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1.
Psychopharmacology (Berl) ; 240(9): 1947-1961, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37436491

ABSTRACT

RATIONALE: 18ß-glycyrrhetinic acid (18ß-GA) has been reported to have anti-inflammatory and neuroprotective effects. However, the therapeutic effect of 18ß-GA in Parkinson's disease (PD) has not been defined. OBJECTIVE: The current study aimed to evaluate the potential therapeutic effects of 18ß-GA in treating PD by mitigating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. RESULTS: The study showed that 18ß-GA has anti-inflammatory effects by upregulating TREM2 expression in BV2 cells, which correlates with the presence of NF-E2-related factor-2 (Nrf2). 18ß-GA reduced inflammation in BV2 cells treated with 1-methyl-4- phenylpyridinium (MPP+) by enhancing TREM2 expression, which promotes an anti-inflammatory microglial phenotype. Repeated administration of 18ß-GA in MPTP-treated mice led to therapeutic effects by enhancing TREM2 expression, resulting in the activation of anti-inflammatory microglia. Moreover, 18ß-GA attenuated the decrease in brain-derived neurotrophic factor (BDNF) levels in both MPP+-induced BV2 cells and MPTP-intoxicated mice, indicating the involvement of BDNF in the beneficial effects of 18ß-GA. CONCLUSIONS: It is probable that activating microglial anti-inflammatory response through TREM2 expression might serve as a novel therapeutic strategy for PD. Additionally, 18ß-GA seems to hold potential as a new therapeutic agent for PD.


Subject(s)
Neuroprotective Agents , Parkinson Disease , Mice , Animals , Microglia/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Anti-Inflammatory Agents/pharmacology , Parkinson Disease/drug therapy , Phenotype , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Mice, Inbred C57BL , Disease Models, Animal
2.
Front Physiol ; 14: 1132724, 2023.
Article in English | MEDLINE | ID: mdl-36846335

ABSTRACT

Objective: To describe the clinical spectrum of severe Chlamydia psittaci pneumonia in order to understand the disease better. Methods: Retrospective analysis was made on 31 patients with severe Chlamydia psittaci pneumonia diagnosed in ICU by next-generation sequencing of metagenome Metagenomic next-generation sequencing(mNGS) from January 2019-November 2022, including clinical characteristics, laboratory examination results, imaging characteristics, treatment, and prognosis. Results: We included 31 patients with severe Chlamydia psittaci pneumonia, 15 of whom had a history of virus exposure. There were 12 cases with multiple bacterial infections, and the common symptoms included fever (31/31,100%), dyspnea (31/31, 100%), cough (22/31, 71.0%), and myalgia (20/31, 64.5%). Laboratory data showed that white blood cells were average or slightly increased, but the levels of C-reactive protein and neutrophils were high. CT findings of the lung were consolidation (19/31, 61.3%) and pleural effusion (11/31, 35.5%). Only one lobe was involved in 11 patients (35.5%). Before diagnosis, 22 patients (71.0%) did not have atypical pathogens in their antimicrobial regimen. After diagnosis, 19 patients (61.3%) received single drug treatment, of which doxycycline or moxifloxacin were the most commonly used drugs. Among 31 patients, three died, nine improved, and nineteen were cured. Conclusion: The clinical manifestations of severe Chlamydia psittaci pneumonia are non-specific. The application of mNGS can improve the diagnostic accuracy of Chlamydia psittaci pneumonia, reduce the unnecessary use of antibiotics, and shorten the course of the disease. Doxycycline-based treatment is effective for severe chlamydia psittaci pneumonia, but it is necessary to understand the secondary bacterial infection and other complications in the course of the disease.

3.
Phytomedicine ; 132: 155332, 2023 Dec 30.
Article in English | MEDLINE | ID: mdl-38851983

ABSTRACT

BACKGROUND: Xiaoyaosan (XYS), a traditional Chinese medicine formulation, has been used in the treatment of depression. However, no studies have yet identified the active compounds responsible for its antidepressant effects in the brain. STUDY DESIGN: We investigated the antidepressants effects of XYS and identified 18ß-glycyrrhetinic acid (18ß-GA) as the primary compound present in the brain following XYS injection. Furthermore, we explored the molecular mechanisms underlying the antidepressant-like effects of both XYS and 18ß-GA. METHODS: To investigate the antidepressant-like effects of XYS and elucidate the associated molecular mechanisms, we employed various methodologies, including cell cultures, the chronic social defeat stress (CSDS) model, behavioral tests, immunoprecipitation, quantitative PCR (qPCR) assays, Western blotting assays, luciferase assays, chromatin immunoprecipitation (ChIP) assays, immunofluorescence staining, and dendritic spine analysis. RESULTS: We identified 18ß-GA as the primary compound in the brain following XYS injection. In vitro, 18ß-GA was found to bind with ERK (extracellular signal-regulated kinase), subsequently activating ERK kinase activity toward both c-Jun and cAMP response element binding protein (CREB). Moreover, 18ß-GA activated brain-derived neurotrophic factor (BDNF) transcription by stimulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2), c-Jun, and CREB, while also inhibiting methyl CpG binding protein 2 (MeCP2) both in vitro and in vivo. Chronic intraperitoneal (i.p.) administration of 18ß-GA exhibited prophylactic antidepressant-like effects in a CSDS model, primarily by activating BDNF transcription in the medial prefrontal cortex (mPFC). Interestingly, a single i.p. injection of 18ß-GA produced rapid and sustained antidepressant-like effects in CSDS-susceptible mice by engaging the BDNF-tropomyosin receptor kinase B (TrkB) signaling pathway in the mPFC. CONCLUSION: These findings suggest that the activation of BDNF transcription in the mPFC underlies the antidepressant-like effects of 18ß-GA, a key component of XYS in the brain.

4.
Transl Psychiatry ; 12(1): 459, 2022 Oct 31.
Article in English | MEDLINE | ID: mdl-36316319

ABSTRACT

The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1+ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.


Subject(s)
Depressive Disorder, Major , Microglia , Animals , Mice , Microglia/metabolism , NF-E2-Related Factor 2/genetics , Arginase/genetics , Arginase/metabolism , Depression/drug therapy , Depression/genetics , Depressive Disorder, Major/metabolism , Phenotype , Mice, Knockout , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Receptors, Immunologic/genetics
5.
Psychopharmacology (Berl) ; 239(9): 2921-2929, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35711008

ABSTRACT

RATIONALE: There is accumulating evidence to support the idea that brain-derived neurotrophic factor (BDNF) is involved in stress resilience. However, the precise molecular mechanisms underlying resilience in major depressive disorder (MDD) remain unknown. OBJECTIVE: The objective of this study was to explore the role of methyl CpG binding protein 2 (MeCP2) and the BDNF/tropomyosin-receptor-kinase B (TrkB) signaling pathway in the stress resilience to chronic social defeat stress (CSDS) in mice. RESULTS: We found that the overexpression of MeCP2 inhibited BDNF transcription, resulting in BDNF mRNA and protein downregulation in neuro-2a cells. The overexpression of MeCP2 increased S80-MeCP2 and decreased S421-MeCP2, BDNF, the ratio of S133-cyclic AMP response element binding protein (CREB)/CREB and p-TrkB/TrkB expression in neuro-2a cells. In addition, using the CSDS mouse model, we found that MeCP2 mRNA levels were decreased in the medial prefrontal cortex (mPFC) of resilient mice and increased in the hippocampus of susceptible mice. BDNF exon IV promoter and BDNF mRNA levels were decreased in the mPFC and hippocampus of susceptible mice. Finally, MeCP2 and S80-MeCP2 protein levels were increased in the mPFC and hippocampus of susceptible mice, whereas the protein expression of S421-MeCP2 and BDNF, the ratio of S133-CREB/CREB, and the levels of p-TrkB/TrkB were decreased in susceptible mice. CONCLUSIONS: These data suggest that the overexpression of MeCP2 inhibits BDNF transcription in neuro-2a cells. The inhibition of MeCP2 expression and activation of the BDNF/TrkB signaling pathway may confer stress resilience in CSDS mice.


Subject(s)
Brain-Derived Neurotrophic Factor , Depressive Disorder, Major , Methyl-CpG-Binding Protein 2 , Social Defeat , Animals , Brain-Derived Neurotrophic Factor/metabolism , Depressive Disorder, Major/metabolism , Hippocampus/metabolism , Methyl-CpG-Binding Protein 2/genetics , Methyl-CpG-Binding Protein 2/metabolism , Mice , RNA, Messenger/metabolism , Receptor, trkB/metabolism , Signal Transduction
6.
Acta Pharmacol Sin ; 43(4): 829-839, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34272506

ABSTRACT

Sulforaphane (SFN) is an organic isothiocyanate and an NF-E2-related factor-2 (Nrf2) inducer that exerts prophylactic effects on depression-like behavior in mice. However, the underlying mechanisms remain poorly understood. Brain-derived neurotrophic factor (BDNF), a neurotrophin, is widely accepted for its antidepressant effects and role in stress resilience. Here, we show that SFN confers stress resilience via BDNF upregulation and changes in abnormal dendritic spine morphology in stressed mice, which is accompanied by rectifying the irregular levels of inflammatory cytokines. Mechanistic studies demonstrated that SFN activated Nrf2 to promote BDNF transcription by binding to the exon I promoter, which is associated with increased Nrf2, and decreased methyl-CpG binding protein-2 (MeCP2), a transcriptional suppressor of BDNF, in BV2 microglial cells. Furthermore, SFN inhibited the pro-inflammatory phenotype and activated the anti-inflammatory phenotype of microglia, which was associated with increased Nrf2 and decreased MeCP2 expression in microglia of stressed mice. Hence, our findings support that Nrf2 induces BDNF transcription via upregulation of Nrf2 and downregulation of MeCP2 in microglia, which is associated with changes in the morphology of damaged dendritic spines in stressed mice. Meanwhile, the data presented here provide evidence for the application of SFN as a candidate for the prevention and intervention of depression.


Subject(s)
Brain-Derived Neurotrophic Factor , Microglia , Animals , Anti-Inflammatory Agents/pharmacology , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Isothiocyanates/pharmacology , Isothiocyanates/therapeutic use , Mice , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Sulfoxides
7.
Mol Psychiatry ; 27(3): 1618-1629, 2022 03.
Article in English | MEDLINE | ID: mdl-34819637

ABSTRACT

(R,S)-ketamine elicits rapid-acting and sustained antidepressant actions in treatment-resistant patients with depression. (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine in rodents; however, the precise molecular mechanisms underlying antidepressant actions of (R)-ketamine remain unknown. Using isobaric Tag for Relative and Absolute Quantification, we identified nuclear receptor-binding protein 1 (NRBP1) that could contribute to different antidepressant-like effects of the two enantiomers in chronic social defeat stress (CSDS) model. NRBP1 was localized in the microglia and neuron, not astrocyte, of mouse medial prefrontal cortex (mPFC). (R)-ketamine increased the expression of NRBP1, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element binding protein (p-CREB)/CREB ratio in primary microglia cultures thorough the extracellular signal-regulated kinase (ERK) activation. Furthermore, (R)-ketamine could activate BDNF transcription through activation of CREB as well as MeCP2 (methyl-CpG binding protein 2) suppression in microglia. Single intracerebroventricular (i.c.v.) injection of CREB-DNA/RNA heteroduplex oligonucleotides (CREB-HDO) or BDNF exon IV-HDO blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Moreover, microglial depletion by colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. In addition, inhibition of microglia by single i.c.v. injection of mannosylated clodronate liposomes (MCLs) significantly blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Finally, single i.c.v. injection of CREB-HDO, BDNF exon IV-HDO or MCLs blocked the beneficial effects of (R)-ketamine on the reduced dendritic spine density in the mPFC of CSDS susceptible mice. These data suggest a novel ERK-NRBP1-CREB-BDNF pathways in microglia underlying antidepressant-like effects of (R)-ketamine.


Subject(s)
Ketamine , Animals , Antidepressive Agents/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Depression/drug therapy , Depression/metabolism , Extracellular Signal-Regulated MAP Kinases , Humans , Ketamine/pharmacology , Ketamine/therapeutic use , Mice , Mice, Inbred C57BL , Microglia/metabolism , Receptors, Cytoplasmic and Nuclear , Stress, Psychological/drug therapy , Stress, Psychological/metabolism , Vesicular Transport Proteins
9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(4): 432-436, 2019 Apr 28.
Article in Chinese | MEDLINE | ID: mdl-31113920

ABSTRACT

OBJECTIVE: To analyze the clinical characteristics and drug resistance in patients with non-tuberculous mycobacteria (NTM) pulmonary disease in Changsha Central Hospital of Hunan Province in recent three years.
 Methods: The clinical data of 153 patients with NTM pulmonary disease, who were diagnosed in Changsha Central Hospital of Hunan Province from February 2014 to May 2017, were retrospectively analyzed. According to the concentration of drug sensitivity test, the patients were divided into a low concentration group and a high concentration group. The status of drug sensitivity and drug resistance were examined.
 Results: Among 153 patients, 79 patients (51.63%) were male, 74 patients (48.37%) were female. The mean ages were (60.27±19.46) years. The NTM pulmonary disease mainly occurred in the individuals with bronchiectasis, and the course of disease was long (mean 7.8 years). The clinical symptoms were not specific and mostly misdiagnosed as pulmonary tuberculosis (92.81%). Mycobacterium avium-intracellulare (56.21%) and mycobacterium chelonae-abscess (20.92%) were the majority. The drug-resistance rate of the first-line and second-line anti-tuberculosis drugs was high. The majority was resistant to more than eight drugs, 38.56% patients in the low concentration group were resistant to total drugs, and 25.49% patients in the high concentration group were resistant to total drugs.
 Conclusion: The NTM pulmonary disease is easily misdiagnosed, and the drug resistance rate is high. Identification of mycobacterium species and detection of drug sensitivity play an important role in clinical diagnosis and treatment.


Subject(s)
Mycobacterium Infections, Nontuberculous , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Nontuberculous Mycobacteria , Retrospective Studies
10.
J Cell Mol Med ; 20(11): 2064-2077, 2016 11.
Article in English | MEDLINE | ID: mdl-27306439

ABSTRACT

Interleukin (IL)-1ß plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. The production of IL-1ß is dependent upon caspase-1-containing multiprotein complexes called inflammasomes and IL-1R1/MyD88/NF-κB pathway. In this study, we explored whether a potential anti-fibrotic agent fluorofenidone (FD) exerts its anti-inflammatory and anti-fibrotic effects through suppressing activation of NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome and the IL-1ß/IL-1R1/MyD88/NF-κB pathway in vivo and in vitro. Male C57BL/6J mice were intratracheally injected with Bleomycin (BLM) or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with haemotoxylin and eosin and Masson's trichrome. Cytokines were measured by ELISA, and α-smooth muscle actin (α-SMA), fibronectin, collagen I, caspase-1, IL-1R1, MyD88 were measured by Western blot and/or RT-PCR. The human actue monocytic leukaemia cell line (THP-1) were incubated with monosodium urate (MSU), with or without FD pre-treatment. The expression of caspase-1, IL-1ß, NALP3, apoptosis-associated speck-like protein containing (ASC) and pro-caspase-1 were measured by Western blot, the reactive oxygen species (ROS) generation was detected using the Flow Cytometry, and the interaction of NALP3 inflammasome-associated molecules were measured by Co-immunoprecipitation. RLE-6TN (rat lung epithelial-T-antigen negative) cells were incubated with IL-1ß, with or without FD pre-treatment. The expression of nuclear protein p65 was measured by Western blot. Results showed that FD markedly reduced the expressions of IL-1ß, IL-6, monocyte chemotactic protein-1 (MCP-1), myeloperoxidase (MPO), α-SMA, fibronectin, collagen I, caspase-1, IL-1R1 and MyD88 in mice lung tissues. And FD inhibited MSU-induced the accumulation of ROS, blocked the interaction of NALP3 inflammasome-associated molecules, decreased the level of caspase-1 and IL-1ß in THP-1 cells. Besides, FD inhibited IL-1ß-induced the expression of nuclear protein p65. This study demonstrated that FD, attenuates BLM-induced pulmonary inflammation and fibrosis in mice via inhibiting the activation of NALP3 inflammasome and the IL-1ß/IL-1R1/MyD88/ NF-κB pathway.


Subject(s)
Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia/complications , Pneumonia/drug therapy , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , Pyridones/therapeutic use , Signal Transduction , Actins/metabolism , Animals , Bleomycin , Caspase 1/metabolism , Chemokine CCL2/metabolism , Collagen Type I/metabolism , Down-Regulation/drug effects , Fibronectins/metabolism , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lung/drug effects , Lung/metabolism , Lung/pathology , Male , Mice, Inbred C57BL , Myeloid Differentiation Factor 88 , NF-kappa B/metabolism , Peroxidase/metabolism , Pneumonia/chemically induced , Pneumonia/metabolism , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Pyridones/pharmacology , Reactive Oxygen Species/metabolism , Receptors, Interleukin/metabolism , Signal Transduction/drug effects , Uric Acid/pharmacology
11.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 40(12): 1327-32, 2015 Dec.
Article in Chinese | MEDLINE | ID: mdl-26739074

ABSTRACT

OBJECTIVE: To analyze the clinical characteristics of patients with bloodstream Acinetobacter baumannii infection in Intensive Care Unit (ICU).
 METHODS: Eighty-three ICU patients with bloodstream Acinetobacter baumannii infection from January 2012 to March 2015 were retrospectively analyzed, including infection-related risk factors, drug-resistant bacteria, treatments and prognosis.
 RESULTS: Among 83 patients, 60 patients (72.29%) were male, 23 (27.71%) were female. The youngest patient was 40 days old, the oldest was 92 years old, the age was (46.23±19.22) years old. In total, there were 20 patients (24.10%) with plural bacterial infection in blood, 60 (72.29%) with more than 3 kinds of disorders, 52 patients suffered homologous bacterial infection in blood and other organs. Among these cases, lower respiratory tract had the highest percentage of homologous bacteria (29 cases), followed by catheter (11 cases), wound secretion (8 cases), cerebrospinal fluid (3 cases) and ascites (1 case). The risk factors of bloodstream infection by Acinetobacter baumannii included catheterization, serious primary disease and basic disease, usage of corticosteroids, surgery and invasive operation and so on. Acinetobacter baumannii were highly resistant. Most of them were multi-drug resistance, and some were pan-drug resistance. It showed more than 80% drug resistant rate to antibiotics except sulbactam, cefopcrazone and amikacin. Among 83 patients, 55 cases (66.26%) were dead, 25 cases (30.12%) were improved and 3 cases (3.62%) were cured.
 CONCLUSION: Acinetobacter baumannii are highly and multidrug-resistant to commonly used antibiotics. Patients in ICU suffering serious basic diseases should be shorten hospitalization time, restricted the use of breathing machine and immunosuppressant. It must carry out disinfection for invasive operation to reduce the risk of bloodstream infections, and the abuse of antibiotics must be avoided to slow bacteria resistance.


Subject(s)
Acinetobacter Infections/blood , Cross Infection/blood , Drug Resistance, Multiple, Bacterial , Intensive Care Units , Acinetobacter Infections/drug therapy , Acinetobacter baumannii/drug effects , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/pharmacology , Child , Child, Preschool , Cross Infection/drug therapy , Female , Humans , Infant , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Young Adult
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