RESUMO
MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant MYC transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) MPEP. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a MYC-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.
Assuntos
Glioblastoma , Fases de Leitura Aberta , Proteínas Proto-Oncogênicas c-myc , Receptor trkB , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Animais , Humanos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fases de Leitura Aberta/genética , Camundongos , Linhagem Celular Tumoral , Receptor trkB/metabolismo , Proliferação de Células/efeitos dos fármacos , Ligação Proteica , Transdução de Sinais , Peptídeos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
Accumulating evidence has shown that some hallucinogens, such as LSD, have fast and persistent effects on anxiety and depression. According to a proposed mechanism, LSD activates the TrkB and HTR2A signaling pathways, which enhance the density of neuronal dendritic spines and synaptic function, and thus promote brain function. Moreover, TrkB signaling is also known to be crucial for neural stem cell (NSC)-mediated neuroregeneration to repair dysfunctional neurons. However, the impact of LSD on neural stem cells remains to be elucidated. In this study, we observed that LSD and BDNF activated the TrkB pathway in human NSCs similarly to neurons. However, unlike BDNF, LSD did not promote NSC proliferation. These results suggest that LSD may activate an alternative mechanism to counteract the effects of BDNF-TrkB signaling on NSCs. Our findings shed light on the previously unrecognized cell type-specificity of LSD. This could be crucial for deepening our understanding of the mechanisms underlying the effects of LSD.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Alucinógenos , Dietilamida do Ácido Lisérgico , Células-Tronco Neurais , Receptor trkB , Transdução de Sinais , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Alucinógenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor trkB/metabolismo , Dietilamida do Ácido Lisérgico/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/citologia , Glicoproteínas de MembranaRESUMO
OBJECTIVE: Previous research has shown that the role of neurotrophic receptor tyrosine kinase 2 (NTRK2) in breast cancer (BRCA) remains ambiguous. To help elucidate this, we conducted a retrospective study to investigate the relationship between NTRK2 protein expression and BRCA. METHODS: The prognostic significance of NTRK2 protein expression patterns was assessed by performing immunohistochemistry assays on 131 BRCA tissues and 56 adjacent normal tissues in a retrospective study. Furthermore, the sensitivity to chemotherapeutic drugs was quantified by "pRRophetic" and the sensitivity to immunotherapy was estimated using The Cancer Immunome Atlas website. RESULTS: NTRK2 protein was expressed at significantly higher levels in BRCA samples compared with normal tissues. The data indicated that NTRK2 expression is an independent risk factor for BRCA patient prognosis. Additionally, the high NTRK2 group exhibited increased sensitivity to certain chemotherapy drugs and achieved higher scores for immune checkpoint blockade therapy compared with the low NTRK2 group. CONCLUSIONS: Our study demonstrated that higher NTRK2 protein expression is related to a less favorable prognosis in BRCA patients, as well as to enhanced sensitivity to specific chemotherapy and immunotherapy drugs.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptor trkB/metabolismo , Receptor trkB/genética , Adulto , Idoso , Imuno-Histoquímica , Regulação Neoplásica da Expressão Gênica , Antineoplásicos/uso terapêuticoRESUMO
OBJECTIVE: This study aimed to explore the mechanism by which noise contributes to the development of Alzheimer's disease (AD)-like lesions. METHOD: Male Wistar rats (24 months) were allocated into two groups (n = 6 per groups): a noise group exposed to 98 dB sound pressure-level white noise for 4 hours daily from 8:00 to 12:00 for 30 days, and a control group without noise exposure. The cognitive functions of the rats were assessed using new-object recognition and Morris water maze tests. Then, hippocampal tissues were collected, and the levels of amyloid ß 1-42 (Aß1-42), Aß1-40, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) were measured using enzyme-linked immunosorbent assay (ELISA). Protein expression was evaluated through Western blot. RESULTS: Noise exposure significantly impaired cognitive and recognition abilities, increased the escape latency, and decreased the number of crossings through the platform quadrant intersection and the time spent in the target quadrant (P < 0.01). The new-object exploration and recognition index of the rats in the noise group markedly decreased (P < 0.01). ELISA results indicated increases in Aß1-40 and Aß1-42 levels and decreases in BDNF and TrkB levels in the rat hippocampus in the noise group (P < 0.01). Western blot analyses revealed that beta-site amyloid precursor protein (APP) cleaving enzyme 1, phosphorylated tau protein, gamma-H2A histone family, member X, checkpoint kinase 2, p53, and p21 were remarkably elevated in the noise group (P < 0.01). CONCLUSION: Chronic noise exposure can cause hippocampal genetic damage in aged rats, leading to cognitive disorders and the development of lesions similar to those observed in AD. Thus, noise is a potential risk factor for neurodegenerative disorders.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Fator Neurotrófico Derivado do Encéfalo , Dano ao DNA , Hipocampo , Ruído , Ratos Wistar , Animais , Doença de Alzheimer/etiologia , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ruído/efeitos adversos , Peptídeos beta-Amiloides/metabolismo , Ratos , Hipocampo/metabolismo , Hipocampo/patologia , Fragmentos de Peptídeos/metabolismo , Receptor trkB/metabolismo , Modelos Animais de Doenças , Aprendizagem em Labirinto/fisiologiaRESUMO
The plasminogen activator inhibitor-1 (PAI-1)âmature brain-derived neurotrophic factor (mBDNF) pathway plays a pivotal role in the conversion of probrain-BDNF (ProBDNF) to mBDNF, but its clinical relevance in patients with alcohol use disorder (AUD) remains unknown. Enzyme-linked immunosorbent assays were used to examine the relevant protein levels of components of the PAI-1âmBDNF pathway in plasma samples from three groups of subjects, and statistical analysis was performed using analysis of variance (ANOVA) and one-way repeated-measures ANOVA. Our findings revealed significant alterations induced by alcohol. (1) AUD was associated with significant decreases in tissue plasminogen activator (tPA), mBDNF, and tropomyosin receptor kinase B (TrkB); significant increases in PAI-1, ProBDNF, and P75 neurotrophin receptor (P75NTR); and inhibited conversion of ProBDNF to mBDNF. (2) Following abstinence, the levels of tPA, mBDNF, and TrkB in the AUD group significantly increased, whereas the levels of PAI-1, ProBDNF, and P75NTR significantly decreased, promoting the conversion of ProBDNF to mBDNF. These clinical outcomes collectively suggest that AUD inhibits the conversion of ProBDNF to mBDNF and that abstinence reverses this process. The PAI-1âmBDNF cleavage pathway is hypothesized to be associated with AUD and abstinence treatment.
Assuntos
Alcoolismo , Fator Neurotrófico Derivado do Encéfalo , Inibidor 1 de Ativador de Plasminogênio , Ativador de Plasminogênio Tecidual , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Alcoolismo/metabolismo , Alcoolismo/sangue , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Masculino , Adulto , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tecidual/sangue , Feminino , Transdução de Sinais , Receptores de Fator de Crescimento Neural/metabolismo , Pessoa de Meia-Idade , Receptor trkB/metabolismo , Abstinência de Álcool , Precursores de Proteínas/metabolismo , Glicoproteínas de Membrana , Proteínas do Tecido NervosoRESUMO
Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores.
Assuntos
Simulação de Acoplamento Molecular , Doenças Neurodegenerativas , Ligação Proteica , Receptor trkB , Receptor trkB/metabolismo , Receptor trkB/agonistas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Animais , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/agonistasRESUMO
Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK, ROS1, NTRK, or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion-positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for >3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.
Assuntos
Glioma , Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Receptor trkB , Humanos , Feminino , Lactente , Pirazóis/uso terapêutico , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Receptor trkB/genética , Receptor trkB/antagonistas & inibidores , Pirimidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Fusão Oncogênica/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Gradação de Tumores , Resultado do Tratamento , Glicoproteínas de Membrana/genéticaRESUMO
OBJECTIVE: To observe the effects of electroacupuncture (EA) at "Baihui" (GV 20) and "Sishencong" (EX-HN 1) on the expression of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) pathway, synaptophysin (SYN), and the levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in the hippocampus of the ischemic side in rats with cerebral ischemia-reperfusion injury (CIRI), and to explore the effects and action mechanism of EA on post-CIRI learning-memory function. METHODS: Forty-eight SPF-grade male SD rats were randomly divided into a sham operation group, a model group, an EA group, and a non-acupoint group, with 12 rats in each group. The CIRI model was established in the model group, the EA group, and the non-acupoint group using the modified ZeaLonga suture method. The rats in the EA group were treated with EA at "Sishencong" (EX-HN 1) and "Baihui" (GV 20), with disperse-dense wave at frequency of 2 Hz/10 Hz and intensity of 1 mA. The rats in the non-acupoint group were treated with EA at non-meridian and non-acupoint points under the ribs bilaterally with the same parameters as the EA group. EA were conducted for 30 min each session, once daily, for 7 days. During the intervention, body weight was measured daily at a fixed time, and neurological deficits were assessed on the 1st, 3rd, and 7th days into intervention. Brain infarct volume was measured using small animal magnetic resonance imaging before and after the intervention. After the intervention, learning-memory function were evaluated using the Morris water maze. Hippocampal morphology was observed with HE staining. The positive expression of SYN in the hippocampus of the ischemic side was detected by immunohistochemistry. BDNF, TrkB, and SYN protein expressions in the hippocampus of the ischemic side were detected by Western blot. IL-1ß and IL-18 levels in the hippocampus of the ischemic side were measured by ELISA. RESULTS: From the 2nd to the 7th day into intervention, compared with the sham operation group, the body weight of rats in the model group was decreased (P<0.01); compared with the model group and the non-acupoint group, the body weight of rats in the EA group was increased (P<0.01). On the 1st day into intervention, compared with the sham operation group, neurological function scores of rats in the model group, the EA group, and the non-acupoint group were increased (P<0.01); on the 3rd and 7th days into intervention, neurological function scores of rats in the model group were higher than those in the sham operation group (P<0.01); on the 7th day, neurological function scores of rats in the EA group were lower than those in the model group and the non-acupoint group (P<0.05). Compared with the sham operation group, escape latency was prolonged (P<0.05), and the number of platform crossings was decreased (P<0.01) in the model group; compared with the model group and the non-acupoint group, escape latency was shortened (P<0.05), and the number of platform crossings was increased (P<0.01) in the EA group. Before intervention, the high signal infarcts were observed in the left ventricles of rats in the model group, the EA group, and the non-acupoint group; after intervention compared with the model group and the non-acupoint group, infarct volume in the EA group was decreased (P<0.01). Neuronal cells in the model group and the non-acupoint group were sparsely and disorderedly arranged, with deep-stained cytoplasm and shrunken nuclei; the number and arrangement of neuronal cells in the EA group were similar to the sham operation group, with less deep-stained cytoplasm and shrunken nuclei compared to the model group. Compared with the sham operation group, the positive expression of SYN, and BDNF TrkB, and SYN protein expressions in the hippocampus of the ischemic side were decreased (P<0.01, P<0.05), while levels of IL-1ß and IL-18 were increased (P<0.01) in the model group; compared with the model group and the non-acupoint group, the positive expression of SYN, and BDNF, TrkB and SYN protein expressions in the hippocampus of the ischemic side were increased (P<0.01, P<0.05), while levels of IL-1ß and IL-18 were decreased (P<0.01) in the EA group. CONCLUSION: EA at "Baihui" (GV 20) and "Sishencong" (EX-HN 1) may improve learning-memory function in rats with CIRI by activating the BDNF/TrkB signaling pathway, reducing neuroinflammatory response, and promoting the recovery of synaptic plasticity.
Assuntos
Isquemia Encefálica , Fator Neurotrófico Derivado do Encéfalo , Eletroacupuntura , Aprendizagem , Memória , Plasticidade Neuronal , Ratos Sprague-Dawley , Receptor trkB , Traumatismo por Reperfusão , Animais , Eletroacupuntura/instrumentação , Masculino , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Traumatismo por Reperfusão/terapia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Receptor trkB/metabolismo , Humanos , Isquemia Encefálica/terapia , Isquemia Encefálica/metabolismo , Pontos de Acupuntura , Hipocampo/metabolismo , Interleucina-1beta/metabolismo , Transdução de SinaisRESUMO
Opioids are widely used, effective analgesics to manage severe acute and chronic pain, although they have recently come under scrutiny because of epidemic levels of abuse. While these compounds act on numerous central and peripheral pain pathways, the neuroanatomical substrate for opioid analgesia is not fully understood. By means of single-cell transcriptomics and manipulation of morphine-responsive neurons, we have identified an ensemble of neurons in the rostral ventromedial medulla (RVM) that regulates mechanical nociception in mice. Among these, forced activation or silencing of excitatory RVMBDNF projection neurons mimicked or completely reversed morphine-induced mechanical antinociception, respectively, via a brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)-dependent mechanism and activation of inhibitory spinal galanin-positive neurons. Our results reveal a specific RVM-spinal circuit that scales mechanical nociception whose function confers the antinociceptive properties of morphine.
Assuntos
Analgésicos Opioides , Fator Neurotrófico Derivado do Encéfalo , Bulbo , Morfina , Neurônios , Nociceptividade , Animais , Masculino , Camundongos , Analgésicos Opioides/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Nociceptividade/efeitos dos fármacos , Receptor trkB/metabolismo , Análise de Célula Única , Medula Espinal/efeitos dos fármacos , Transcriptoma , FemininoRESUMO
Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.
Assuntos
Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Receptor trkA , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Humanos , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Receptor trkC/antagonistas & inibidores , Receptor trkC/genética , Receptor trkC/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese químicaRESUMO
Age-related conditions, such as sarcopenia, cause physical disabilities for an increasing section of society. At the neuromuscular junction, the postsynaptic-derived neurotrophic factors brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) have neuroprotective functions and contribute to the correct regulation of the exocytotic machinery. Similarly, presynaptic muscarinic signalling plays a fundamental modulatory function in this synapse. However, whether or not these signalling pathways are compromised in ageing neuromuscular system has not yet been analysed. The present study analyses, through Western blotting, the differences in expression and activation of the main key proteins of the BDNF/NT-4 and muscarinic pathways related to neurotransmission in young versus ageing Extensor digitorum longus (EDL) rat muscles. The main results show an imbalance in several sections of these pathways: (i) a change in the stoichiometry of BDNF/NT-4, (ii) an imbalance of Tropomyosin-related kinase B receptor (TrkB)-FL/TrkB-T1 and neurotrophic receptor p 75 (p75NTR), (iii) no changes in the cytosol/membrane distribution of phosphorylated downstream protein kinase C (PKC)ßI and PKCε, (iv) a reduction in the M2-subtype muscarinic receptor and P/Q-subtype voltage-gated calcium channel, (v) an imbalance of phosphorylated mammalian uncoordinated-18-1 (Munc18-1) (S313) and synaptosomal-associated protein 25 (SNAP-25) (S187), and (vi) normal levels of molecules related to the management of acetylcholine (Ach). Based on this descriptive analysis, we hypothesise that these pathways can be adjusted to ensure neurotransmission rather than undergoing negative alterations caused by ageing. However, further studies are needed to assess this hypothetical suggestion. Our results contribute to the understanding of some previously described neuromuscular functional age-related impairments. Strategies to promote these signalling pathways could improve the neuromuscular physiology and quality of life of older people.
Assuntos
Envelhecimento , Fator Neurotrófico Derivado do Encéfalo , Junção Neuromuscular , Receptor trkB , Transdução de Sinais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Animais , Junção Neuromuscular/metabolismo , Envelhecimento/metabolismo , Ratos , Receptor trkB/metabolismo , Fatores de Crescimento Neural/metabolismo , Masculino , Receptores Muscarínicos/metabolismo , Transmissão Sináptica , Receptores de Fator de Crescimento Neural/metabolismo , Ratos WistarRESUMO
Menopausal depression, often associated with hormonal fluctuations such as decreased estrogen levels, imposes significant mental health burdens. Despite the antidepressant biological properties of standardized rice bran supplement (RBS), its impact on menopausal depression and underlying mechanisms remains largely unexplored. In this study, we investigated the antidepressant effects of RBS in a mouse model of estrogen deficiency-induced depression. Ovariectomized (OVX) mice received oral doses of RBS (250 and 1000 mg/kg) and 17ß estradiol over a 20-week period. RBS administration resulted in decreased immobility time in the tail suspension and forced swim tests, along with increased locomotor activity in the open field test. Furthermore, RBS enhanced nitric oxide production and neuronal nitric oxide synthase (nNOS) expression in the hippocampi of OVX mice. Additionally, RBS administration phosphorylated extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), and tropomyosin receptor kinase B and increased the protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. These findings suggest that RBS alleviated depressive behaviors in OVX mice by augmenting hippocampal nNOS expression and activating the ERK-CREB-BDNF signaling pathway. Therefore, based on these results, we propose that RBS is a promising agent to treat menopausal depression, a challenging condition.
Assuntos
Antidepressivos , Fator Neurotrófico Derivado do Encéfalo , Depressão , Suplementos Nutricionais , Hipocampo , Óxido Nítrico Sintase Tipo I , Oryza , Ovariectomia , Animais , Oryza/química , Feminino , Camundongos , Depressão/tratamento farmacológico , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Suplementos Nutricionais/análise , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Comportamento Animal/efeitos dos fármacos , Humanos , Menopausa/efeitos dos fármacos , Modelos Animais de Doenças , Óxido Nítrico/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , MAP Quinases Reguladas por Sinal Extracelular/metabolismoRESUMO
The disturbance of brain biochemical substances serves as a primary cause and aggravating factor of depression. This study aimed to investigate the principal components of Picea mariana and its effect on reserpine-induced depression mice,w ith its relationship with brain central transmitters and related proteins. The main constituents of P. mariana essential oil (PMEO) were analyzed by GC-MS spectrometry. The quiescent time in the tail suspension test (TST) and forced swim test (FST), along with the weight change of the mice was detected. The number of normal neurons was quantified through Nissl staining. Immunohistochemistry was employed to determine the levels of 5HT-1A and 5HT-2A in the brain. Western blotting was utilized to detect 5HT-2A, CRF and TrkB protein levels. RT-qPCR was used to detect the mRNA levels of 5HT-1A, 5HT-2A, TrkB, CRF, and BDNF. The main active ingredients of PMEOs were (-) -bornyl acetate (44.95%), γ-Terpinene (14.17%), and ß-Pinene (10.12%). PMEOs effectively improved the retardation and weight loss due to anorexia in depression-like mice. This improvement was associated with an increase in the number of normal neurons. After administering different doses of PMEOs, the levels of 5HT-1A, 5HT-2A, CRF, and TrkB were found to be increased in brain tissue. RT-qPCR revealed that the mRNA levels of CRF, 5HT-1A, and 5HT-2A were generally upregulated, whereas TrkB and BDNF were downregulated. PMEO can effectively alleviate depression induced by reserpine, which may be attributed to its regulation of 5HT-1A, 5HT-2A, CRF and TrkB protein expression, thus reducing brain nerve injury.
Assuntos
Antidepressivos , Depressão , Modelos Animais de Doenças , Óleos Voláteis , Reserpina , Animais , Camundongos , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Masculino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Receptor trkB/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Cromatografia Gasosa-Espectrometria de MassasRESUMO
Brain-derived neurotrophic factor (BDNF) content and signaling has been identified as one potential regulator of amyloid precursor protein (APP) processing. Recently published work has demonstrated that BDNF reduces BACE1 activity while also elevating the inhibition of GSK3ß in the prefrontal cortex of male C57BL/6J mice. These results provide evidence that BDNF alters APP processing by reducing BACE1 activity, which may act through GSK3ß inhibition. The purpose of this study was to further explore the role of GSK3ß in BDNF-induced regulation on BACE1 activity. We utilized a cell culture and an in vitro activity assay model to pharmacologically target BDNF and GSK3ß signaling to confirm its involvement in the BDNF response. Treatment of differentiated SH-SY5Y neuronal cells with 75 ng/mL BDNF resulted in elevated pTrkB content, pAkt content, pGSK3ß content, and reduced BACE1 activity. An in vitro BACE1 activity assay utilizing mouse prefrontal cortex (n = 6/group) supplemented with BDNF, BDNF + ANA12 (Trkb antagonist), or BDNF + wortmannin (Akt inhibitor) demonstrated that BDNF reduced BACE1 activity; however, in the presence of TrkB or Akt inhibition, this effect was abolished. An in vitro ADAM10 activity assay utilizing mouse prefrontal cortex (n = 6/group) supplemented with BDNF, BDNF + ANA12 (Trkb antagonist), or BDNF + wortmannin (Akt inhibitor) demonstrated that BDNF did not alter ADAM10 activity. However, inhibiting BDNF signaling reduced ADAM10 activity. Collectively these studies suggest that GSK3ß inhibition may be necessary for BDNF-induced reductions in BACE1 activity. These findings will allow for the optimization of future therapeutic strategies by selectively targeting TrkB activation and GSK3ß inhibition.
Assuntos
Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Fator Neurotrófico Derivado do Encéfalo , Glicogênio Sintase Quinase 3 beta , Camundongos Endogâmicos C57BL , Neurônios , Proteínas Proto-Oncogênicas c-akt , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Humanos , Ácido Aspártico Endopeptidases/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Camundongos , Masculino , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Transdução de Sinais , Linhagem Celular Tumoral , Receptor trkB/metabolismo , Receptor trkB/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismoRESUMO
Clinical evidence suggests that early malnutrition promotes symptoms related to psychiatric disorders later in life. Nevertheless, the molecular mechanisms underpinning nutritional injury induce depression remains unknown. The purpose of the present study was to evaluate whether perinatal protein restriction increases vulnerability to developing depressive-like behavior in adulthood by focusing on anhedonia, a core symptom of depression. To this, male adult Wistar rats submitted to a protein restriction schedule at perinatal age (PR-rats), were subjected to the sucrose preference test (SPT), the novel object recognition test (NORT), the forced swim test (FST), and the elevated plus maze (EPM), and compared to animals fed with a normoprotein diet. To investigate neurobiological substrates linked to early protein undernutrition-facilitated depressive-like behavior, we assessed the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the nucleus accumbens (NAc), and evaluated the reversal of anhedonic-like behavior by infusing ANA-12. We found that early malnutrition decreased sucrose preference, impaired performance in the NORT and increased immobility time in the FST. Furthermore, perinatal protein-restriction-induced anhedonia correlated with increased BDNF and p-TrkB protein levels in the NAc, a core structure in the reward circuit linked with anhedonia. Finally, bilateral infusion of the TrkB antagonist ANA-12 into the NAc shell ameliorated a reduced sucrose preference in the PR-rats. Altogether, these findings revealed that protein restriction during pregnancy and lactation facilitates depressive-like behavior later in life and may increase the risk of developing anhedonia by altering BDNF-TrkB in the NAc shell.
Assuntos
Anedonia , Fator Neurotrófico Derivado do Encéfalo , Núcleo Accumbens , Ratos Wistar , Receptor trkB , Transdução de Sinais , Animais , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Anedonia/fisiologia , Ratos , Receptor trkB/metabolismo , Feminino , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Gravidez , Dieta com Restrição de Proteínas , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Depressão/metabolismo , Depressão/psicologia , Azepinas , BenzamidasRESUMO
Postmenopausal osteoporosis (PMO) is characterized by bone loss and microstructural damage, and it is most common in older adult women. Currently, there is no cure for PMO. The flavonoid chemical 7,8-dihydroxyflavone (7,8-DHF) specifically activates tropomyosin receptor kinase B (TRKB). Furthermore, 7,8-DHF has various biological characteristics, including anti-inflammatory and antioxidant effects. However, the specific implications and fundamental mechanisms of 7,8-DHF in PMO remain unclear. We used protein imprinting, flow cytometry, tissue staining, and other methods to estimate the preventive mechanisms of 7,8-DHF against hydrogen peroxide (H2O2)-induced apoptosis in primary mouse bone marrow mesenchymal stem cells (BMSCs), osteogenic differentiation ability, and bone mass in ovariectomized (OVX) mice. We found that 7,8-DHF effectively prevented H2O2-induced reductions in the viability and osteogenic differentiation capacity of primary BMSCs. Mechanistically, 7,8-DHF induced the TRKB to activate the PI3K/AKT/NRF2 pathway. In vivo experiments with the OVX mouse model confirmed that 7,8-DHF can inhibit oxidative stress and promote bone formation, indicating that 7,8-DHF improves the viability and osteogenic differentiation ability of BMSCs stimulated via H2O2 by activating the TRKB/PI3K/AKT and NRF2 pathways, thereby improving PMO.
Assuntos
Flavonas , Peróxido de Hidrogênio , Células-Tronco Mesenquimais , Fator 2 Relacionado a NF-E2 , Osteogênese , Osteoporose Pós-Menopausa , Estresse Oxidativo , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptor trkB , Transdução de Sinais , Animais , Estresse Oxidativo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Camundongos , Feminino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Flavonas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Humanos , Receptor trkB/metabolismo , Receptor trkB/genética , Diferenciação Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Ovariectomia , Camundongos Endogâmicos C57BLRESUMO
Depression is a widespread disease, with high mortality and recurrence rates. Recent studies have shown that elevated cytokine levels are implicated in the molecular mechanisms of depression. Oxidative stress contributes to the stimulation of cytokine production. Growing evidence suggests that ginsenoside Re (Gs-Re) exerts a neuroprotective effect on the hippocampus by suppressing oxidative stress and inflammation. However, the effect and mechanism of Gs-Re in the treatment of depression remain understudied. This study aimed to evaluate the neuroprotective and antidepressant-like effects of Gs-Re and the possible underlying mechanisms. In this article, the antidepressant-like effect of the Gs-Re was studied both in vitro (H2O2-induced oxidative stress in HT-22 cells) and in vivo (reserpine-induced depressive model mice). Our results indicated that, at the cellular level, Gs-Re effectively enhanced cell survival following H2O2 stimulation, inhibited the mass production of oxidative stress markers (MDA and ROS), and prevented the occurrence of apoptosis. Moreover, Gs-Re significantly reduced the levels of proinflammatory cytokines IL-1ß, IL-6, and TNF-α and restored the abnormal mitochondrial membrane potential. Subsequently, Gs-Re treatment reversed reserpine-induced neuroinflammation and depressive-like behaviors in vivo and inhibited microglia overactivation. Furthermore, the alterations in the BDNF/TrkB/ERK/CREB signaling pathway induced by H2O2 or reserpine in HT-22 cells or in the mouse hippocampus were significantly reversed by Gs-Re. K252a blocked the improvement of Gs-Re on depression-like behavior and eliminated the inhibition of oxidative stress and neuroinflammation in vivo. This study suggested that Gs-Re produces neuroprotective and depressive effects by inhibiting oxidative stress and inflammation and activating the BDNF/TrkB/ERK/CREB pathway.
Assuntos
Antidepressivos , Fator Neurotrófico Derivado do Encéfalo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Depressão , Ginsenosídeos , Estresse Oxidativo , Transdução de Sinais , Animais , Estresse Oxidativo/efeitos dos fármacos , Ginsenosídeos/farmacologia , Ginsenosídeos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Antidepressivos/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Receptor trkB/metabolismoRESUMO
Rice protein peptide (RPP) has been reported to alleviate the symptoms of dextran sulfate sodium (DSS)-induced colitis, but its potential protective effect and fundamental neurobiological mechanisms against DSS-induced inflammatory bowel disease (IBD), coupled with depression and cognitive impairment, remain unclear. In this study, RPP treatment in DSS-induced mice inhibited decreases in body weight and colon length and improved intestinal barrier function and behavioral performance. RPP treatment enhanced phenylalanine and tyrosine metabolism in the brains of mice, and it upregulated metabolites such as l-dopa, phenylethylamine, and 3,4-dihydroxyphenylacetate. Additionally, RPP treatment enhanced the brain-derived neurotrophic factor (BDNF) by upregulating the BDNF/TrkB/CREB signaling pathway. Spearman's correlation analysis revealed that the phenylalanine and tyrosine contents in the brain were significantly negatively correlated with the BDNF/TrkB/CREB signaling pathway and behavioral performance. In conclusion, this study suggested that RPP may serve as a unique nutritional strategy for preventing IBD and its associated cognitive impairment and depression symptoms.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Depressão , Sulfato de Dextrana , Oryza , Peptídeos , Fenilalanina , Transdução de Sinais , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Camundongos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Masculino , Fenilalanina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Depressão/metabolismo , Depressão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Peptídeos/administração & dosagem , Humanos , Oryza/química , Oryza/metabolismo , Sulfato de Dextrana/efeitos adversos , Proteínas de Plantas/metabolismo , Camundongos Endogâmicos C57BL , Receptor trkB/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite/tratamento farmacológico , Comportamento Animal/efeitos dos fármacosRESUMO
5-Hydroxytryptamine (5-HT) plays a substantial role in mitigating depression and anxiety. However, the potential effects of 5-HT against posttraumatic stress disorder (PTSD) and its underlying mechanisms remain unclear. Elevated plus maze test evaluates anxiety-related behaviors, and the open field test is used to assess overall activity levels and anxiety. Inflammatory cytokine levels were determined using ELISA. The levels of 5-HT and dopamine were measured using HPLC. mRNA and protein levels were examined by PCR and Western blot, respectively. Rats exposed to single prolonged stress (SPS) exhibited typical PTSD-like phenotypes, with decreased levels of 5-HT in the hippocampus and significant reductions in its downstream targets, brain-derived neurotrophic factor (BDNF) and TrkB. In addition, it was discovered that the autophagy signaling pathway might be involved in regulating hippocampal BDNF in rats exposed to SPS. Subsequent treatment with an intracerebral injection of sh-SERT significantly inhibited anxiety and cognitive dysfunction in rats. Moreover, sh-SERT treatment was observed to substantially reverse the increase in autophagy signaling protein expression and consequently improve the expression of BDNF and TrkB proteins, which had been reduced. The current study demonstrates that sh-SERT exhibits significant anti-PTSD effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity.NEW & NOTEWORTHY The study demonstrated that sh-SERT exhibits significant anti-posttraumatic stress disorder (PTSD) effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity.
Assuntos
Autofagia , Fator Neurotrófico Derivado do Encéfalo , Hipocampo , Plasticidade Neuronal , Ratos Sprague-Dawley , Serotonina , Transtornos de Estresse Pós-Traumáticos , Animais , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Masculino , Serotonina/metabolismo , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ansiedade/tratamento farmacológico , Receptor trkB/metabolismo , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Modelos Animais de DoençasRESUMO
BACKGROUND: Neurodevelopmental disorders (NDDs) like intellectual disability (ID) are highly heritable, but the environment plays an important role. For example, endocrine disrupting chemicals (EDCs), including bisphenol A (BPA) and its analogues, have been termed neuroendocrine disruptors. This study aimed to evaluate the influence of different genetic polymorphisms (SNPs) on cognitive function in Spanish schoolchildren according to dietary bisphenol exposure. METHODS: A total of 102 children aged 6-12 years old were included. Ten SNPs in genes involved in brain development, synaptic plasticity, and neurotransmission (BDNF, NTRK2, HTR2A, MTHFR, OXTR, SLC6A2, and SNAP25) were genotyped. Then, dietary exposure to bisphenols (BPA plus BPS) was estimated and cognitive functions were assessed using the WISC-V Spanish form. RESULTS: BDNF rs11030101-T and SNAP25 rs363039-A allele carriers scored better on the fluid reasoning domain, except for those inheriting the BDNF rs6265-A allele, who had lower scores. Secondly, relevant SNP-bisphenol interactions existed in verbal comprehension (NTRK2 rs10868235 (p-int = 0.043)), working memory (HTR2A rs7997012 (p-int = 0.002), MTHFR rs1801133 (p-int = 0.026), and OXTR rs53576 (p-int = 0.030)) and fluid reasoning (SLC6A2 rs998424 (p-int = 0.004)). CONCLUSIONS: Our findings provide the first proof that exploring the synergistic or additive effects between genetic variability and bisphenol exposure on cognitive function could lead to a better understanding of the multifactorial and polygenic aetiology of NDDs.