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1.
J Transl Med ; 21(1): 71, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36732752

RESUMO

BACKGROUND: Patients suffering from chronic pain often also exhibit depression symptoms. Soluble epoxide hydrolase (sEH) inhibitors can decrease blood levels of inflammatory cytokines. However, whether inhibiting sEH signaling is beneficial for the comorbidity of pain and depression is unknown. METHODS: According to a sucrose preference test (SPT), spared nerve injury (SNI) mice were classified into pain with or without an anhedonia phenotype. Then, sEH protein expression and inflammatory cytokines were assessed in selected tissues. Furthermore, we used sEH inhibitor TPPU to determine the role of sEH in chronic pain and depression. Importantly, agonists and antagonists of aryl hydrocarbon receptor (AHR) and translocator protein (TSPO) were used to explore the pathogenesis of sEH signaling. RESULTS: In anhedonia-susceptible mice, the tissue levels of sEH were significantly increased in the medial prefrontal cortex (mPFC), hippocampus, spinal cord, liver, kidney, and gut. Importantly, serum CYP1A1 and inflammatory cytokines, such as interleukin 1ß (IL-1ß) and the tumor necrosis factor α (TNF-α), were increased simultaneously. TPPU improved the scores of mechanical withdrawal threshold (MWT) and SPT, and decreased the levels of serum CYP1A1 and inflammatory cytokines. AHR antagonist relieved the anhedonia behaviors but not the algesia behaviors in anhedonia-susceptible mice, whereas an AHR agonist abolished the antidepressant-like effect of TPPU. In addition, a TSPO agonist exerted a similar therapeutic effect to that of TPPU, whereas pretreatment with a TSPO antagonist abolished the antidepressant-like and analgesic effects of TPPU. CONCLUSIONS: sEH underlies the mechanisms of the comorbidity of chronic pain and depression and that TPPU exerts a beneficial effect on anhedonia behaviors in a pain model via AHR and TSPO signaling.

2.
Mol Psychiatry ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670198

RESUMO

Ketamine, a commonly used general anesthetic, can produce rapid and sustained antidepressant effect. However, the efficacy and safety of the perioperative application of ketamine on postoperative depression remains uncertain. We performed a meta-analysis to determine the effect of perioperative intravenous administration of ketamine on postoperative depression. Randomized controlled trials comparing ketamine with placebo in patients were included. Primary outcome was postoperative depression scores. Secondary outcomes included postoperative visual analog scale (VAS) scores for pain and adverse effects associated with ketamine. Fifteen studies with 1697 patients receiving ketamine and 1462 controls were enrolled. Compared with the controls, the ketamine group showed a reduction in postoperative depression scores, by a standardized mean difference (SMD) of -0.97, 95% confidence interval [CI, -1.27, -0.66], P < 0.001, I2 = 72% on postoperative day (POD) 1; SMD-0.65, 95% CI [-1.12, -0.17], P < 0.001, I2 = 94% on POD 3; SMD-0.30, 95% CI [-0.45, -0.14], P < 0.001, I2 = 0% on POD 7; and SMD-0.25, 95% CI [-0.38, -0.11], P < 0.001, I2 = 59% over the long term. Ketamine reduced VAS pain scores on POD 1 (SMD-0.93, 95% CI [-1.58, -0.29], P = 0.005, I2 = 97%), but no significant difference was found between the two groups on PODs 3 and 7 or over the long term. However, ketamine administration distinctly increased the risk of adverse effects, including nausea and vomiting (risk ratio [RR] 1.40, 95% CI [1.12, 1.75], P = 0.003, I2 = 30%), headache (RR 2.47, 95% CI [1.41, 4.32], P = 0.002, I2 = 19%), hallucination (RR 15.35, 95% CI [6.24, 37.34], P < 0.001, I2 = 89%), and dizziness (RR 3.48, 95% CI [2.68, 4.50], P < 0.001, I2 = 89%) compared with the controls. In conclusion, perioperative application of ketamine reduces postoperative depression and pain scores with increased risk of adverse effects.

3.
New Phytol ; 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36597715

RESUMO

Guard cells control the opening of stomatal pores in the leaf surface, with the use of a network of protein kinases and phosphatases. Loss of function of the CBL-interacting protein kinase 23 (CIPK23) was previously shown to decrease the stomatal conductance, but the molecular mechanisms underlying this response still need to be clarified. CIPK23 was specifically expressed in Arabidopsis guard cells, using an estrogen-inducible system. Stomatal movements were linked to changes in ion channel activity, determined with double-barreled intracellular electrodes in guard cells and with the two-electrode voltage clamp technique in Xenopus oocytes. Expression of the phosphomimetic variant CIPK23T190D enhanced stomatal opening, while the natural CIPK23 and a kinase-inactive CIPK23K60N variant did not affect stomatal movements. Overexpression of CIPK23T190D repressed the activity of S-type anion channels, while their steady-state activity was unchanged by CIPK23 and CIPK23K60N . We suggest that CIPK23 enhances the stomatal conductance at favorable growth conditions, via the regulation of several ion transport proteins in guard cells. The inhibition of SLAC1-type anion channels is an important facet of this response.

4.
Cell Rep Med ; 4(1): 100878, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36599350

RESUMO

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.


Assuntos
Antineoplásicos , Neoplasias , Animais , Camundongos , Interleucina-6 , Linfócitos T CD8-Positivos , Antineoplásicos/uso terapêutico , Imunoterapia
5.
Neuropharmacology ; 225: 109383, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36565851

RESUMO

Ketamine can produce rapid-acting antidepressant effects in treatment-resistant patients with depression. Although alterations in glutamatergic and GABAergic neurotransmission in the brain play a role in depression, the precise molecular mechanisms in these neurotransmission underlying ketamine's antidepressant actions remain largely unknown. Mice exposed to FSS (forced swimming stress) showed depression-like behavior and decreased levels of GABA (γ-aminobutyric acid), but not glutamate, in the hippocampus. Ketamine increased GABA levels and decreased glutamate levels in the hippocampus of mice exposed to FSS. There was a correlation between GABA levels and depression-like behavior. Furthermore, ketamine increased the levels of enzymes and transporters on the GABAergic neurons (SAT1, GAD67, GAD65, VGAT and GAT1) and astrocytes (EAAT2 and GAT3), without affecting the levels of enzymes and transporters (SAT2, VGluT1 and GABAAR γ2) on glutamatergic neurons. Moreover, ketamine caused a decreased expression of GABAAR α1 subunit, which was specifically expressed on GABAergic neurons and astrocytes, an increased GABA synthesis and metabolism in GABAergic neurons, a plasticity change in astrocytes, and an increase in ATP (adenosine triphosphate) contents. Finally, GABAAR antagonist bicuculline or ATP exerted a rapid antidepressant-like effect whereas pretreatment with GABAAR agonist muscimol blocked the antidepressant-like effects of ketamine. In addition, pharmacological activation and inhibition of GABAAR modulated the synthesis and metabolism of GABA, and the plasticity of astrocytes in the hippocampus. The present data suggest that ketamine could increase GABA synthesis and astrocyte plasticity through downregulation of GABAAR α1, increases in GABA, and conversion of GABA into ATP, resulting in a rapid-acting antidepressant-like action. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Ketamina , Receptores de GABA-A , Camundongos , Animais , Receptores de GABA-A/metabolismo , Ketamina/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/metabolismo , Hipocampo/metabolismo , Antagonistas GABAérgicos , Neurônios GABAérgicos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Depressão/tratamento farmacológico
6.
Neuropharmacology ; 222: 109305, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36354092

RESUMO

Depression is a well-known serious mental illness, and the onset of treatment using traditional antidepressants is frequently delayed by several weeks. Moreover, numerous patients with depression fail to respond to therapy. One major breakthrough in antidepressant therapy is that subanesthetic ketamine doses can rapidly alleviate depressive symptoms within hours of administering a single dose, even in treatment-resistant patients. However, specific mechanisms through which ketamine exerts its antidepressant effects remain elusive, leading to concerns regarding its rapid and long-lasting antidepressant effects. N-methyl-d-aspartate receptor (NMDAR) antagonists like ketamine are reportedly associated with serious side effects, such as dissociative symptoms, cognitive impairment, and abuse potential, limiting the large-scale clinical use of ketamine as an antidepressant. Herein, we reviewed the pharmacological properties of ketamine and the mechanisms of action underlying the rapid antidepressant efficacy, including the disinhibition hypothesis and synaptogenesis, along with common downstream effector pathways such as enhanced brain-derived neurotrophic factor and tropomyosin-related kinase B signaling, activation of the mechanistic target of rapamycin complex 1 and transforming growth factor ß1. We focused on evidence supporting the relevance of these potential mechanisms of ketamine and its metabolites in mediating the clinical efficacy of the drug. Given its reported antidepressant efficacy in preclinical studies and limited undesirable adverse effects, (R)-ketamine may be a safer, more controllable, rapid antidepressant. Overall, understanding the potential mechanisms of action of ketamine and its metabolites in combination with pharmacology may help develop a new generation of rapid antidepressants that maximize antidepressant effects while avoiding unfavorable adverse effects. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Disfunção Cognitiva , Ketamina , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Depressão , Psicoterapia , Transtornos Dissociativos
7.
Brain Behav Immun Health ; 27: 100573, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36583066

RESUMO

The spleen is a key immune-related organ that plays a role in communication between the brain and the immune system through the brain-spleen axis and brain-gut-microbiota axis. However, how the gut microbiota affects spleen and brain function remains unclear. Here, we investigated whether microbiome depletion induced by administration of an antibiotic cocktail (ABX) affects spleen and brain function. Treatment with ABX for 14 days resulted in a significant decrease in spleen weight and significant alterations in splenic functions, including the percentage of neutrophils, NK cells, macrophages, and CD8+ T cells. Furthermore, ABX treatment resulted in the depletion of a large portion of the gut microbiota. Untargeted metabolomics analysis showed that ABX treatment caused alterations in the levels of certain compounds in the plasma, spleen, and brain. Moreover, ABX treatment decreased the expression of microglia marker Iba1 in the cerebral cortex. Interestingly, correlations were found between the abundance of different microbiome components and metabolites in various tissues, as well as splenic cell populations and spleen weight. These findings suggest that ABX-induced microbiome depletion and altered metabolite levels may affect spleen and brain function through the gut-microbiota-spleen-brain axis.

8.
Pharmacol Biochem Behav ; 222: 173500, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36476377

RESUMO

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT2AR) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT2AR in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT2AR-related psychedelic effects. It is, therefore, unlikely that 5-HT2AR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed.


Assuntos
Alucinógenos , Ketamina , Camundongos , Animais , Alucinógenos/farmacologia , Lipopolissacarídeos/farmacologia , Lisurida , Ketamina/farmacologia , Serotonina , Antidepressivos/farmacologia , Depressão/tratamento farmacológico
9.
Neurobiol Dis ; 176: 105951, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36493975

RESUMO

Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut-microbiota-brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve.


Assuntos
Doenças Desmielinizantes , Microbiota , Esclerose Múltipla , Animais , Camundongos , Encéfalo/metabolismo , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Esclerose Múltipla/metabolismo , Nervo Vago/metabolismo
10.
J Stroke Cerebrovasc Dis ; 32(2): 106915, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36535133

RESUMO

OBJECTIVES: Large vessel occlusion (LVO)-related acute ischemic stroke due to infective endocarditis (IE) is a rare condition. At onset, most patients are severely ill, whereas on rare occasion, they develop mild neurological symptoms. As far as we are aware, this is the first report of IE related internal carotid artery (ICA) occlusion with low National Institutes of Health Stroke Scale (NIHSS) (<6) score treated with endovascular thrombectomy. CASE PRESENTATION: A 24-year-old woman had undergone dental treatment 3 weeks before and had a persistent low-grade fever for a week. She presented to the emergency department with a chief complaint of motor weakness of the right upper limb after waking up. She had only mild paralysis of the right upper limb (NIHSS score 1). Magnetic resonance imaging showed scattered infarcts in the left frontal lobe and cerebral angiography showed that the left ICA had been occluded immediately distal to its origin. The symptom disappeared after the occluded artery was completely recanalized by mechanical thrombectomy. On postoperative day 1, blood cultures were positive and echocardiography was performed, which revealed a verrucous mitral valve and a diagnosis of IE. On postoperative day 2, the patient underwent cardiac surgery for valve replacement. Thereafter, there was no recurrence of cerebral infarction, and the patient was discharged home on day 50 with a modified Rankin Scale 0. CONCLUSIONS: Early endovascular thrombectomy for low NIHSS score LVO due to IE resulted in a good treatment course. IE should be part of the differential diagnosis of LVO in the young patients.


Assuntos
Arteriopatias Oclusivas , Isquemia Encefálica , Endocardite , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Feminino , Humanos , Adulto Jovem , Adulto , Acidente Vascular Cerebral/etiologia , AVC Isquêmico/complicações , Resultado do Tratamento , Trombectomia/efeitos adversos , Arteriopatias Oclusivas/complicações , Endocardite/complicações , Estudos Retrospectivos , Isquemia Encefálica/complicações , Procedimentos Endovasculares/efeitos adversos
11.
Psychiatry Res ; 320: 115020, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36571897

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA), the most widely used illicit compound worldwide, is the most attractive therapeutic drug for post-traumatic stress disorder (PTSD). Recent observational studies of US adults demonstrated that lifetime MDMA use was associated with lower risk of depression. Here, we examined whether repeated administration of MDMA can affect resilience versus susceptibility in mice exposed to chronic social defeat stress (CSDS). CSDS produced splenomegaly, anhedonia-like phenotype, and higher plasma levels of interleukin-6 (IL-6) in the saline-treated mice. In contrast, CSDS did not cause these changes in the MDMA-treated mice. Analysis of gut microbiome found several microbes altered between saline + CSDS group and MDMA + CSDS group. Untargeted metabolomics analysis showed that plasma levels of N-epsilon-methyl-L-lysine in the saline + CSDS group were significantly higher than those in the control and MDMA + CSDS groups. Interestingly, there were positive correlations between plasma IL-6 levels and the abundance of several microbes (or plasma N-epsilon-methyl-L-lysine) in the three groups. Furthermore, there were also positive correlations between the abundance of several microbes and N-epsilon-methyl-L-lysine in the three groups. In conclusion, these data suggest that repeated administration of MDMA might contribute to stress resilience in mice subjected to CSDS through gut-microbiota-brain axis.

12.
JAMA Netw Open ; 5(12): e2244514, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36454569

RESUMO

Importance: Postoperative sleep disturbance (PSD) is common in patients after surgery. Objective: To examine the effect of intraoperative esketamine infusion on the incidence of PSD in patients who underwent gynecological laparoscopic surgery. Design, Setting, and Participants: This single-center, double-blind, placebo-controlled randomized clinical trial was conducted from August 2021 to April 2022 in the First Affiliated Hospital of Zhengzhou University in China. Participants included patients aged 18 to 65 years with an American Society of Anesthesiologist Physical Status classification of I to III (with I indicating a healthy patient, II a patient with mild systemic disease, and III a patient with severe systemic disease) who underwent gynecological laparoscopic surgery. Patients were randomly assigned to either the esketamine group or control group. Data were analyzed using the per protocol principle. Interventions: Patients in the esketamine group received a continuous infusion of esketamine, 0.3 mg/kg/h, intraoperatively. Patients in the control group received an equivalent volume of saline. Main Outcomes and Measures: The primary outcome was the incidence of PSD on postoperative days (PODs) 1 and 3. Postoperative sleep disturbance was defined as a numeric rating scale score of 6 or higher or an Athens Insomnia Scale score of 6 points or higher. The secondary outcomes included postoperative anxiety and depression scores using the Hospital Anxiety and Depression Scale, postoperative pain using the visual analog scale, postoperative hydromorphone consumption, and risk factors associated with PSD. Results: A total of 183 female patients were randomized to the control group (n = 91; median [IQR] age, 45 [35-49] years) and the esketamine group (n = 92; median [IQR] age, 43 [32-49] years). The incidence of PSD in the esketamine group was significantly lower than in the control group on POD 1 (22.8% vs 44.0%; odds ratio [OR], 0.38 [95% CI, 0.20-0.72]; P = .002) and POD 3 (7.6% vs 19.8%; OR, 0.33 [95% CI, 0.13-0.84]; P = .02). There were no differences in postoperative depression and anxiety scores between the 2 groups. Postoperative hydromorphone consumption in the first 24 hours (3.0 [range, 2.8-3.3] mg vs 3.2 [range, 2.9-3.4] mg; P = .04) and pain scores on movement (3 [3-4] vs 4 [3-5] points; P < .001) were significantly lower in the esketamine group than in the control group. On multivariable logistic regression, preoperative depression (OR, 1.31; 95% CI, 1.01-1.70) and anxiety (OR, 1.67; 95% CI, 1.04-1.80) scores, duration of anesthesia (OR, 1.04; 95% CI, 1.00-1.08), and postoperative pain score (OR, 1.92; 95% CI, 1.24-2.96) were identified as risk factors associated with PSD. Conclusions and Relevance: Results of this trial showed the prophylactic effect of intraoperative esketamine infusion on the incidence of PSD in patients who underwent gynecological laparoscopic surgery. Further studies are needed to confirm these results. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100048587.


Assuntos
Laparoscopia , Transtornos do Sono-Vigília , Humanos , Feminino , Pessoa de Meia-Idade , Adulto , Hidromorfona , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia , Laparoscopia/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Sono
13.
Genes Cells ; 2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36527312

RESUMO

We recently identified walbRep, a satellite DNA residing in the genome of the red-necked wallaby Notamacropus rufogriseus. It originates from the walb endogenous retrovirus and is organized in a manner in which the provirus structure is retained. The walbRep repeat units feature an average pairwise nucleotide identity as high as 99.5%, raising the possibility of a recent origin. The tammar wallaby N. eugenii is a species estimated to have diverged from the red-necked wallaby 2-3 million years ago. In PCR analyses of these two and other related species, walbRep-specific fragment amplification was observed only in the red-necked wallaby. Sequence database searches for the tammar wallaby resulted in sequence alignment lists that were sufficiently powerful to exclude the possibility of walbRep existence. These results suggested that the walbRep formation occurred in the red-necked wallaby lineage after its divergence from the tammar wallaby lineage, thus in a time span of maximum 3 million years.

14.
Mol Neurobiol ; 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36414910

RESUMO

Schizophrenia presents clinical and biological differences between males and females. This study investigated transcriptional profiles in the dorsolateral prefrontal cortex (DLPFC) using postmortem data from the largest RNA-sequencing (RNA-seq) database on schizophrenic cases and controls. Data for 154 male and 113 female controls and 160 male and 93 female schizophrenic cases were obtained from the CommonMind Consortium. In the RNA-seq database, the principal component analysis showed that sex effects were small in schizophrenia. After we analyzed the impact of sex-specific differences on gene expression, the female group showed more significantly changed genes compared with the male group. Based on the gene ontology analysis, the female sex-specific genes that changed were overrepresented in the mitochondrion, ATP (phosphocreatine and adenosine triphosphate)-, and metal ion-binding relevant biological processes. An ingenuity pathway analysis revealed that the differentially expressed genes related to schizophrenia in the female group were involved in midbrain dopaminergic and γ-aminobutyric acid (GABA)-ergic neurons and microglia. We used methylated DNA-binding domain-sequencing analyses and microarray to investigate the DNA methylation that potentially impacts the sex differences in gene transcription using a maternal immune activation (MIA) murine model. Among the sex-specific positional genes related to schizophrenia in the PFC of female offspring from MIA, the changes in the methylation and transcriptional expression of loci ACSBG1 were validated in the females with schizophrenia in independent postmortem samples by real-time PCR and pyrosequencing. Our results reveal potential genetic risks in the DLPFC for the sex-dependent prevalence and symptomology of schizophrenia.

15.
Front Plant Sci ; 13: 978586, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36311083

RESUMO

Plant respiratory burst oxidase homologs (RBOHs) are plasma membrane-localized NADPH oxidases that generate superoxide anion radicals, which then dismutate to H2O2, into the apoplast using cytoplasmic NADPH as an electron donor. PaRBOH1 is the most highly expressed RBOH gene in developing xylem as well as in a lignin-forming cell culture of Norway spruce (Picea abies L. Karst.). Since no previous information about regulation of gymnosperm RBOHs exist, our aim was to resolve how PaRBOH1 is regulated with a focus on phosphorylation. The N-terminal part of PaRBOH1 was found to contain several putative phosphorylation sites and a four-times repeated motif with similarities to the Botrytis-induced kinase 1 target site in Arabidopsis AtRBOHD. Phosphorylation was indicated for six of the sites in in vitro kinase assays using 15 amino-acid-long peptides for each of the predicted phosphotarget site in the presence of protein extracts of developing xylem. Serine and threonine residues showing positive response in the peptide assays were individually mutated to alanine (kinase-inactive) or to aspartate (phosphomimic), and the wild type PaRBOH1 and the mutated constructs transfected to human kidney embryogenic (HEK293T) cells with a low endogenous level of extracellular ROS production. ROS-producing assays with HEK cells showed that Ca2+ and phosphorylation synergistically activate the enzyme and identified several serine and threonine residues that are likely to be phosphorylated including a novel phosphorylation site not characterized in other plant species. These were further investigated with a phosphoproteomic study. Results of Norway spruce, the first gymnosperm species studied in relation to RBOH regulation, show that regulation of RBOH activity is conserved among seed plants.

16.
Biomolecules ; 12(10)2022 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-36291673

RESUMO

Brain-derived neurotrophic factor (BDNF), as the most widely distributed and widely studied neurotrophic factor in the mammalian brain, plays a key role in depression and the mechanisms of action for antidepressants. Currently, there is a large number of studies on the role of BDNF in the pathogenesis and therapeutic mechanism of depression. The quantity and quality of these studies, however, are unknown. To give beginners a quicker introduction to this research topic, we therefore performed a bibliometric analysis. A total of 5300 publications were included. We obtained the publications on this topic from the Web of Science database, and a variety of bibliographic elements were collected, including annual publications, authors, countries/regions, institutions, journals, and keywords. Moreover, we found that oxidative stress and neuroinflammation are the hotspots in the field in very recent years. Collectively, this study provides a comprehensive summary and analysis on the role of BDNF in depression and its treatment and offers meaningful values for beginners on this topic.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Depressão , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Bibliometria , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Estresse Oxidativo , Mamíferos/metabolismo
17.
Clin Cardiol ; 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36300885

RESUMO

BACKGROUND: Early detection of atrial fibrillation (AF) is important. Japan has a universal screening system, and regular health screening (HS) is available to support AF detection without a hospital visit. However, health-related outcomes and other characteristics of HS-detected and conventionally diagnosed AF remain unknown. HYPOTHESIS: That the characteristics and health-related outcomes of patients with HS-detected AF may differ from those of patients whose AF was detected by other procedures. METHODS: In total, 3318 consecutive newly referred AF cases were enrolled; demographic characteristics and health-related and clinical outcomes were compared between two groups created based on the mode of AF detection (the HS and non-HS groups). Health-related outcomes were assessed using the AF Effect on QualiTy-of-life (AFEQT) questionnaire at baseline and after 1 year of follow-up. RESULTS: AF was detected by HS in 25.0% of patients; these patients had lower CHADS2 scores (1.01 vs. 1.50, p < .001), higher prevalence of persistent AF (odds ratio, 95% confidence interval; 2.21, 1.88-2.60) and asymptomatic presentation (3.19, 2.71-3.76), and better baseline QoL scores (83.6 vs. 75.0; p < .001). Catheter ablation was more frequently performed in the HS group at follow-up (44.4% vs. 34.1%; p < .001). At 1-year follow-up, the AFEQT scores of the HS group were significantly better in most subdomains. CONCLUSIONS: In the Japanese registry, AF was detected via HS in 25% of patients referred to specialty centers for management. Notably, the overall health status of patients with HS-detected AF improved after medical interventions, including catheter ablations.

18.
Neuropharmacology ; 219: 109250, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36088985

RESUMO

MicroRNAs (or miRNAs) are short, regulatory RNAs that act as post-transcriptional repressors of gene expression. Recently, we reported that the nuclear factor of activated T cells 4 (NFATc4) signaling might contribute to sustained prophylactic effects of new antidepressant (R)-ketamine in lipopolysaccharide (LPS)-treated inflammation model of depression. In this study, we examined the role of miRNAs (miR-149 and miR-7688-5p) which can regulate NFATc4 in the prefrontal cortex (PFC) of male mice after administration of LPS (1.0 mg/kg). There was a positive correlation between the expression of Nfatc4 and the expression of miR-149 in the PFC. There was also a negative correlation between gene expression of Nfatc4 and gene expression of miR-7688-5p in the PFC. Gut microbiota analysis showed that pretreatment with (R)-ketamine (10 mg/kg) could restore altered composition of gut microbiota in LPS-treated mice. A network analysis showed that gut microbiota may regulate gene expression of Nfatc4 and miR-149 (or miR-7688-5p) in the PFC. Finally, inhibition of miR-149 by antagomiR-149 blocked LPS-induced depression-like behavior by attenuating LPS-induced expression of NFATc4 in the PFC. These findings suggest that the regulation of NFATc4 signaling by miR-149 might play a role in persistent prophylactic effects of (R)-ketamine, and that gut microbiota may regulate the gene expression of miRNAs in the PFC through gut-microbiota-brain axis.


Assuntos
Ketamina , MicroRNAs , Animais , Antagomirs/metabolismo , Antagomirs/farmacologia , Antidepressivos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ketamina/metabolismo , Ketamina/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Córtex Pré-Frontal
19.
Mol Clin Oncol ; 17(4): 144, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36157321

RESUMO

Duodenal gastrointestinal stromal tumors (D-GISTs) are a rare and relatively small subset of GISTs whose imaging features are not well known. The present study aimed to evaluate the enhancement pattern of D-GISTs compared with that of gastric GISTs (G-GISTs) using dynamic computed tomography. This single-center, retrospective, clinicopathological analysis was conducted on 10 patients with D-GISTs who underwent surgery between June 2006 and October 2018. In the same period, 25 patients with G-GISTs underwent surgery and were enrolled. The contrast ratio was defined as the ratio between Hounsfield units in contrast enhanced and unenhanced images in different phases, and these ratios were compared between the D-GIST and G-GIST groups. Furthermore, microvessel density, analyzed by immunohistochemical staining for CD31, was compared between the D-GIST and G-GIST groups. The contrast ratio of D-GIST was significantly higher than that of G-GIST in the arterial, portal and delayed phases (P<0.01, P<0.01 and P=0.02, respectively). The microvessel density of the D-GISTs was significantly higher than that of the G-GISTs (P<0.0001). D-GISTs were more hypervascular than G-GISTs on both imaging and pathological analyses.

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