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1.
Zhen Ci Yan Jiu ; 46(7): 580-5, 2021 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-34369678

RESUMO

OBJECTIVE: To observe the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the depressive behavior in depression rats, so as to explore its mechanism underlying improvement of depression. METHODS: A total of 24 male Sprague Dawley rats were randomly divided into normal, depression model, taVNS, tnVNS (transcutaneous auricular none-vagus nerve stimulaton) groups (n=6 in each group). The depression model was established by chronic unpredictable mild stimulation combined with solitary raising for 35 consecutive days. After 14 days modeling, transcutaneous electrostimulation (2 mA, 2 Hz/15 Hz) was applied to auricular concha or auricular margin, respectively. Each intervention was conducted for 30 minutes, once daily for 21 days. The depression-like behavior was evaluated by forced swimming immobility time and body weight. The expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and interleukin-18 (IL-18) protein in the prefrontal cortex were detected by Western blot. RESULTS: Following modeling, the increase amount of body weight was decreased, the forced swimming immobility time and expression TLR4, MyD88 and IL-18 protein in the prefrontal cortex were increased in the model group than those in the normal group (P<0.01). Following the treatment and compared with the model group, the increase amount of body weight in the taVNS group was obviously increased (P<0.05), the swimming immobility time and the expression of TLR4, MyD88, IL-18 protein in the taVNS and tnVNS groups were significantly decreased (P<0.01). CONCLUSION: TaVNS is able to improve depression in depression rats, which is probably related to its effect in inhibiting inflammatory response of TLR4/MyD88 signaling pathway in prefrontal cortex.


Assuntos
Estimulação Elétrica Nervosa Transcutânea , Estimulação do Nervo Vago , Animais , Depressão/genética , Depressão/terapia , Interleucina-18/genética , Masculino , Fator 88 de Diferenciação Mieloide/genética , Córtex Pré-Frontal , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética , Nervo Vago
2.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360568

RESUMO

Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects the brain and spinal cord. There are several disease courses in MS including relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). Up to 50% of MS patients experience depressive disorders. Major depression (MD) is a serious comorbidity of MS. Many dysfunctions including neuroinflammation, peripheral inflammation, gut dysbiosis, chronic oxidative and nitrosative stress, and neuroendocrine and mitochondrial abnormalities may contribute to the comorbidity between MS and MD. In addition to these actions, medical treatment and microRNA (miRNA) regulation may also be involved in the mechanisms of the comorbidity between MS and MD. In the study, I review many common miRNA biomarkers for both diseases. These common miRNA biomarkers may help further explore the association between MS and MD.


Assuntos
Depressão/patologia , Regulação da Expressão Gênica , MicroRNAs/genética , Esclerose Múltipla/patologia , Animais , Depressão/complicações , Depressão/genética , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/genética
3.
Zh Nevrol Psikhiatr Im S S Korsakova ; 121(5. Vyp. 2): 61-66, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34405659

RESUMO

Recent findings in candidate genes for depression showed significant replication failures and thus appeared irrelevant. Much of the earlier studies' limitations can be overcome by the strategy of genome-wide association studies (GWAS), which aims to identify associations between different genomic variants and phenotypic traits without pathophysiological hypotheses application. With the use of such studies, it seems possible to calculate polygenic risk scores (PRS) as a promising approach for predicting depression risk. The aim of this review is to analyze modern approaches of genetic research used to assess the risk of depression in a population.


Assuntos
Depressão , Estudo de Associação Genômica Ampla , Depressão/genética , Predisposição Genética para Doença , Humanos , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único
4.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445375

RESUMO

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.


Assuntos
Depressão/psicologia , Córtex Pré-Frontal/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/metabolismo , Técnicas de Silenciamento de Genes , Ácido Glutâmico/metabolismo , Elevação dos Membros Posteriores , Masculino , Camundongos , Serotonina/metabolismo , Natação
5.
Nutrients ; 13(8)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445045

RESUMO

In recent years, strong evidence has emerged that exposure to a maternal high-fat diet (HFD) provokes changes in the structure, function, and development of the offspring's brain and may induce several neurodevelopmental and psychiatric illnesses. The aims of this study were to evaluate the effects of a maternal HFD during pregnancy and lactation on depressive-like behavior and Cnr1 gene expression (encoding the CB1 receptor) in brain structures of rat offspring and to investigate the epigenetic mechanism involved in this gene expression. We found that a maternal HFD during pregnancy and lactation induced a depressive-like phenotype at postnatal days (PNDs) 28 and 63. We found that a maternal HFD decreased the Cnr1 mRNA levels in the prefrontal cortex with the increased levels of miR-212-5p and methylation of CpG islands at the Cnr1 promoter and reduced the level of Cnr1 gene expression in the dorsal striatum with an increased level of miR-154-3p in adolescent male offspring. A contrasting effect of a maternal HFD was observed in the hippocampus, where upregulation of Cnr1 gene expression was accompanied by a decrease of miR-154-3p (at PNDs 28 and 63) and miR-212-5p (at PND 63) expression and methylation of CpG islands at the Cnr1 promoter in male offspring. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several epigenetic mechanisms in the brains of rat offspring, which may be related to long-lasting alterations in the next generation and produce behavioral changes in offspring, including a depressive-like phenotype.


Assuntos
Depressão/genética , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Receptor CB1 de Canabinoide/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Epigênese Genética , Feminino , Expressão Gênica , Lactação/genética , Masculino , Gravidez , Ratos
6.
J Coll Physicians Surg Pak ; 31(8): 998-1000, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34320725

RESUMO

The aim of this study is to explore whether there is an association between the genotype of serotonin-transporter-linked polymorphic region (5-HTTLPR) and migraine combined with depression. One hundred and sixteen patients with migraine and depressive disorder (Group A) and 116 patients with simple migraine (Group B) admitted in Mental Health Center, Zhejiang University School of Medicine, China, from January 2018 to April 2020 were included in the present study. Polymerase chain reaction (PCR) and restriction fragment length polymorphism techniques were used for detection of 5-HTTLPR genotype. The 5-HTTLPR genotype and allele frequency between the two groups were compared. The results showed that there was no significant difference in 5-HTTLPR genotype (L/L, L/S and S/S) frequency and allele (S and L) frequency between Group A and Group B (p=0.794 and 0.491, respectively). In conclusion, 5-HTTLPR genotype might not be related to the onset of migraine combined with depression. Key Words: Migraine, Depressive disorder, Serotonin-transporter-linked polymorphic region (5-HTTLPR).


Assuntos
Transtornos de Enxaqueca , Serotonina , Alelos , China/epidemiologia , Depressão/epidemiologia , Depressão/genética , Genótipo , Humanos , Transtornos de Enxaqueca/genética , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
7.
Biochemistry (Mosc) ; 86(6): 693-703, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225592

RESUMO

Differential effect of the neonatal proinflammatory stress (NPS) on the development of neuroinflammation in the hippocampus and induction of the depressive-like behavior in juvenile and adult male and female rats was studied. NPS induction by bacterial lipopolysaccharide in the neonatal period upregulated expression of the Il6 and Tnf mRNAs accompanied by the development of depressive-like behavior in the adult male rats. NPS increased expression of the mRNAs for fractalkine and its receptor in the ventral hippocampus of the juvenile male rats, but did not affect expression of mRNAs for the proinflammatory cytokines and soluble form of fractalkine. NPS downregulated expression of fractalkine mRNA in the dorsal hippocampus of juvenile males. No significant effects of NPS were found in the female rats. Therefore, the NPS induces long-term changes in the expression of neuroinflammation-associated genes in different regions of the hippocampus, which ultimately leads to the induction of neuroinflammation and development of depressive-like behavior in male rats.


Assuntos
Quimiocina CX3CL1/genética , Depressão/etiologia , Hipocampo/metabolismo , Inflamação/metabolismo , Interleucina-6/genética , Fator de Necrose Tumoral alfa/genética , Animais , Animais Recém-Nascidos , Receptor 1 de Quimiocina CX3C/genética , Depressão/genética , Depressão/metabolismo , Depressão/fisiopatologia , Feminino , Regulação da Expressão Gênica , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/genética , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Caracteres Sexuais
8.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299230

RESUMO

The precise neural mechanisms underlying the pathogenesis of depression are largely unknown, though stress-induced brain inflammation and serotonergic plasticity are thought to be centrally involved. Moreover, we previously demonstrated that neuropeptide FF receptor 2 (NPFFR2) overexpression provokes depressive-like behaviors in mice. Here, we assess whether NPFFR2 is involved in priming of depressive-like behaviors and downregulation of serotonergic 1A receptor (5HT1AR) after lipopolysaccharide (LPS) treatment. The forced swimming test (FST) and sucrose preference test (SPT) were used to quantify depressive-like phenotypes in wild-type (WT) and NPFFR2-knockout (KO) mice. A single dose of LPS (i.p. 1 mg/kg) readily caused increases in toll-like receptor 4 and tumor necrosis factor-α along with decreases in 5-HT1AR mRNA in the ventral hippocampus of WT mice. Furthermore, LPS treatment of WT mice increased immobility time in FST and decreased sucrose preference in SPT. In contrast, none of these effects were observed in NPFFR2-KO mice. While WT mice injected with lentiviral 5-HT1AR shRNA in the ventral hippocampus displayed an unaltered response after LPS challenge, LPS-challenged NPFFR2-KO mice displayed a profound decrease in sucrose preference when pretreated with 5-HT1AR shRNA. Taken together, these results suggest that NPFFR2 modulates LPS-induced depressive-like behavioral phenotypes by downregulating 5HT1AR in the ventral hippocampus.


Assuntos
Depressão/genética , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Neuropeptídeos/genética , Animais , Comportamento Animal/fisiologia , Depressão/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/genética , Receptores de Neuropeptídeos/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
J Youth Adolesc ; 50(10): 2079-2095, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34259955

RESUMO

Ample evidence suggested that parental responsiveness, demandingness, and autonomy granting protect adolescents from depressive symptoms. However, what is less well understood is how parenting practices reduce the risk of depressive symptoms. This study tested the protective effects of parenting practices and inhibitory control on depressive symptoms, along with the mediating role of inhibitory control and the moderating role of the COMT gene in linking parenting practices to depressive symptoms. The study utilized cross-sectional data from a community sample of Chinese Han adolescents (N = 943, Mage = 15.25 years, SD = 0.70 years; 51.9% girls). Results showed that parental responsiveness and autonomy granting promoted higher inhibitory control, which in turn was associated with lower depressive symptoms. Further, the mediation effects were moderated by the COMT gene. For adolescents with ValVal homozygotes, both responsiveness and autonomy granting were related to higher levels of inhibitory control, which reduced risk for depressive symptoms, but the mediation effects were not observed among Met allele carriers. The mediating role of inhibitory control did not hold in the parental demandingness model. Findings support the cognitive theory that inhibitory control is a proximal factor linking parenting practices to depressive symptoms exclusively in ValVal homozygotes. These results also suggested that differentiating different dimensions of parenting practices may help to further clarify the processes by which parenting practices eventuate depressive symptoms.


Assuntos
Catecol O-Metiltransferase , Poder Familiar , Adolescente , Catecol O-Metiltransferase/genética , Criança , Educação Infantil , Estudos Transversais , Depressão/genética , Feminino , Humanos , Masculino
10.
Artigo em Inglês | MEDLINE | ID: mdl-34199135

RESUMO

The metabolism of bioamine in the central nervous system contributes to the development of addiction. We examined the roles of hostility and depression in the association between internet gaming disorder (IGD) and monoamine oxidase-A (MAOA) EcoRV polymorphism (rs1137070). A total of 69 adults with IGD and 138 without IGD were recruited through diagnostic interviewing. We evaluated participants for rs1137070, depression, and hostility. The participants with the TT genotype of rs1137070 had a higher odds ratio of 2.52 (1.37-4.64) for IGD compared with the C carriers. Expressive hostility behavior and hostility cognition mediated the association between rs1137070 and IGD. Indicating lower MAOA activity, the TT genotype predicted IGD and higher expressive hostility behavior and hostility cognition. Expressive hostility behavior and hostility cognition may underline the association between rs1137070 and IGD. Assessment of and intervention for hostility behavior and cognition should be provided to attenuate the risk of IGD, particularly in those with the TT genotype. Further brain imaging or neurobiological studies are required to elucidate the possible mechanism underlying the association between MAOA activity and IGD.


Assuntos
Comportamento Aditivo , Jogos de Vídeo , Adulto , Comportamento Aditivo/genética , Depressão/epidemiologia , Depressão/genética , Hostilidade , Humanos , Internet , Transtorno de Adição à Internet , Monoaminoxidase , Polimorfismo Genético
11.
J Affect Disord ; 292: 565-573, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34147969

RESUMO

BACKGROUND: The brain-gut-microbiota axis plays a crucial role in the bidirectional interactions between the brain and the gut. Soluble epoxide hydrolase (coded by the Ephx2 gene) plays an important role in inflammation, which has been implicated in stress-related depression. Ephx2 knock-out (KO) mice exposed to chronic social defeat stress (CSDS) did not show depression-like behaviors, indicating stress resilience. Here we examined whether the brain-gut-microbiota axis influences the resilience in Ephx2 KO mice. METHODS: Effects of fecal microbiota transplantation (FMT) from CSDS-susceptible (or control) mice in wild-type (WT) mice and Ephx2 KO mice treated with an antibiotic cocktail (ABX) were investigated. Behavioral, biochemical tests and 16S ribosome RNA analysis were performed. RESULTS: FMT from CSDS-susceptible mice produced anhedonia-like behavior in ABX-treated WT and Ephx2 KO mice. The 16S ribosome RNA analysis showed that Faecalibaculum rodentium (F. rodentium) may be responsible for the observed anhedonia-like behavior following FMT from CSDS-susceptible mice. Ingestion of F. rodentium for 14 days produced depression- and anhedonia-like behaviors, higher blood levels of interleukin-6, and reduced expression of synaptic proteins in the prefrontal cortex of ABX-treated Ephx2 KO mice. Furthermore, subdiaphragmatic vagotomy blocked the development of these behavioral abnormalities after ingestion of F. rodentium. LIMITATIONS: Detailed mechanisms are unclear. CONCLUSIONS: These findings suggest that F. rodentium might contribute to the conversion of resilient Ephx2 KO mice into KO mice with depression-like phenotypes. The brain-gut-microbiota axis via the subdiaphragmatic vagus nerve plays a crucial role in susceptibility and resilience to stress.


Assuntos
Depressão , Microbioma Gastrointestinal , Animais , Encéfalo , Depressão/genética , Ingestão de Alimentos , Epóxido Hidrolases , Firmicutes , Microbioma Gastrointestinal/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Estresse Psicológico , Nervo Vago
12.
J Psychiatr Res ; 140: 149-158, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118634

RESUMO

BACKGROUND: Maternal smoking during pregnancy (MSDP) has been reported to be associated with increased anxiety and depression behaviors in offspring. However, there is still scant evidence to support the link between MSDP and anxiety/depression. METHODS: Using the subjects from the UK Biobank cohort (n = 371,903-432,881). Logistic regression analyses were first conducted to test the correlation between MSDP and anxiety/depression in offspring. Second, genome-wide gene-environment interaction study (GWGEIS) analyses were conducted by PLINK, using MSDP as environmental factor. Genetic correlation analysis of anxiety/depression and smoking was conducted by the LDSC software using the published genome-wide association study (GWAS) summary data of four smoking traits (n = 337,334-1,232,091), anxiety (n = 31,880) and depression (n = 490,359). Finally, pathway enrichment analysis was carried out to detect the pathway involved in the development of offspring anxiety caused by the interaction of MSDP × SNPs. RESULTS: Observational analyses showed that anxiety and depression status in offspring were significantly associated with MSDP (all p < 0.0001). Further GWEGI analyses observed significant MSDP-gene interaction effects at UNC80 gene for anxiety (p = 9.09 × 10-9). LDSC did not detect significant genetic correlation between anxiety and smoking traits. Pathway analysis identified 19 significant pathways for anxiety, such as MANALO_HYPOXIA_UP (FDR = 5.50 × 10-4), REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS (FDR = 0.0304) and ONDER_CDH1_TARGETS_2_UP (FDR = 0.0371). CONCLUSION: Our study results suggested the important impact of MDSP on the risk of anxiety in offspring, partly attributing to environment-gene interactions effects.


Assuntos
Interação Gene-Ambiente , Efeitos Tardios da Exposição Pré-Natal , Ansiedade/epidemiologia , Ansiedade/genética , Bancos de Espécimes Biológicos , Proteínas de Transporte , Depressão/epidemiologia , Depressão/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar , Reino Unido/epidemiologia
13.
J Psychiatr Res ; 140: 221-227, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118640

RESUMO

OBJECTIVES: This study examined the moderation of an oxytocin receptor (OXTR) gene in the link between childhood adversity and depressive symptoms among incarcerated males. METHODS: Questionnaires about adverse childhood experiences and depressive symptoms, as well as genomic DNA from blood were collected among 608 incarcerated males (Mage = 32.4 years, SD = 9.41, 18-74 years). Moderation analysis was applied to examine the interaction between adverse childhood experiences (including abuse, neglect, and household dysfunction) and the OXTR polymorphisms (rs2254298, rs53576) in predicting depressive symptoms. RESULTS: Incarcerated males had relatively higher prevalence of childhood adversity (70.2%) and depressive symptoms (49.8%). Higher childhood adversity was associated with increased depressive symptoms, and the effect was more pronounced in the GG homozygotes of OXTR rs2254298 (b = 0.406, p < .001), as compared with the AA/AG carriers (b = 0.236, p < .001). By contrast, the OXTR rs53576 did not interact with childhood adversity in predicting depressive symptoms. CONCLUSIONS: Chinese incarcerated males with the GG genotype of OXTR rs2254298 have higher vulnerability in the effect of childhood adversity on depressive symptoms.


Assuntos
Experiências Adversas da Infância , Prisioneiros , Adulto , Criança , Depressão/epidemiologia , Depressão/genética , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptores de Ocitocina/genética
14.
Phytomedicine ; 88: 153598, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111615

RESUMO

INTRODUCTION: Depression is one of the leading causes of death worldwide. Lower antioxidant concentrations and increased oxidative stress levels contribute to the development of depression. Effective and tolerable medications are urgently needed. Nrf2 and PRDX2 are promising targets in the treatment of oxidative stress and, therefore, promising for the development of novel antidepressants. Ursolic acid (UA), a natural triterpenoid found in various plants is known to exert neuroprotective and antioxidant effects. Skn-1 (which corresponds to human Nrf2) and prdx2 deficient mutants of the nematode Caenorhabditis elegans are suitable models to study the effect of UA on these targets. Additionally, stress assays are used to mimic stress or depressed state. METHODS: We examined the antioxidant activity of UA in Caenorhabditis elegans wildtype and skn-1- and prdx2-deficient strains by H2DCF-DA and juglone assays as well as osmotic and heat stress assays. Additionally, we analyzed the binding of UA to human PRDX2 and Skn-1 proteins by molecular docking and microscale thermophoresis. RESULTS: UA exerted strong antioxidant activities. Additionally, induction of stress resistance towards osmotic and heat stress was observed. qRT-PCR revealed that UA upregulated the gene expression of skn-1 and prdx2. Molecular docking studies supported these findings. CONCLUSION: Our findings implicate that the strong antioxidant activity of UA may exert anti-depressive effects by its interaction with the Skn-1 transcription factor, which is part of a detoxification network, and the antioxidant PRDX2 protein, which protects the organism from the detrimental effects of radical oxygen species.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Depressão/genética , Estresse Fisiológico/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Simulação de Acoplamento Molecular , Mutação , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxinas/genética , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genética , Triterpenos/química
16.
ACS Chem Neurosci ; 12(12): 2151-2166, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34060807

RESUMO

Depression has drawn increasing attention from the public around the world in recent years. Studies have shown that liver injury caused by chronic stress is relevant to depression and neurotransmitter changes. It is essential to clarify the relationship between neurotransmitter changes and hepatic gene expression in depression. In this study, we used the chronic unpredictable mild stress (CUMS) model combined with UHPLC-MS to explore the changes of neurotransmitters in serum and hippocampus and to decipher the differential gene expression in the liver by using the RNA-Seq combined with multivariate statistical analysis. Compared with the control group, the levels of neurotransmitters including 5-hydroxytryptamine (5-HT), acetylcholine, glutamate (Glu), and dopamine (DA) in the hippocampus and 5-HT, norepinephrine, γ-aminobutyric acid (GABA), and 5-hydroxyindoleacetic acid in serum were significantly changed in the CUMS rats. The results of liver transcriptomic analysis and correlation analysis showed that the Glu, DA, 5-HT, and GABA were impacted by 68 liver genes which were mainly enriched in three pathways including circadian rhythm, serotonergic synapse, and p53 signaling pathway. The expressive levels of clock genes and serotonergic synapse genes were validated by using q-PCR, and the diurnal rhythms of neurotransmitters were validated by in vivo hippocampus microdialysis. The CUMS stressors might cause phase advance of Glu and GABA by adjusting clock genes. The transcriptomic technique combined with correlation analysis and in vivo microdialysis could be used to discover comprehensive pathways of depression. It provides a new strategy for the rational assessment of the mechanism of disease.


Assuntos
Ritmo Circadiano , Depressão , Animais , Ritmo Circadiano/genética , Depressão/genética , Modelos Animais de Doenças , Fígado , Neurotransmissores , Ratos , Estresse Psicológico , Transcriptoma
17.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062902

RESUMO

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1­adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D­ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D­AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Receptores Adrenérgicos alfa 1/genética , Animais , Antidepressivos/classificação , Citalopram/farmacologia , Depressão/etiologia , Depressão/genética , Depressão/patologia , Desipramina/farmacologia , Fluoxetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imipramina/farmacologia , Mianserina/farmacologia , Camundongos , Células PC12 , Ratos , Reboxetina/farmacologia , Transdução de Sinais/efeitos dos fármacos
18.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068557

RESUMO

Depression is a prominent complex psychiatric disorder, usually complicated through expression of comorbid conditions, with chronic pain being among the most prevalent. This comorbidity is consistently associated with a poor prognosis and has been shown to negatively impact patient outcomes. With a global rise in this condition presenting itself, the importance of discovering long-term, effective, and affordable treatments is crucial. Electroacupuncture has demonstrated renowned success in its use for the treatment of pain and is a widely recognized therapy in clinical practice for the treatment of various psychosomatic disorders, most notably depression. Our study aimed to investigate the effects and mechanisms of Acid-Saline (AS) inducing states of chronic pain and depression comorbidity in the cerebellum, using the ST36 acupoint as the therapeutic intervention. Furthermore, the role of TRPV1 was relatedly explored through the use of TRPV1-/- mice (KO). The results indicated significant differences in the four behavioral tests used to characterize pain and depression states in mice. The AS and AS + SHAM group showed significant differences when compared to the Control and AS + EA groups in the von Frey and Hargreaves's tests, as well as the Open-Field and Forced Swimming tests. This evidence was further substantiated in the protein levels observed in immunoblotting, with significant differences between the AS and AS + SHAM groups when compared to the AS + EA and AS + KO groups being identified. In addition, immunofluorescence visibly served to corroborate the quantitative outcomes. Conclusively these findings suggest that AS-induced chronic pain and depression comorbidity elicits changes in the cerebellum lobules VI, VII, VIII, which are ameliorated through the use of EA at ST36 via its action on TRPV1 and related molecular pathways. The action of TRPV1 is not singular in CPDC, which would suggest other potential targets such as acid-sensing ion channel subtype 3 (ASIC3) or voltage-gated sodium channels (Navs) that could be explored in future studies.


Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Dor Crônica/genética , Depressão/genética , Canais de Cátion TRPV/genética , Ácidos/toxicidade , Pontos de Acupuntura , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/efeitos da radiação , Dor Crônica/induzido quimicamente , Dor Crônica/complicações , Dor Crônica/terapia , Comorbidade , Depressão/complicações , Depressão/patologia , Modelos Animais de Doenças , Eletroacupuntura , Humanos , Camundongos , Camundongos Knockout , Solução Salina/toxicidade , Natação
19.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065586

RESUMO

Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors.


Assuntos
Depressão/genética , Epigênese Genética/genética , Histona Desacetilases/genética , Acetilação/efeitos dos fármacos , Animais , Epigenômica/métodos , Inibidores de Histona Desacetilases/farmacologia , Humanos
20.
Transl Psychiatry ; 11(1): 306, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021117

RESUMO

Depression is the most prevalent mental disorder with substantial morbidity and mortality. Although genome-wide association studies (GWASs) have identified multiple risk variants for depression, due to the complicated gene regulatory mechanisms and complexity of linkage disequilibrium (LD), the biological mechanisms by which the risk variants exert their effects on depression remain largely unknown. Here, we perform a transcriptome-wide association study (TWAS) of depression by integrating GWAS summary statistics from 807,553 individuals (246,363 depression cases and 561,190 controls) and summary-level gene-expression data (from the dorsolateral prefrontal cortex (DLPFC) of 1003 individuals). We identified 53 transcriptome-wide significant (TWS) risk genes for depression, of which 23 genes were not implicated in risk loci of the original GWAS. Seven out of 53 risk genes (B3GALTL, FADS1, TCTEX1D1, XPNPEP3, ZMAT2, ZNF501 and ZNF502) showed TWS associations with depression in two independent brain expression quantitative loci (eQTL) datasets, suggesting that these genes may represent promising candidates. We further conducted conditional analyses and identified the potential risk genes that driven the TWAS association signal in each locus. Finally, pathway enrichment analysis revealed biologically pathways relevant to depression. Our study identified new depression risk genes whose expression dysregulation may play a role in depression. More importantly, we translated the GWAS associations into risk genes and relevant pathways. Further mechanistic study and functional characterization of the TWS depression risk genes will facilitate the diagnostics and therapeutics for depression.


Assuntos
Estudo de Associação Genômica Ampla , Transcriptoma , Depressão/genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
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