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1.
J Psychiatry Neurosci ; 49(3): E157-E171, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38692693

RESUMO

BACKGROUND: Critical adolescent neural refinement is controlled by the DCC (deleted in colorectal cancer) protein, a receptor for the netrin-1 guidance cue. We sought to describe the effects of reduced DCC on neuroanatomy in the adolescent and adult mouse brain. METHODS: We examined neuronal connectivity, structural covariance, and molecular processes in a DCC-haploinsufficient mouse model, compared with wild-type mice, using new, custom analytical tools designed to leverage publicly available databases from the Allen Institute. RESULTS: We included 11 DCC-haploinsufficient mice and 16 wild-type littermates. Neuroanatomical effects of DCC haploinsufficiency were more severe in adolescence than adulthood and were largely restricted to the mesocorticolimbic dopamine system. The latter finding was consistent whether we identified the regions of the mesocorticolimbic dopamine system a priori or used connectivity data from the Allen Brain Atlas to determine de novo where these dopamine axons terminated. Covariance analyses found that DCC haploinsufficiency disrupted the coordinated development of the brain regions that make up the mesocorticolimbic dopamine system. Gene expression maps pointed to molecular processes involving the expression of DCC, UNC5C (encoding DCC's co-receptor), and NTN1 (encoding its ligand, netrin-1) as underlying our structural findings. LIMITATIONS: Our study involved a single sex (males) at only 2 ages. CONCLUSION: The neuroanatomical phenotype of DCC haploinsufficiency described in mice parallels that observed in DCC-haploinsufficient humans. It is critical to understand the DCC-haploinsufficient mouse as a clinically relevant model system.


Assuntos
Encéfalo , Receptor DCC , Dopamina , Haploinsuficiência , Animais , Receptor DCC/genética , Encéfalo/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/anatomia & histologia , Dopamina/metabolismo , Camundongos , Masculino , Expressão Gênica , Vias Neurais , Fatores Etários , Feminino , Camundongos Endogâmicos C57BL , Envelhecimento/genética , Envelhecimento/fisiologia
2.
Br J Cancer ; 130(10): 1725-1731, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38538728

RESUMO

BACKGROUND: Advances in upper gastrointestinal endoscopic technology have enabled early detection and treatment of hypopharyngeal cancer. However, in-depth pharyngeal observations require sedation and are invasive. It is important to establish a minimally invasive and simple evaluation method to identify high-risk patients. METHODS: Eighty-seven patients with superficial hypopharyngeal cancer and 51 healthy controls were recruited. We assessed the methylation status of DCC, PTGDR1, EDNRB, and ECAD, in tissue and saliva samples and verified the diagnostic accuracy by methylation analyses of their promoter regions using quantitative methylation-specific PCR. RESULTS: Significant differences between cancer and their surrounding non-cancerous tissues were observed in the methylation values of DCC (p = 0.003), EDNRB (p = 0.001), and ECAD (p = 0.043). Using receiver operating characteristic analyses of the methylation values in saliva samples, DCC showed the highest area under the curve values for the detection of superficial hypopharyngeal cancer (0.917, 95% confidence interval = 0.864-0.970), compared with those for EDNRB (0.680) and ECAD (0.639). When the cutoff for the methylation values of DCC was set at ≥0.163, the sensitivity to detect hypopharyngeal cancer was 82.8% and the specificity was 90.2%. CONCLUSIONS: DCC methylation in saliva samples could be a non-invasive and efficient tool for early detection of hypopharyngeal cancer in high-risk patients.


Assuntos
Metilação de DNA , Neoplasias Hipofaríngeas , Saliva , Feminino , Humanos , Masculino , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Receptor DCC/genética , Detecção Precoce de Câncer/métodos , Genes DCC/genética , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/diagnóstico , Regiões Promotoras Genéticas , Receptor de Endotelina B/genética , Curva ROC , Saliva/química
3.
J Integr Neurosci ; 23(3): 47, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38538215

RESUMO

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


Assuntos
Neoplasias Ósseas , Dor do Câncer , Netrina-1 , Animais , Ratos , Neoplasias Ósseas/complicações , Dor do Câncer/etiologia , Receptor DCC/metabolismo , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/farmacologia , Netrina-1/genética , Nociceptores/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , RNA Interferente Pequeno , Transdução de Sinais , Microambiente Tumoral , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
4.
J Egypt Natl Canc Inst ; 36(1): 10, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38556604

RESUMO

BACKGROUND: Colorectal cancer (CRC) ranks third in cancer incidence globally and is the second leading cause of cancer-related mortality. The nucleoside diphosphate kinase 1 (NME1) and netrin 1 receptor (DCC) genes have been associated with resistance against tumorigenesis and tumor metastasis. This study investigates the potential association between NME1 (rs34214448 G > T and rs2302254 C > T) and DCC (rs2229080 G > C and rs714 A > G) variants and susceptibility to colorectal cancer development. METHODS: Samples from 232 colorectal cancer patients and 232 healthy blood donors underwent analysis. Variants were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Associations were assessed using odds ratios (OR), and the p values were adjusted with Bonferroni test. RESULTS: Individuals carrying the G/T and T/T genotypes for the NME1 rs34214448 variant exhibited a higher susceptibility for develop colorectal cancer (OR = 2.68, 95% CI: 1.76-4.09, P = 0.001 and OR = 2.47, 95% CI: 1.37-4.47, P = 0.001, respectively). These genotypes showed significant associations in patients over 50 years (OR = 2.87, 95% CI: 1.81-4.54, P = 0.001 and OR = 2.99, 95% CI: 1.54-5.79, P = 0.001 respectively) and with early Tumor-Nodule-Metastasis (TNM) stage (P = 0.001), and tumor location in the rectum (P = 0.001). Furthermore, the DCC rs2229080 variant revealed that carriers of the G/C genotype had an increased risk for develop colorectal cancer (OR = 2.00, 95% CI: 1.28-3.11, P = 0.002) and were associated with age over 50 years, sex, and advanced TNM stages (P = 0.001). CONCLUSIONS: These findings suggest that the NME1 rs34214448 and DCC rs2229080 variants play a significant role in colorectal cancer development.


Assuntos
Neoplasias Colorretais , Neoplasias Gástricas , Humanos , Pessoa de Meia-Idade , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Genótipo , Neoplasias Gástricas/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Estudos de Casos e Controles , Receptor DCC/genética , Nucleosídeo NM23 Difosfato Quinases/genética
5.
J Pak Med Assoc ; 74(2): 287-293, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38419228

RESUMO

Objective: To identify the mutation in codon 201 of the deleted in colorectal cancer gene in colorectal cancer, and to correlate that mutation to the histopathological grading of colorectal cancer. METHODS: The cross-sectional study was conducted from February 2019 to February 2021 after approval from the ethics review board of the Dow University of Health Sciences, Karachi, and comprised biopsy-proven colorectal cancer patients regardless of age and gender. After histopathological reporting, formalin-fixed paraffin-embedded tissue blocks of colorectal cancer were used for deoxyribonucleic acid extraction, followed by polymerase chain reaction optimisation and deoxyribonucleic acid Sanger sequencing for mutational analysis. Data was analysed using SPSS 25. RESULTS: Of the 100 biopsy specimens assessed, 45(45%) were selected. Of them, 13(29%) samples failed to show any band on gel electrophoresis. The remaining 32(71%) samples were used for Sanger sequencing. Of these, 1(3%) sample did not sequence, while 31(97%) showed sequencing. All the sequenced samples identified a mutation in codon 201 of exon 3 in the deleted in colorectal cancer gene; 30(97%) showed homozygosity, and 1(3%) showed heterozygosity. No significant association of point mutation was noted with various demographic and clinicopathological parameters (p>0.05). Conclusion: The deleted in colorectal cancer gene's missense mutation in codon 201 was frequently observed in colorectal cancer patients.


Assuntos
Neoplasias Colorretais , Genes DCC , Humanos , Neoplasias Colorretais/genética , Estudos Transversais , Mutação , Códon , DNA , Receptor DCC/genética
6.
Mov Disord ; 39(2): 400-410, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38314870

RESUMO

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Discinesias , Transtornos dos Movimentos , Masculino , Feminino , Humanos , Netrina-1/genética , Receptor DCC/genética , Transtornos dos Movimentos/genética , Mutação de Sentido Incorreto/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética
7.
JAMA Neurol ; 81(2): 187, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38048091

RESUMO

This case report describes the evaluation of 16-year-old twins with chromosomal microarray and mirror movements.


Assuntos
Genes DCC , Transtornos dos Movimentos , Humanos , Transtornos dos Movimentos/genética , Mutação , Mãos , Receptor DCC/genética
8.
Int J Radiat Biol ; 100(3): 371-384, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37934907

RESUMO

PURPOSE: The risk of brain exposure to ionizing radiation increases gradually due to the extensive application of nuclear technology in medical, industrial, and aerospace fields. Radiation-induced brain injury (RBI) is highly likely to cause a wide range of neurological complications, including schizophrenia, Alzheimer's disease (AD), depression. Ginkgolide B (GB) is one of the effective active components extracted from ginkgo biloba leaves, exerts protective effects on CNS, which is involved in the regulation of the Hippo signaling pathway. MST1, as one of the core kinases of the Hippo pathway, participated in regulating cell proliferation, differentiation, and apoptosis. However, it remains unclear whether GB attenuates radiation brain injury (RBI) and whether the radioprotective effect of GB refers to MST1 signaling. Hence, our study aimed to explore the radiation protection effect and the potential mechanism of GB. MATERIALS AND METHODS: C57BL/6 mice were stimulated with an X-ray (20 Gy) to establish an RBI model. Then, morris water maze test (MWM) and step-down passive avoidance test (SDPAT) were used to assess the learning and memory function of mice. The open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were used to assess changes in locomotor activity and hopelessness. Besides, X-ray-stimulated SH-SY5Y cells were used to verify the radioprotective effect of GB. Immunofluorescence double staining, Dihydroethidium (DHE), western blot, and flow cytometry were used to explore the role of DCC/MST1 signaling in RBI. RESULTS: In this study, X-ray-treated mice exhibited cognitive impairment and depression-like behavior, which was ameliorated by GB treatment. GB also reduced the ROS production and the number of TUNEL-positive cells in the hippocampus. Moreover, GB increased the protein levels of p-AKT and Bcl2, while decreased the protein levels of MST1, p-p38, p-JNK, cleaved-caspase-3 and Bax both in vivo and in vitro. Additionally, exogenous Netrin-1 alleviated X-ray-induced ROS production and apoptosis, whereas knockout of Netrin-1 receptor DCC abolished the protective effect of GB. CONCLUSION: Oxidative stress and MST1-mediated neuronal apoptosis participated in radiation-induced cognitive impairment and depression-like behaviors, and modulation of DCC by GB was an effective intervention against RBI.


Assuntos
Lesões Encefálicas , Ginkgolídeos , Lactonas , Neuroblastoma , Proteção Radiológica , Animais , Humanos , Camundongos , Apoptose , Encéfalo/metabolismo , Receptor DCC/metabolismo , Camundongos Endogâmicos C57BL , Netrina-1/farmacologia , Espécies Reativas de Oxigênio/metabolismo
9.
Zh Nevrol Psikhiatr Im S S Korsakova ; 123(12): 116-123, 2023.
Artigo em Russo | MEDLINE | ID: mdl-38147391

RESUMO

OBJECTIVE: To investigate the associations of OPRM1 gene rs179971, OPRK1 gene rs6473797 and DCC gene rs8084280 polymorphisms with non-suicidal self-injury (NSSI) characteristics and motivations in adults. MATERIAL AND METHODS: A pilot sample included 28 adult patients with history of NSSI (89.3% (n=25) women, median age (Q1-Q3) - 23 (21.25-25) years). Most patients (78.6%, n=20) had a diagnosis of bipolar disorder. NSSI characteristics and motivations were assessed using the Inventory of Statements about Self-Injury (ISAS) scale. The Childhood Trauma Questionnaire (CTQ) was used to control for childhood trauma - one of the most important environmental factors associated with NSSI. The Baratt Impulsivity Scale (BIS) and the Buss-Perry Aggression Questionnaire (BPAQ) were also used to assess impulsivity and aggression, respectively. RT-PCR was used for genotyping, a genetic effect was assessed using the dominant model. Mann-Whitney U-test, Pearson χ2-test and multiple linear regression were used for statistical analysis. RESULTS: Carriers of the minor G allele of OPRM1 gene rs1779971 had a higher level of aggression assessed by BPAQ (p=0.02). The minor C allele of OPRK1 gene rs6473797 was associated with an increase of the subjective importance of «Affect regulation¼ (B=2.23; CI 95% [0.39-4.06]; p=0.022) and «Anti-dissociation¼ (B=3.31; CI 95% [0.18-6.44]; p=0.039) motivations, whereas the minor T allele of DCC gene rs8084280, on the contrary, was associated with a decrease of the importance of «Affect regulation¼ (B=-1.74; CI 95% [-3.30 - -0.18]; p=0.032). Moreover, this effect was found after adjusting for diagnosis, sex, age, and the presence of childhood trauma. CONCLUSIONS: To our knowledge, this is the first study on the association of genetic markers with NSSI motivations. The results of this pilot study demonstrate that OPRK1 and DCC gene polymorphisms can determine differences in motivations for self-harm, however, these results require confirmation in large samples.


Assuntos
Receptor DCC , Polimorfismo Genético , Receptores Opioides kappa , Receptores Opioides mu , Comportamento Autodestrutivo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Receptor DCC/genética , Receptor DCC/metabolismo , Comportamento Autodestrutivo/genética , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Marcadores Genéticos/genética , Inquéritos e Questionários , Comportamento Impulsivo , Agressão , Polimorfismo Genético/genética
10.
Environ Sci Pollut Res Int ; 30(41): 94976-94987, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37542692

RESUMO

Sustainable investment is widely regarded as an important market-based approach to achieving inclusive green growth. To achieve the inclusive green growth objective, companies providing sustainable products must be profitable enough to attract private capital. Oil price changes can however affect the profitability of such companies. This study assesses volatility transmission between crude oil prices and sustainable investment in the USA. Using the dynamic conditional correlation-generalized autoregressive conditional heteroskedasticity (DCC-GARCH) method, daily data from September 28, 2012, to October 19, 2022, is analyzed. There are several key findings from this analysis. The risk connectedness of crude oil and sustainable investment is found to vary with time. Results further show that the risk connectedness increases in periods of important economic and geopolitical events. The greatest risk connectedness of crude oil and sustainable investment is observed during the outbreak of coronavirus disease (COVID-19). Moreover, the result shows that crude oil is the main risk transmitter, whereas, both the energy efficiency and pollution mitigation indices (i.e., sustainable investment) are risk receivers, and crude oil is constantly dominating sustainable investment. The study findings provide valuable insights for investors and policymakers alike.


Assuntos
COVID-19 , Petróleo , Estados Unidos , Humanos , Investimentos em Saúde , Surtos de Doenças , Poluição Ambiental , Receptor DCC
11.
Eur J Pharmacol ; 956: 175940, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37541362

RESUMO

Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance.


Assuntos
Antipsicóticos , Receptor DCC , Esquizofrenia , Animais , Camundongos , Antipsicóticos/uso terapêutico , Receptor DCC/genética , Camundongos Endogâmicos C57BL , Olanzapina/farmacologia , Fenótipo , Córtex Pré-Frontal , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
12.
Cell Rep ; 42(8): 112947, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37572323

RESUMO

The molecular code that controls synapse formation and maintenance in vivo has remained quite sparse. Here, we identify that the secreted protein Adamtsl3 functions as critical hippocampal synapse organizer acting through the transmembrane receptor DCC (deleted in colorectal cancer). Traditionally, DCC function has been associated with glutamatergic synaptogenesis and plasticity in response to Netrin-1 signaling. We demonstrate that early post-natal deletion of Adamtsl3 in neurons impairs DCC protein expression, causing reduced density of both glutamatergic and GABAergic synapses. Adult deletion of Adamtsl3 in either GABAergic or glutamatergic neurons does not interfere with DCC-Netrin-1 function at glutamatergic synapses but controls DCC signaling at GABAergic synapses. The Adamtsl3-DCC signaling unit is further essential for activity-dependent adaptations at GABAergic synapses, involving DCC phosphorylation and Src kinase activation. These findings might be particularly relevant for schizophrenia because genetic variants in Adamtsl3 and DCC have been independently linked with schizophrenia in patients.


Assuntos
Neurônios , Sinapses , Humanos , Receptor DCC/metabolismo , Netrina-1/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo , Sinapses/metabolismo , Animais
13.
J Dev Orig Health Dis ; 14(4): 501-507, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37431265

RESUMO

Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.


Assuntos
Resistência à Insulina , MicroRNAs , Humanos , Masculino , Gravidez , Feminino , Ratos , Animais , Netrina-1/genética , Netrina-1/metabolismo , Células HEK293 , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Insulina/metabolismo , Roedores/genética , Roedores/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Sinais (Psicologia) , Córtex Pré-Frontal/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Receptor DCC/metabolismo
14.
Nat Commun ; 14(1): 4035, 2023 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-37419977

RESUMO

Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual's sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.


Assuntos
Anfetamina , Dopamina , Feminino , Camundongos , Masculino , Animais , Anfetamina/farmacologia , Dopamina/metabolismo , Netrina-1/metabolismo , Receptor DCC/genética , Receptor DCC/metabolismo , Axônios/metabolismo
15.
J Affect Disord ; 339: 943-953, 2023 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-37487843

RESUMO

BACKGROUND: People with severe mental illness have a higher risk of cardiometabolic disease than the general population. Traditionally attributed to sociodemographic, behavioural factors and medication effects, recent genetic studies have provided evidence of shared biological mechanisms underlying mental illness and cardiometabolic disease. We aimed to determine whether signals in the DCC locus, implicated in psychiatric and cardiometabolic traits, were shared or distinct. METHODS: In UK Biobank, we systematically assessed genetic variation in the DCC locus for association with metabolic, cardiovascular and psychiatric-related traits in unrelated "white British" participants (N = 402,837). Logistic or linear regression were applied assuming an additive genetic model and adjusting for age, sex, genotyping chip and population structure. Bonferroni correction for the number of independent variants was applied. Conditional analyses (including lead variants as covariates) and trans-ancestry analyses were used to investigate linkage disequilibrium between signals. RESULTS: Significant associations were observed between DCC variants and smoking, anhedonia, body mass index (BMI), neuroticism and mood instability. Conditional analyses and linkage disequilibrium structure suggested signals for smoking and BMI were distinct from each other and the mood traits, whilst individual mood traits were inter-related in a complex manner. LIMITATIONS: Restricting analyses in non-"white British" individuals to the phenotypes significant in the "white British" sample is not ideal, but the smaller samples sizes restricted the phenotypes possible to analyse. CONCLUSIONS: Genetic variation in the DCC locus had distinct effects on BMI, smoking and mood traits, and therefore is unlikely to contribute to shared mechanisms underpinning mental and cardiometabolic traits.


Assuntos
Doenças Cardiovasculares , Sistema Cardiovascular , Humanos , Bancos de Espécimes Biológicos , Fenótipo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Reino Unido/epidemiologia , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Receptor DCC/genética
16.
Sci Adv ; 9(19): eadd5501, 2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-37172092

RESUMO

Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified ARHGEF7, a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1-mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1-induced increase in cell surface Dcc. Mice heterozygous for Arhgef7 have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how ARHGEF7 mutation causes MM.


Assuntos
Fatores de Crescimento Neural , Proteínas Supressoras de Tumor , Camundongos , Animais , Receptor DCC/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Fatores de Crescimento Neural/metabolismo , Netrina-1/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Axônios/metabolismo
17.
Cell Rep ; 42(5): 112455, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37149867

RESUMO

Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline, they are suggested to switch from being attracted to being repelled in order to approach and to subsequently leave the midline. A molecular mechanism that is hypothesized to underlie this switch in axonal responses is the silencing of Netrin1/Deleted in Colorectal Carcinoma (DCC)-mediated attraction by the repulsive SLIT/ROBO1 signaling. Using in vivo approaches including CRISPR-Cas9-engineered mouse models of distinct Dcc splice isoforms, we show here that commissural axons maintain responsiveness to both Netrin and SLIT during midline crossing, although likely at quantitatively different levels. In addition, full-length DCC in collaboration with ROBO3 can antagonize ROBO1 repulsion in vivo. We propose that commissural axons integrate and balance the opposing DCC and Roundabout (ROBO) signaling to ensure proper guidance decisions during midline entry and exit.


Assuntos
Proteínas do Tecido Nervoso , Receptores Imunológicos , Animais , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Orientação de Axônios , Axônios/metabolismo , Netrinas , Regulação da Expressão Gênica no Desenvolvimento , Receptor DCC
18.
Cortex ; 161: 38-50, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36889039

RESUMO

Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is "congenital mirror movement disorder", which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC.


Assuntos
Agenesia do Corpo Caloso , Transtornos dos Movimentos , Feminino , Humanos , Masculino , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Receptor DCC/genética , Mutação/genética , Neuroimagem
19.
Biomed Pharmacother ; 161: 114528, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36931029

RESUMO

Osteoarthritis (OA) is a chronic progressive degenerative joint disease. Owing to its complex pathogenesis, OA treatment is typically challenging. Necroptosis is a form of programmed cell death mainly mediated by the serine/threonine kinases, RIPK1 and RIPK3, and mixed lineage kinase-like domain (MLKL). In this study, we found that the multi-targeted kinase inhibitor DCC-2036 can inhibit TSZ (TNF-α, Smac mimetic, and z-VAD-FMK)-induced necroptosis of chondrocytes and synovial fibroblast cells (SFs). In addition, we found that oral DCC-2036 inhibited chondrocyte damage in a rat model of OA induced by intra-articular injection of monosodium iodoacetate (MIA). A mechanistic study showed that DCC-2036 directly inhibited the activities of RIPK1 and RIPK3 kinases to block necroptosis, inhibiting the inflammatory response and protecting chondrocytes. In summary, our research suggests that DCC-2036, a new necroptosis inhibitor targeting RIPK1 and RIPK3 kinase activity, may be useful for the clinical treatment of OA and provides a new direction for the research and treatment of OA.


Assuntos
Osteoartrite , Proteínas Quinases , Ratos , Animais , Proteínas Quinases/metabolismo , Necroptose , Apoptose , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Receptor DCC
20.
CNS Neurosci Ther ; 29(7): 1817-1829, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36852451

RESUMO

AIMS: Multiple guidance cues, such as netrin-1 (NTN-1)/deleted in colorectal carcinoma (DCC), control the guidance of axons and help establish functional neural circuits during development. However, the function of these guidance molecules during the neurodegenerative process is unclear. METHODS: To access the alterations of NTN-1 and DCC during the onset and progression of PD, we first established two subacute and one chronic PD model. Then, we investigated the relationship between the NTN-1/DCC pathway and cell death in SH-SY5Y cells. Finally, we conducted correlation studies between plasma NTN-1 and parkinsonian symptoms in patients to understand how this pathway contributes to PD. RESULTS: We found that the imbalance of NTN-1 and DCC was a common feature of nigral DA neuron injury in PD mouse models. We investigated that MPP+ inhibited NTN-1 expression and increased DCC expression in a concentration- and time-dependent manner. We further discovered a significant decrease in plasma NTN-1 levels and a positive correlation with UPDRS scores in PD patients. CONCLUSION: Our findings confirmed the imbalance of NTN-1/DCC signaling during nigral degeneration in experimental PD models and found for the first time a correlation of plasma NTN-1 with PD symptoms in patients.


Assuntos
Neuroblastoma , Doença de Parkinson , Camundongos , Animais , Humanos , Fatores de Crescimento Neural/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Netrina-1 , Células Cultivadas , Axônios/metabolismo , Receptor DCC
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