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1.
Cardiology ; 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596284

RESUMO

INTRODUCTION: Data on first-line ablation treatment for patients with symptomatic atrial fibrillation (AF) are scarce. This study indirectly compared the efficacy and safety of cryoballoon ablation (CBA) vs. radiofrequency ablation (RFA) as initial therapy for symptomatic AF. METHODS: We searched the EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov databases for randomized controlled trials (RCTs) that compared CBA or RFA with antiarrhythmic drugs (AADs) as first-line treatment for AF from the time of database establishment up to December 2021. The odds ratio (OR) with a 95% confidence interval (CI) was used as a measure of the treatment effect. RESULTS: Six RCTs (3 CBA, 3 RFA) that enrolled a total of 1215 patients were included in this analysis. There were no significant differences in atrial arrhythmia (AA) (OR 0.993, 95% CI 0.602-1.638), symptomatic AA (OR 0.638, 95% CI 0.344-1.182), or serious adverse events (OR 1.474, 95% CI, 0.404-5.376) between the two ablation techniques. The incidences of additional CBA therapy (OR 2.693, 95% CI 1.277-5.681) and patients who crossed over to AAD therapy (OR 0.345 95% CI 0.179-0.664) in the CBA group were significantly lower than that in the RFA group. CONCLUSION: Among patients with paroxysmal AF receiving initial therapy, CBA and RFA share a similar efficacy and safety profile. When pulmonary vein isolation is performed by CBA, study crossover and the need for additional ablation are substantially lower.

2.
Psychiatry Res Neuroimaging ; 328: 111578, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36525761

RESUMO

BACKGROUND: Insomnia is one of the major symptom relevant factors in major depressive disorder (MDD), but the neurological mechanisms underlying the multiple effect between insomnia and depression have not been well interpreted. This study aimed at exploring the potential mechanisms between insomnia and depression based on amygdala-based resting-state functional connectivity (RSFC). METHODS: In total 56 MDD patients with low insomnia (MDD-LI) patients, 46 MDD patients with high insomnia (MDD-HI) patients, and 57 healthy controls (HCs) were employed and underwent a resting-state functional magnetic resonance imaging (fMRI) scan. ANOVA test was performed on RSFC value for three groups. Correlation analysis was conducted to evaluate the relationship between abnormal RSFC values and clinical features. RESULTS: We found that MDD-HI mainly showed increased RSFC in (bilateral superior temporal gyrus (STG), and decreased RSFC in left supplementary motor area (SMA) and bilateral postcentral gyrus (PoCG) compared with MDD-LI. Correlation analysis indicated that RSFC of the bilateral amygdala with STG were positively associated with the sleep disturbance score and adjust HAMD score. CONCLUSION: Our findings suggest that RSFC in temporal lobe and other specifically activated regions may be associated with neural circuits involved with insomnia in MDD. These provide new evidence for understanding the potential mechanisms of major depression and insomnia from the perspective of functional connectivity.


Assuntos
Transtorno Depressivo Maior , Distúrbios do Início e da Manutenção do Sono , Humanos , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/patologia , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/diagnóstico por imagem , Tonsila do Cerebelo , Lobo Temporal , Imageamento por Ressonância Magnética
3.
Bioorg Chem ; 131: 106150, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36508940

RESUMO

Gliotoxin is a representative compound of the epipolythiodioxopiperazine (ETP) class of fungal metabolites. Histone Lysine Specific Demethylase 1 (LSD1) is highly expressed in a variety of cancers. Herein, a series of 6-heterocyclic carboxylic ester derivatives of gliotoxin was designed and synthesized as new LSD1 inhibitors and their biological evaluations in human gastric MGC-803 and HGC-27 cells were carried out. All of the derivatives effectively suppressed the enzymatic activities of LSD1. In particular, compound 4e exhibited excellent LSD1 inhibition with IC50 = 62.40 nM, as well as anti-proliferation against MGC-803 and HGC-27 cells with IC50 values of 0.31 µM and 0.29 µM, respectively. 4e also had a remarkable capacity to inhibit the colony formation, suppress migration and induce the apoptosis of these two cancer cell lines. In sum, our findings identified and characterized the 6-heterocyclic carboxylic ester derivatives of gliotoxin as potent and cellular active LSD1 inhibitors, which may provide a novel chemotype of LSD1 inhibitors for gastric cancer treatment.


Assuntos
Antineoplásicos , Gliotoxina , Neoplasias Gástricas , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Gliotoxina/farmacologia , Gliotoxina/uso terapêutico , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Proliferação de Células , Histona Desmetilases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
5.
Front Aging Neurosci ; 14: 1029533, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389078

RESUMO

Astrocytic Ca2+ transients are essential for astrocyte integration into neural circuits. These Ca2+ transients are primarily sequestered in subcellular domains, including primary branches, branchlets and leaflets, and endfeet. In previous studies, it suggests that aging causes functional defects in astrocytes. Until now, it was unclear whether and how aging affects astrocytic Ca2+ transients at subcellular domains. In this study, we combined a genetically encoded Ca2+ sensor (GCaMP6f) and in vivo two-photon Ca2+ imaging to determine changes in Ca2+ transients within astrocytic subcellular domains during brain aging. We showed that aging increased Ca2+ transients in astrocytic primary branches, higher-order branchlets, and terminal leaflets. However, Ca2+ transients decreased within astrocytic endfeet during brain aging, which could be caused by the decreased expressions of Aquaporin-4 (AQP4). In addition, aging-induced changes of Ca2+ transient types were heterogeneous within astrocytic subcellular domains. These results demonstrate that the astrocytic Ca2+ transients within subcellular domains are affected by aging differently. This finding contributes to a better understanding of the physiological role of astrocytes in aging-induced neural circuit degeneration.

7.
J Ethnopharmacol ; 303: 115879, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36370966

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, the lateral roots of Aconitum carmichaelii Debx, plays an irreplaceable role in treating Yang deficiency and cold coagulation syndromes. However, Fuzi has a narrow margin of safety since its pharmacological constituents, Aconitum alkaloids, have potential cardiotoxicity and neurotoxicity. The current quality markers (Q-markers) for the control of Fuzi's efficacy and toxicity are 3 monoester-diterpenoid alkaloids, namely, benzoylaconine (BAC), benzoylhypaconine and benzoylmesaconine (BMA) and 3 diester-diterpenoid alkaloids, namely, aconitine (AC), hypaconitine and mesaconitine (MA). However, mounting evidence indicates that the current 6 Q-markers may not be efficacy- or toxicity-specific enough for Fuzi. AIM OF THE STUDY: The aim of this study was to explore and evaluate efficacy- or toxicity-specific potential quality markers (PQ-markers) of Fuzi. MATERIALS AND METHODS: PQ-markers were explored by analyzing 30 medicinal samples and alkaloids exposed in mouse. Pharmacokinetics of PQ-markers on C57BL/6J mice were determined. Anti-inflammatory effects of PQ-markers were evaluated by λ-carrageenan-induced paw edema model and lipopolysaccharide-induced RAW264.7 cell inflammatory model, while analgesic effects were assessed by acetic acid-induced pain model and Hargreaves test. Cardiotoxicity and neurotoxicity of PQ-markers were assessed by histological and biochemical analyses, while acute toxicity was evaluated by modified Kirschner method. RESULTS: After in vitro and in vivo explorations, 7 PQ-markers, namely, neoline (NE), fuziline (FE), songorine (SE), 10-OH mesaconitine (10-OH MA), talatizamine, isotalatizidine and 16ß-OH cardiopetalline, were found. In the herbal medicines, NE, FE, SE and 10-OH MA were found in greater abundance than many other alkaloids. Specifically, the amounts of NE, FE and SE in the Fuzi samples were all far higher than that of BAC, and the contents of 10-OH MA in 56.67% of the samples were higher than that of AC. In mouse plasma and tissues, NE, FE, SE, talatizamine, isotalatizidine and 16ß-OH cardiopetalline had higher contents than the other alkaloids, including the 6 current Q-markers. The pharmacokinetics, efficacy and toxicity of NE, FE, SE and 10-OH MA were further evaluated. The average oral bioavailabilities of NE (63.82%), FE (18.14%) and SE (49.51%) were higher than that of BMA (3.05%). Additionally, NE, FE and SE produced dose-dependent anti-inflammatory and analgesic effects, and their actions were greater than those of BMA. Concurrently, the toxicities of NE, FE and SE were lower than those of BMA, since no cardiotoxicity or neurotoxicity was found in mice after NE, FE and SE treatment, while BMA treatment notably increased the creatine kinase activity and matrix metalloproteinase 9 level in mice. The average oral bioavailability of 10-OH MA (7.02%) was higher than that of MA (1.88%). The median lethal dose (LD50) of 10-OH MA in mice (0.11 mg/kg) after intravenous injection was close to that of MA (0.13 mg/kg). Moreover, 10-OH MA produced significant cardiotoxicity and neurotoxicity, and notable anti-inflammatory and analgesic effects that were comparable to those of MA. CONCLUSIONS: Seven PQ-markers of Fuzi were found after in vitro and in vivo explorations. Among them, NE, FE and SE were found to be more efficacy-specific than BMA, and 10-OH MA was as toxicity-specific as MA.

8.
J Vis Exp ; (188)2022 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-36342149

RESUMO

The aim of this study was to explore the use of hyperbaric oxygen to enhance the radiosensitivity of human glioma cells. Sub-cultured U251 human glioma cells were randomly divided into four groups: an untreated control group, cells treated with hyperbaric oxygen (HBO) only, cells treated with X-ray irradiation (X-ray) only, and cells treated with both HBO and X-ray. Cell morphology, cell proliferation activity, cell cycle distribution, and apoptosis were observed in these groups to evaluate the role of HBO in improving the radiosensitivity of glioma cells. With the increase in X-ray doses (0 Gy, 2 Gy, 4 Gy, 6 Gy, 8 Gy), the survival fraction (SF) of glioma cells gradually decreased. Significantly lower SF was observed for the cells treated with the HBO and X-ray together than in the X-ray group for each dose (all P < 0.05). The proliferation inhibition was significantly higher in the HBO combined with X-ray group than in the X-ray group for each dose (all P < 0.05) for the U251 cell line. The percentage of G2/M phase cells was significantly higher in the HBO combined with X-ray (2 Gy) group (26.70% ± 2.46%) and the HBO group (22.36% ± 0.91%) than in the control group (11.56% ± 2.01%) and X-ray (2 Gy) group (10.35% ± 2.69%) (all P < 0.05). U251 cell apoptosis was significantly higher in the HBO combined with X-ray (2 Gy) group than in the HBO group, the X-ray (2 Gy) group, and the control group (all P < 0.05). We conclude that HBO can enhance the proliferation inhibition and apoptosis of glioma U251 cells by blocking glioma cells in the G2/M phase and improve the radiosensitivity of U251 glioma cells.


Assuntos
Glioma , Oxigenoterapia Hiperbárica , Radiossensibilizantes , Humanos , Linhagem Celular Tumoral , Glioma/radioterapia , Glioma/metabolismo , Radiossensibilizantes/farmacologia , Tolerância a Radiação , Apoptose , Oxigênio
9.
ISA Trans ; 2022 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-36336476

RESUMO

Environmental adaptability and real-time control are significant to the actual application of biped robots. The current Spring-Loaded Inverted Pendulum (SLIP) walking exhibits the compliant interaction with environments. However, the movability and controllability of this model is limited owing to the lack of ankles. Moreover, complicated nonlinear optimization problems in gait generation bring difficulties to real-time control. To overcome these problems, this study proposes an online whole-stage gait planning method to enhance the bipedal walking performance. Firstly, considering the role of ankles, this study applies the proposed template model called Variable Spring-Loaded Inverted Pendulum with Finite-sized Foot (VSLIP-FF) model. Then a Finite State Machine (FSM)-based gait pattern including the corresponding bio-inspired gait strategies is established, which extends the single cyclic gait to the whole-stage gait. Secondly, to realize real-time gait planning, an online gait generator based on a neural network is applied to reduce the calculational burden. Finally, the method is applied on the simulation prototype and real robot platform for verification. Experimental results validate that the proposed method can achieve an autonomous gait with the online planning time of 0.01s, and the step length range is expanded by 37.52% compared with the traditional SLIP model.

10.
BMC Psychiatry ; 22(1): 744, 2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-36451150

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a high risk factor for suicide, with up to 20% of MDD patients attempting suicide during their lifetime. Current treatments for MDD are slow onset of action, low efficiency, and the inability to control suicidal behaviors quickly and effectively. Intravenous ketamine has been shown to have a rapid but transient antidepressant effect, but there is still lack evidence on the efficacy and safety of intravenous esketamine in reducing suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. We designed a study to investigate the effect of short-term repeated intravenous infusion of esketamine three times in MDD patients with suicidal ideation. METHODS: This study features a randomized, double-blind, placebo-controlled trial (RCT) comparing short-term repeated intravenous infusions of esketamine with placebo as a supplement to conventional antidepressants with an intervention period of 6 days and one infusion every other day, followed by 4 weeks of follow-up. These methods support the examination of the efficacy, safety, tolerability, and mechanism of action of short-term repeated intravenous infusions of esketamine in MDD patients with suicidal ideation. DISCUSSION: This is the first RCT to explore the efficacy and safety of short-term repeated infusion of esketamine on suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. If proven effective and tolerated, it will provide evidence for rapid and effective treatment of suicidal ideation and depressive symptoms in MDD individuals with suicidal ideation. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2000041232 . Registered 22 December 2020.


Assuntos
Transtorno Depressivo Maior , Ketamina , Suicídio , Humanos , Ideação Suicida , Ketamina/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Brain Behav Immun ; 108: 98-117, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36427810

RESUMO

Growing evidence suggests the involvement of the microbiota-gut-brain axis in cognitive impairment induced by sleep deprivation (SD), however how the microbiota-gut-brain axis work remains elusive. Here, we discovered that chronic SD induced intestinal dysbiosis, activated NLRP3 inflammasome in the colon and brain, destructed intestinal/blood-brain barrier, and impaired cognitive function in mice. Transplantation of "SD microbiota" could almost mimic the pathological and behavioral changes caused by chronic SD. Furthermore, all the behavioral and pathological abnormalities were practically reversed in chronic sleep-deprived NLRP3-/- mice. Regional knockdown NLRP3 expression in the gut and hippocampus, respectively. We observed that down-regulation of NLRP3 in the hippocampus inhibited neuroinflammation, and ameliorated synaptic dysfunction and cognitive impairment induced by chronic SD. More intriguingly, the down-regulation of NLRP3 in the gut protected the intestinal barrier, attenuated the levels of peripheral inflammatory factors, down-regulated the expression of NLRP3 in the brain, and improved cognitive function in chronic SD mice. Our results identified gut microbiota as a driver in chronic SD and highlighted the NLRP3 inflammasome as a key regulator within the microbiota-gut-brain axis.

12.
Neuron ; 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36272414

RESUMO

The hippocampal CA2 region plays a key role in social memory. The encoding of such memory involves afferent activity from the hypothalamic supramammillary nucleus (SuM) to CA2. However, the neuronal circuits required for consolidation of freshly encoded social memory remain unknown. Here, we used circuit-specific optical and single-cell electrophysiological recordings in mice to explore the role of sleep in social memory consolidation and its underlying circuit mechanism. We found that SuM neurons projecting to CA2 were highly active during rapid-eye-movement (REM) sleep but not during non-REM sleep or quiet wakefulness. REM-sleep-selective optogenetic silencing of these neurons impaired social memory. By contrast, the silencing of another group of REM sleep-active SuM neurons that projects to the dentate gyrus had no effect on social memory. Therefore, we provide causal evidence that the REM sleep-active hypothalamic neurons that project to CA2 are specifically required for the consolidation of social memory.

13.
Neuroimage Clin ; 36: 103230, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36274375

RESUMO

BACKGROUND: The default mode network (DMN) is implicated in the pathophysiology of major depressive disorder (MDD), and functional connectivity (FC) involved in DMN is suggested to be associated with antidepressant remission. The goal of this study is to recognize relationships between FC within DMN and early amelioration in MDD patients and to further test the capacity of FC to predict early efficacy. METHODS: In total 66 MDD patients and 57 healthy controls were recruited for resting-state functional magnetic resonance imaging scans at baseline. After four weeks of treatment with Escitalopram or Venlafaxine, patients were divided into subgroups with remitters (R, n = 31) and non-remitters (NR, n = 35). Independent component analysis (ICA) was used to compare intranetwork functional connectivity (intra-FC) in DMN between the three groups. RESULTS: Relative to NR-MDD group and HCs, the R-MDD group showed significantly higher intra-FC in the right angular gyrus of DMN, and the intra-FC was positively correlated with the reduction ratio of the depressive symptom scores. The ROC curve analysis revealed that intra-FC exhibited a high diagnostic value for remission. CONCLUSION: These findings indicated that intra-FC related to the DMN is a prognostic marker that can potentially predict early remission of symptoms after antidepressant treatment.

14.
Eur J Pharm Sci ; 179: 106303, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36252521

RESUMO

The bioavailability of most flavonoids is low but effective in vivo; however, the mechanism of the efficacy of flavonoids has not been elucidated. Kaempferol is typical flavonoids., preliminary research indicates that kaempferol has a significant anti-colon cancer and anti-inflammatory effect. We reported previously that the triple recycling pathways significantly increase the local bioavailability of flavonoids and prolong the residence time of flavonoids in the liver and intestines, which is likely the mode by which flavonoids exert local efficacy. Notably, Efflux transporters (ETs), such as Breast cancer resistance protein (BCRP) and Multi drug resistance-associated protein 2 (MRP2), are the main regulatory molecules of the enterohepatic triple recycling pathways. Thus, our current study explored the regulation of kaempferol by BCRP and MRP2 and the role of BCRP and MRP2 in the suppression of Dextran sulfate sodium (DSS)-induced colitis by kaempferol. Herein, four mouse model was constructed, and the Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was established to simultaneously quantify kaempferol and its 3 metabolites and investigate the oral pharmacokinetic characteristics and tissue distribution of these compounds. In Bcrp-/--Mrp2-/- mice, the movement of kaempferol via the enterohepatic triple recycling was blocked, and the preventative and therapeutic effects of this compound on acute colitis were inhibited. BCRP and MRP2 defects hindered the efflux of kaempferol and its phase II metabolites and increased the plasma levels. Our study revealed that the disposal of kaempferol was regulated by the ETs BCRP and MRP2, and most importantly, the results will help elucidate the mechanism by which kaempferol suppresses the transformation of colitis into colon cancer.


Assuntos
Colite , Neoplasias , Camundongos , Animais , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Quempferóis/farmacologia , Proteínas de Neoplasias/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Espectrometria de Massas em Tandem , Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Membrana Transportadoras , Colite/induzido quimicamente , Colite/tratamento farmacológico
15.
Nat Plants ; 8(10): 1160-1175, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36241731

RESUMO

Rapid production of H2O2 is a hallmark of plant responses to diverse pathogens and plays a crucial role in signalling downstream of various receptors that perceive immunogenic patterns. However, mechanisms by which plants sense H2O2 to regulate immunity remain poorly understood. We show that endogenous H2O2 generated upon immune activation is sensed by the thiol peroxidase PRXIIB via oxidation at Cys51, and this is essential for stomatal immunity against Pseudomonas syringae. We further show that in immune-stimulated cells, PRXIIB conjugates via Cys51 with the type 2C protein phosphatase ABA insensitive 2 (ABI2), subsequently transducing H2O2 signal to ABI2. This oxidation dramatically sensitizes H2O2-mediated inhibition of the ABI2 phosphatase activity in vitro and is required for stomatal immunity in plants. Together, our results illustrate a redox relay, with PRXIIB as a sensor for H2O2 and ABI2 as a target protein, that mediates reactive oxygen species signalling during plant immunity.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/metabolismo , Ácido Abscísico/metabolismo , Arabidopsis/metabolismo , Peróxido de Hidrogênio/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Peroxidase/metabolismo , Compostos de Sulfidrila/metabolismo , Imunidade Vegetal , Oxirredução , Peroxidases/metabolismo
16.
Front Neurosci ; 16: 956056, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36188452

RESUMO

Background: Ketamine, a robust antidepressant, has promising potential in the treatment of major depressive disorder (MDD). However, it does not work for all MDD patients, and the mechanism underlying its anti-depressive effects is unclear. Researchers have explored the mechanisms of ketamine action in MDD patients through MRI, a technique that measures brain activity intuitively. Notably, many MRI results were inconsistent because they selected different brain regions as seeds, particularly with respect to functional connectivity (FC) analysis. To eliminate the influence of prior seeds as much as possible, we used the significantly different results in degree centrality (DC) analysis as seeds to explore the FC changes in MDD patients to identify an imaging biomarker of ketamine's effect. Methods: Forty-four MDD patients and 45 healthy controls (HCs) were included in the study. Patients, aged 18-65, received six intravenous ketamine injections over 12 days. Depressive symptoms were estimated and MRI scans were performed at baseline and the day after the sixth infusion. We estimated FC differences between responders, non-responders and HCs using the region that showed significant differences between responders and non-responders in DC analysis as the seed. The correlation between the MADRS changes and zFC values was performed, and the potential of zFC values to be a neuroimaging biomarker was explored using the receiver operating characteristic curve. Result: Compared with non-responders, responders had significantly decreased DC values in the right middle frontal gyrus (MFG). In the analysis of FC using the region that showed significant differences in DC as a seed, there was a significant difference in the region of the right supplementary motor area (SMA) among responders, non-responders, and HCs. This region also overlapped with the bilateral median cingulate gyrus. In post hoc analysis, responders had higher FC than non-responders and HCs, and non-responders had lower FC than HCs. Importantly, the FC between the MFG and SMA (overlapping bilateral median cingulate gyrus) was correlated with the improvement of symptoms, which was estimated by the Mongomery-Asberg Depression Scale (MADRS). FC has the potential to be an imaging biomarker that can predict the ketamine effect in MDD patients according to the receiver operating characteristic curve analysis. Conclusion: Our results revealed that FC between the SMG and SMA and mACC was highly correlated with depressive symptoms and has the potential to be a neuroimaging biomarker to predict the effect of ketamine in MDD.

17.
Mediators Inflamm ; 2022: 1870579, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36133743

RESUMO

Osteoarthritis (OA), a chronic degenerative joint disease, always occurred in the aging population. There is evidence suggests that chondrocytes' survival, inflammation, and apoptosis play critical roles in OA pathogenesis. LMX1B has been shown to be involved in antiosteogenic function in early patterning of the calvaria. However, the role and mechanism of LMX1B in OA is not unknown. The present study observed that LMX1B was highly expressed in OA patients compared with normal patients. Besides, we found that IL-1ß increased LMX1B mRNA and protein expression in SW1353 and C28/I2 chondrocytes. LMX1B knockdown increased IL-1ß-induced cell viability and proliferation and suppressed cell apoptosis and inflammation response, including IFN-γ, TNF-α, IL-6, prostaglandin E2 (PGE2), and NO both in SW1353 and C28/I2. Furthermore, LMX1B silence inhibited MMP-3 and MMP-13 expression both in SW1353 and C28/I2 cells. Also, the activation of the NF-κB and NLRP3 signaling pathway was suppressed in LMX1B silence cells by decreasing the p-p65 and NLRP3 protein expressions. Additionally, inhibition of NF-κB by PDTC suppressed NLRP3 expression. Moreover, NLRP3 overexpression reversed the effects of LMX1B silence on chondrocytes' survival, proliferation, apoptosis, and inflammation. Finally, we confirmed that LMX1B depletion had protective effects in OA rats in vivo.


Assuntos
Condrócitos , Proteínas com Homeodomínio LIM/metabolismo , Osteoartrite , Fatores de Transcrição/metabolismo , Idoso , Animais , Apoptose/genética , Células Cultivadas , Dinoprostona/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteoartrite/metabolismo , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Nat Commun ; 13(1): 5522, 2022 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130931

RESUMO

'Turn-on' fluorescence probes for detecting H2O2 in cells are established, but equivalent tools to monitor the products of its reaction with protein cysteines have not been reported. Here we describe fluorogenic probes for detecting sulfenic acid, a redox modification inextricably linked to H2O2 signaling and oxidative stress. The reagents exhibit excellent cell permeability, rapid reactivity, and high selectivity with minimal cytotoxicity. We develop a high-throughput assay for measuring S-sulfenation in cells and use it to screen a curated kinase inhibitor library. We reveal a positive association between S-sulfenation and inhibition of TK, AGC, and CMGC kinase group members including GSK3, a promising target for neurological disorders. Proteomic mapping of GSK3 inhibitor-treated cells shows that S-sulfenation sites localize to the regulatory cysteines of antioxidant enzymes. Our studies highlight the ability of kinase inhibitors to modulate the cysteine sulfenome and should find broad application in the rapidly growing field of redox medicine.


Assuntos
Cisteína , Ácidos Sulfênicos , Antioxidantes/metabolismo , Cisteína/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Peróxido de Hidrogênio/metabolismo , Oxirredução , Proteômica
19.
J Affect Disord ; 319: 70-78, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36075401

RESUMO

OBJECTIVE: The resting-state functional magnetic resonance imaging (rs-fMRI) have been used to explore functional abnormality of the brain in MDD patients with suicidal ideation (SI). However, few studies reported the variability and concordance of alterations of rs-fMRI indices in MDD with SI. In this study, we aimed to explore the variability and concordance of alterations of rs-fMRI indices in MDD with SI. METHODS: A sliding window analysis was performed among 36 MDD patients with SI, 66 MDD patients without SI (NSI), and 50 healthy controls (HCs). Furthermore, the correlation between voxel-wise concordance and cognitive function was examined in the SI group. RESULTS: The SI group had a lower dynamics degree centrality (dDC) value than the NSI group in left inferior occipital gyrus, and a lower voxel mirrored homotopic connectivity (dVMHC) value than the NSI group in the right and left inferior occipital gyrus. The mean values of volume wise concordance of HCs group shown higher than SI group and NSI group. SI group revealed decreased voxel-wise concordance in right cerebellum, left fusiform gyrus, left lingual gyrus, right middle temporal gyrus, left postcentral gyrus, and right supplementary motor area compared to NSI group. Moreover, the voxel-wise concordance of left middle occipital gyrus was negatively correlated with verbal learning and memory and working memory in the SI group. LIMITATION: This is a cross-sectional analysis, limiting causal inferences. CONCLUSIONS: The abnormal voxel-wise concordance of left middle occipital gyrus could be useful in understanding the pathophysiology of MDD patients with SI.


Assuntos
Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Ideação Suicida , Estudos Transversais , Encéfalo/diagnóstico por imagem
20.
Front Neurosci ; 16: 937145, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35928017

RESUMO

Accumulating evidence indicates the presence of structural and functional abnormalities of the posterior cingulate cortex (PCC) in patients with major depressive disorder (MDD) with suicidal ideation (SI). Nevertheless, the subregional-level dynamic functional connectivity (dFC) of the PCC has not been investigated in MDD with SI. We therefore sought to investigate the presence of aberrant dFC variability in PCC subregions in MDD patients with SI. We analyzed resting-state functional magnetic resonance imaging (fMRI) data from 31 unmedicated MDD patients with SI (SI group), 56 unmedicated MDD patients without SI (NSI group), and 48 matched healthy control (HC) subjects. The sliding-window method was applied to characterize the whole-brain dFC of each PCC subregion [the ventral PCC (vPCC) and dorsal PCC (dPCC)]. In addition, we evaluated associations between clinical variables and the aberrant dFC variability of those brain regions showing significant between-group differences. Compared with HCS, the SI and the NSI groups exhibited higher dFC variability between the left dPCC and left fusiform gyrus and between the right vPCC and left inferior frontal gyrus (IFG). The SI group showed higher dFC variability between the left vPCC and left IFG than the NSI group. Furthermore, the dFC variability between the left vPCC and left IFG was positively correlated with Scale for Suicidal Ideation (SSI) score in patients with MDD (i.e., the SI and NSI groups). Our results indicate that aberrant dFC variability between the vPCC and IFG might provide a neural-network explanation for SI and may provide a potential target for future therapeutic interventions in MDD patients with SI.

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