described that they display essential functions in non-neuronal tissues, such as reproductive organs among others. Studies have shown that several types of cancer overexpress neurotrophins such as NGF and BDNF, which might contribute to tumor progression and angiogenesis. Besides, in recent years the FDA has approved the use of pharmacologic inhibitors of pan-TRK receptors in patients with TRKs fusion-positive cancers. In this review, we discuss the mechanisms by which neurotrophins stimulate tumor progression and angiogenesis, with emphasis on gynecological cancers.