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1.
J Proteomics ; : 104190, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33766670

RESUMO

Chronic stressors represented risk factors for the etiology or exacerbation of several gastrointestinal diseases. The goal of the present study was to examine whether chronic restraint stress (CRS) could initiate and aggravate colonic inflammation, integrity damage and metabolic disturbance of rats. Firstly, increased inflammatory cytokines (interferon-γ (IFN-γ), tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10)) and decreased tight junction (TJ) proteins (occludin and zonula occludins-1 (ZO-1)) in rat colon were observed. Secondly, untargeted metabolomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass (UPLC-Q-TOF/MS) revealed that TRP metabolism was the most prominently affected. Thirdly, quantification of TRP and its metabolites via prominence ultrafast liquid chromatography coupled with a QTRAP 5500 mass (UFLC-QTRAP-5500/MS) showed that TRP, kynurenine (KYN), kynurenic acid (KA) and 3-hydroxykynurenine (3-HK) were significantly increased. At the same time, 5-hydroxytryptamine (5-HT) was unchanged and 5-hydroxyindolacetic acid (5-HIAA) was significantly decreased in the colon of CRS rats. Besides, TRP metabolic enzyme changes were with the same trends as the corresponding metabolites. Thus, our data showed that CRS could initiate colonic inflammation, integrity damage and colonic metabolism disturbance, especially TRP-KYN metabolism pathway of rats, which may provide an experimental background for future research on stress-related gastrointestinal dysfunction. SIGNIFICANCE: Chronic exposure to psychological stress could induce metabolic imbalance of the body, and stressful life events were intimately correlated with frequent relapses in patients with intestinal disorders. The present study showed that chronic restraint stress (CRS) could initiate and aggravate colonic inflammation, integrity damage and metabolic disturbance, especially tryptophan-kynurenine metabolism of rats. Tryptophan-kynurenine pathway may be involved in the initiation and development of diseases induced by chronic stress. This research may shed light on future research on stress-related gastrointestinal dysfunction.

2.
Arch Pharm (Weinheim) ; : e2000458, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33683726

RESUMO

Adenosine monophosphate-activated protein kinase (AMPK) plays a key role in maintaining whole-body homeostasis and has been regarded as a therapeutic target for the treatment of diabetic nephropathy (DN). Herein, a series of 1,2,4-oxadiazole-containing pyrazolo[3,4-b]pyridinone derivatives is reported as AMPKɑ1ß1γ1 activators. The in vitro biological assay demonstrated that compounds 12k (EC50 [AMPKα1γ1ß1] = 180 nM) and 13q (EC50 [AMPKα1γ1ß1] = 2 nM) displayed significant enzyme activation. Mechanism studies indicated that both compounds reduced the levels of reactive oxygen species in a rat kidney fibroblast cell line (NRK-49F) stimulated by transforming growth factor-ß and induced early apoptosis of NRK-49F cells at 10 µM. Molecular docking studies suggested that 13q exhibited critical hydrogen-bond interactions with the critical amino acid residues Lys29, Lys31, Asn111, and Asp88 at the binding site of the AMPK protein. These results enrich the structure pool of AMPK activators and provide novel lead compounds for the subsequent development of compounds with a promising therapeutic potential against DN.

3.
J Agric Food Chem ; 69(7): 2129-2137, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33560125

RESUMO

Cajaninstilbene acid (CSA), an active stilbene isolated from the leaves of pigeon pea (Cajanus cajan), exhibits several bioactivities. To develop CSA as a potential nutraceutical and provide pharmacokinetic foundations for its further in vivo bioactivity studies, this study aims to explore its absorption, metabolism, and excretion systematically. Human colon adenocarcinoma (Caco-2) cell monolayers were utilized to investigate the CSA transport mechanism. CSA metabolites were identified in rat biological samples and quantified to explore their excretion routes. CSA exhibited a high permeability and was transported across Caco-2 monolayers mainly by passive transport via the transcellular process. Four new CSA metabolites were found in vivo, namely, CSA-2-COO-glucuronide, 6,12-dihydroxy CSA, 3-hydroxy-5-methoxystilbene-3-O-glucuronide, and 6-hydroxy CSA-3-O-glucuronide, in addition to our previously reported metabolite CSA-3-O-glucuronide. These metabolites were mainly excreted in bile. Our results indicate that metabolism but not absorption is the major barrier limiting the oral bioavailability of CSA.

4.
Neurobiol Learn Mem ; 179: 107383, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33460788

RESUMO

BACKGROUND: Inaccurate fear memories can be maladaptive and potentially portrait a core symptomatic dimension of fear adaptive disorders such as post-traumatic stress disorder (PTSD), which is generally characterized by an intense and enduring memory for the traumatic events. Evidence exists in support of epigenetic regulation of fear behavior. Brd4, a member of the bromodomain and extra-terminal domain (BET) protein family, serves as a chromatin "reader" by binding to histones in acetylated lysine residues, and hence promotes transcriptional activities. However, less is known whether Brd4 participates in modulating cognitive activities especially memory formation and extinction. Here we provide evidence for a role of Brd4 in modulation of auditory fear memory. Auditory fear conditioning resulted in a biphasic Brd4 activation in the anterior cingulate cortex (ACC) and hippocampus of adult mice. Thus, Brd4 phosphorylation occurred 6 h and 3-14 days, respectively, after auditory fear conditioning. Systemic inhibition of Brd4 with a BET inhibitor, JQ1, impaired the extinction of remote (i.e., 14 days after conditioning) fear memory. Further, conditional Brd4 knockout in excitatory neurons of the forebrain impaired remote fear extinction as observed in the JQ1-treated mice. Herein, we identified that Brd4 is essential for extinction of remote fear in rodents. These results thus indicate that Brd4 potentially plays a role in the pathogenesis of PTSD.

5.
Theranostics ; 11(2): 715-730, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391501

RESUMO

Rationale: Brain-derived neurotrophic factor precursor (proBDNF) is expressed in the central nervous system (CNS) and the immune system. However, the role of proBDNF in the pathogenesis of multiple sclerosis (MS) is unknown. Methods: Peripheral blood and post-mortem brain and spinal cord specimens were obtained from multiple sclerosis patients to analyze proBDNF expression in peripheral lymphocytes and infiltrating immune cells in the lesion site. The proBDNF expression profile was also examined in the experimental autoimmune encephalomyelitis (EAE) mouse model, and polyclonal and monoclonal anti-proBDNF antibodies were used to explore their therapeutic effect in EAE. Finally, the role of proBDNF in the inflammatory immune activity of peripheral blood mononuclear cells (PBMCs) was verified in vitro experiments. Results: High proBDNF expression was detected in the circulating lymphocytes and infiltrated inflammatory cells at the lesion sites of the brain and spinal cord in MS patients. In the EAE mouse model, proBDNF was upregulated in CNS and in circulating and splenic lymphocytes. Systemic but not intracranial administration of anti-proBDNF blocking antibodies attenuated clinical scores, limited demyelination, and inhibited proinflammatory cytokines in EAE mice. Immuno-stimulants treatment increased the proBDNF release and upregulated the expression of p75 neurotrophic receptors (p75NTR) in lymphocytes. The monoclonal antibody against proBDNF inhibited the inflammatory response of PBMCs upon stimulations. Conclusion: The findings suggest that proBDNF from immune cells promotes the immunopathogenesis of MS. Monoclonal Ab-proB may be a promising therapeutic agent for treating MS.

6.
J Ethnopharmacol ; 265: 113317, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32861821

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Polygalae (RP) has been traditionally used for the treatment of various psychiatric disorders in East Asia. AIM OF THE STUDY: Depression is a severe mental disease with high prevalence in people, and neurobiology changes of depression are not fully clarified yet. The present study aimed to investigate the antidepressant effect and underlying mechanism of RP in behavioral despair mice and chronic restraint stress (CRS)-induced rats. MATERIALS AND METHODS: ICR mice were treated with various doses of RP (0.13-1.0 g/kg) for 14 days and then subjected to forced swimming test (FST). Wistar rats were exposed to 6-hour restraint stress daily for 28 days, and RP (0.5 and 1 g/kg) was administered by gavage 1 h prior to CRS procedure. Subsequently, behavioral tests were performed and brains were collected for biochemical analysis. RESULTS: RP reduced immobility time of mice in FST and reversed abnormal behaviors of rats induced by CRS in sucrose preference test, novelty-suppressed feeding test, open field test and FST. Moreover, RP could enhance the expression of LC3-II and beclin1 and decrease the level of p62 both in cortex of mice and prefrontal cortex (PFC) of rats, and regulate the dysfunction of AMPK-mTOR pathway in PFC of CRS rats. Activated microglia, impaired astrocyte, elevated protein expression of NLRP3, ASC and caspase-1, and increased mRNA levels of proinflammatory cytokines were observed in PFC of CRS rats, all of which were corrected by RP treatment. CONCLUSION: RP exerted remarkable antidepressant activity in behavioral despair mice and CRS-induced rats, probably by promoting autophagy and inhibiting neuroinflammation.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/administração & dosagem , Autofagia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Wistar , Restrição Física , Natação
8.
Phys Chem Chem Phys ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300901

RESUMO

Metamaterial emitters with spectrally tunable radiation in the mid-infrared region have aroused great interest in thermal management engineering applications. Nevertheless, it is still a great challenge to economically and conveniently manufacture easily scalable thermal emitters with wide-range tunable spectra. This work theoretically and experimentally demonstrates a conceptually simple and absorption-tunable design strategy for thermal emitters with tailorable spectral responses in the mid-infrared wavelength, based on the nanocomposite structure. This strategy introduces aluminum-doped zinc oxide (AZO) nanoparticles with intrinsic resonance into the top layer as an improvement to the traditional Fabry-Perot resonance system, and thereby excellent permittivity properties that are inaccessible to natural materials are obtained. With a field build-up generated in not just the middle spacer but also the top nanocomposite layer, the absorption bands can be tailored in a wider range. Moreover, according to the calculated relationship between the overall absorption and structural parameters, the tailorability of the absorption spectra can be achieved. As a proof of concept, infrared stealth and day-time radiative cooling performances are demonstrated based on spectrally different infrared emitters. This design and theoretical strategy leads to multipurpose metamaterials with tunable resonance responses for advanced thermal management engineering or even beyond infrared fields.

9.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(6): 667-671, 2020 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-33377345

RESUMO

OBJECTIVE: To explore the changes in bone height of the maxillary sinus floor at different sinus ridge heights after transcrestal sinus floor elevation (tSFE) with the simultaneous implantation of short implants. METHODS: A total of 74 Bicon short implants were implanted into 37 patients during the same period of maxillary sinus elevation. The residual bone height (RBH)<4 mm group has 43 sites, and the RBH≥4 mm group has 31 sites. After 5 years of follow-up observation, the implant survival rate and the change in bone height achieved in the maxillary sinus over time were measured and analyzed via clinical examination and X-ray imaging. RESULTS: In the 74 implantation sites, the elevation height of the sinus floor was (6.64±1.32) mm and the bone height of the sinus floor was (3.35±1.29) mm 5 years after loading. No statistical difference was observed in the bone resorption of the implant neck between the RBH<4 mm and RBH≥4 mm groups. Meanwhile, a statistical difference was noted in the bone height obtained in the maxillary sinus between the two groups. CONCLUSIONS: When RBH in the maxillary posterior tooth area was <4 mm, the simultaneous implantation of Bicon short implants with tSFE can achieve a high implant survival rate and bone gain in the maxillary sinus, but does not increase the absorption of the alveolar ridge bone.


Assuntos
Implantes Dentários , Levantamento do Assoalho do Seio Maxilar , Implantação Dentária Endo-Óssea , Humanos , Maxila , Seio Maxilar/diagnóstico por imagem , Seio Maxilar/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
10.
Int J Nanomedicine ; 15: 10371-10384, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376326

RESUMO

Purpose: Many exopolysaccharides (EPS) have significant emulsifying activity. Some EPS produced by the marine bacterial strain FYS have stronger emulsifying activity in the form of nanoparticles, suggesting that they could potentially form Pickering emulsions. We prepared novel EPS/CT Pickering nanoemulsions (ECPN) with EPS as emulsifiers and assessed their ability to ameliorate the poor permeability of calcipotriol (CT) in skin affected by psoriasis vulgaris. Methods: A strain of marine bacterium FYS was identified. Molecular weight, monosaccharide composition and microstructure of EPS were determined by gel permeation chromatography, high-performance liquid chromatography and scanning electron microscopy. EPS nanoparticles were prepared by adjusting the pH, and the emulsifying activity was studied at different pH. ECPN were prepared by ultrasound and optimized by the response surface method. The size distribution, microstructure, stability and in vitro drug release of ECPN were studied. The therapeutic effect of ECPN on psoriasis vulgaris was explored by animal experiments and characterizing histomorphology in vivo. Results: A phylogenetic tree revealed that FYS was a Bacillus halodurans strain. EPS produced by the strain were heteropolysaccharides with a three-dimensional network composed of glucose, galactose, glucuronic acid, rhamnose, galacturonic acid and mannose (32.0:34.3:9.7:7.4:10.3:6.3). The EPS can form nanoparticles at pH = 4-6 with enhanced emulsifying ability. Transmission electron microscopy revealed that EPS nanoparticles adhered to the surface of oil droplets to stabilize the emulsions via a Pickering emulsification mechanism. The prepared ECPN have high stability with a sustained-release effect. Finally, animal experiments showed that ECPN effectively shortened the treatment course of psoriasis vulgaris. Conclusion: EPS is highly possible to have the potential Pickering emulsification mechanism. The stability of the nanoemulsion was high. ECPN also showed potential for use in the treatment of psoriasis vulgaris. This study provides new insight into the medical applications of EPS and the treatment of psoriasis.


Assuntos
Calcitriol/análogos & derivados , Emulsões/química , Polissacarídeos Bacterianos/química , Psoríase/tratamento farmacológico , Animais , Bacillus/química , Bacillus/genética , Calcitriol/administração & dosagem , Calcitriol/farmacologia , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Emulsificantes/química , Emulsões/administração & dosagem , Concentração de Íons de Hidrogênio , Camundongos , Peso Molecular , Nanopartículas/química , Filogenia , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/patologia
11.
Neuropharmacology ; 184: 108410, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33242526

RESUMO

Substantial evidence has revealed that abnormalities in synaptic plasticity play important roles during the process of depression. LASP1 (LIM and SH3 domain protein 1), a member of actin-binding proteins, has been shown to be associated with the regulation of synaptic plasticity. However, the role of LASP1 in the regulation of mood is still unclear. Here, using an unpredictable chronic mild stress (UCMS) paradigm, we found that the mRNA and protein levels of LASP1 were decreased in the hippocampus of stressed mice and that UCMS-induced down-regulation of LASP1 was abolished by chronic administration of fluoxetine. Adenosine-associated virus-mediated hippocampal LASP1 overexpression alleviated the UCMS-induced behavioral results of forced swimming test and sucrose preference test in stressed mice. It also restored the dendritic spine density, elevated the levels of AKT (a serine/threonine protein kinase), phosphorylated-AKT, insulin-like growth factor 2, and postsynaptic density protein 95. These findings suggest that LASP1 alleviates UCMS-provoked behavioral defects, which may be mediated by an enhanced dendritic spine density and more activated AKT-dependent LASP1 signaling, pointing to the antidepressant role of LASP1.

12.
Bioorg Chem ; 105: 104453, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33197849

RESUMO

CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.

13.
J Exp Clin Cancer Res ; 39(1): 235, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168027

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) are crucial in the invasion, angiogenesis, progression, and metastasis of hepatocellular carcinoma (HCC). The lncRNA MYLK-AS1 promotes the growth and invasion of HCC through the EGFR/HER2-ERK1/2 signaling pathway. However, the clinical significance of MYLK-AS1 in HCC still needs to be further determined. METHODS: Bioinformatic analysis was performed to determine the potential relationship among MYLK-AS1, miRNAs and mRNAs. A total of 156 samples of normal liver and paired HCC tissues from HCC patients were used to evaluate MYLK-AS1 expression by qRT-PCR. Human HCC cell lines were used to evaluate the colony formation, cell proliferation, migration, invasion, cell cycle and apoptosis after transfection of lentiviral short-hairpin RNAs (shRNAs) targeting MYLK-AS1 or MYLK-AS1 vectors. The competitive endogenous RNA (ceRNA) mechanism was clarified using fluorescence in situ hybridization (FISH), Western blotting, qPCR, RNA binding protein immunoprecipitation (RIP), and dual luciferase reporter analysis. RESULTS: MYLK-AS1 up-regulation was detected in the HCC tumor tissues and cell lines associated with the enhancement of the angiogenesis and tumor progression. The down-regulation of MYLK-AS1 reversed the effects on angiogenesis, proliferation, invasion and metastasis in the HCC cells and in vivo. MYLK-AS1 acted as ceRNA, capable of regulating the angiogenesis in HCC, while the microRNA miR-424-5p was the direct target of MYLK-AS1. Promoting the angiogenesis and the tumor proliferation, the complex MYLK-AS1/miR-424-5p activated the VEGFR-2 signaling through E2F7, whereas the specific targeting of E2F transcription factor 7 (E2F7) by miR-424-5p, was indicated by the mechanism studies. CONCLUSIONS: MYLK-AS1 and E2F7 are closely related to some malignant clinicopathological features and prognosis of HCC, thus the MYLK-AS1/ miR-424-5p/E2F7 signaling pathway might represent a promising treatment strategy to combat HCC.

14.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 1556-1559, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018289

RESUMO

Because of the significance of bronchial lesions as indicators of early lung cancer and squamous cell carcinoma, a critical need exists for early detection of bronchial lesions. Autofluorescence bronchoscopy (AFB) is a primary modality used for bronchial lesion detection, as it shows high sensitivity to suspicious lesions. The physician, however, must interactively browse a long video stream to locate lesions, making the search exceedingly tedious and error prone. Unfortunately, limited research has explored the use of automated AFB video analysis for efficient lesion detection. We propose a robust automatic AFB analysis approach that distinguishes informative and uninformative AFB video frames in a video. In addition, for the informative frames, we determine the frames containing potential lesions and delineate candidate lesion regions. Our approach draws upon a combination of computer-based image analysis, machine learning, and deep learning. Thus, the analysis of an AFB video stream becomes more tractable. Using patient AFB video, 99.5%/90.2% of test frames were correctly labeled as informative/uninformative by our method versus 99.2%/47.6% by ResNet. In addition, ≥97% of lesion frames were correctly identified, with false positive and false negative rates ≤3%.Clinical relevance-The method makes AFB-based bronchial lesion analysis more efficient, thereby helping to advance the goal of better early lung cancer detection.


Assuntos
Broncoscopia , Neoplasias Pulmonares , Lesões Pré-Cancerosas , Brônquios , Fluorescência , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Lesões Pré-Cancerosas/diagnóstico por imagem
15.
Clin Lab ; 66(10)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33073951

RESUMO

BACKGROUND: Diabetic foot (DF) is a common complication of diabetes with insidious onset, making it difficult for patients to receive timely diagnosis and treatment. This study aimed to evaluate the change in lipoprotein-associated phospholipase A2 (Lp-PLA2) and interleukin-18 (IL-18) in the serum of type 2 diabetes mellitus (T2DM) pa-tients with and without DF, thereby assessing the association between progression of DF and levels of Lp-PLA2 together with IL-18. METHODS: In this study, 50 patients with diabetes without foot ulcers (group I, T2DM group), 135 patients with diabetes with foot ulcers (group II, DF group), and 30 matched healthy controls (group III) were enrolled. Fasting venous blood was collected for detection of inflammatory markers including Lp-PLA2, IL-18, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor 1 (PAI-1), fibrinogen (FIB), C-reactive protein (CRP), and WBC and neutrophil percentage (Neu%). Baseline indicators such as glycated hemoglobin (HbA1C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were tested simultaneously. RESULTS: The serum levels of Lp-PLA2 and IL-18 increased significantly with T2DM progression and were positively associated with severity of T2DM, with the highest concentrations identified in patients with Wagner grade 4 ulcers (p < 0.05). Univariate logistic regression analysis showed that age, diabetes course, Lp-PLA2, IL-18, FIB, CRP, and WBC and Neu% were risk factors for DF. Multivariate logistic regression analysis revealed that Lp-PLA2, IL-18, FIB, and CRP were independent risk factors for DF. CONCLUSIONS: Increased serum levels of Lp-PLA2 and IL-18 were positively associated with the progression of DF disease. Detection of Lp-PLA2 and IL-18 can assist clinicians' assessment of the severity of DF. Dynamic detection can also help understand disease progression and treatment efficacy.

16.
J Med Chem ; 63(19): 11215-11234, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32914624

RESUMO

Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.

17.
Neurotox Res ; 38(4): 1063, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32948991

RESUMO

Dr. Chang-Qi Li should be added as co-author because Fig. 1 originated from him.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32787766

RESUMO

BACKGROUND: The long interspersed element-1 (LINE-1, L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for post-traumatic stress disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood. OBJECTIVE: The present study investigated the roles of L1 in the reconsolidation of context-dependent fear memory. METHODS: The current study used male mice obtained at two months of age. Mice underwent fear conditioning and fear recall in observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in a total of 5 min. The medial prefrontal cortex (mPFC) and hippocampus of the mice were removed and snap-frozen in nitrogen liquid for further analysis. Open Reading Frame 1 (ORF1) mRNA, and Open Reading Frame 2 (ORF2) mRNA of L1 were analyzed by Real-Time Quantitative Polymerase Chain Reaction. After the reactivation of fear memory, lamivudine was administered to inhibit L1 retrotransposition and its effects on fear memory reconsolidation were observed. RESULTS: The expression of ORF1 and ORF2 mRNA in the mPFC and hippocampus after the recent (24 hours) and remote (14 days) fear memory recall exhibited an augmentation via different temporal and spatial patterns. The reconsolidation and spontaneous recovery of fear memory were markedly inhibited in mice administrated with lamivudine, which could block L1. The expression of DNA methyltransferase (Dnmt) mRNA was diminished following lamivudine treatment in the remote fear memory recall. CONCLUSIONS: The retrotransposition of L1 participated in the reconsolidation of fear memory after the reactivation of fear memory , and with lamivudine treatment, spontaneous recovery was decreased with time after the recent and remote fear memory recall, which might provide more clues for understanding the roles of L1 in fear memory and the possible strategy for treating PTSD.

19.
Neuropharmacology ; 177: 108255, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32730819

RESUMO

Fear extinction is an important preclinical model for behavior therapy in human anxiety disorders, such as post-traumatic stress disorder (PTSD). Histone acetylation is involved in the extinction of fear memory. As the "readers" of histone acetylation markers, the role of the bromodomain and extraterminal domain (BET) proteins in fear extinction is still unclear. In the present study, we found that suppression of BET proteins using small molecule JQ-1 had no effects on the acquisition of auditory fear or on the extinction of recent auditory fear, but it impaired the extinction of remote auditory fear. We found that insulin like growth factor 2 (IGF-2) mRNA and protein were up-regulated in the anterior cingulate cortex (ACC) after the extinction training of remote fear memory, and that this effect was inhibited by JQ-1 administration. Further, the local delivery of IGF-2 protein to the ACC region rescued the impaired extinction of remote memory caused by JQ-1 administration, which suggesting IGF-2 mediates the effects of JQ-1 on remote memory extinction. Gene expression profiling analysis demonstrated that JQ-1 treatment inhibited the up-regulated expression of a key set of neuroplasticity-related genes following remote memory extinction. Together, these findings establish BET proteins as epigenetic mediator for the extinction of remote fear memory. In particular, the findings of this study imply that as a prospective preclinical cancer drug, JQ-1 (or other BET bromodomain inhibitors) should be modified to prevent it from crossing the blood brain barrier and causing neurological side effects.

20.
Front Mol Neurosci ; 13: 80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714143

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disease in the elderly with a pathogenesis that remains unclear. We aimed to explore its pathogenesis through plasma integrated metabolomics and proteomics analysis. The clinical data of consecutively recruited PD patients and healthy controls were assessed. Fasting plasma samples were obtained and analyzed using metabolomics and proteomics methods. After that, differentially expressed metabolites and proteins were identified for further bioinformatics analysis. No significant difference was found in the clinical data between these two groups. Eighty-three metabolites were differentially expressed in PD patients identified by metabolomics analysis. These metabolites were predominately lipid and lipid-like molecules (63%), among which 25% were sphingolipids. The sphingolipid metabolism pathway was enriched and tended to be activated in the following KEGG pathway analysis. According to the proteomics analysis, forty proteins were identified to be differentially expressed, seven of which were apolipoproteins. Furthermore, five of the six top ranking Gene Ontology terms from cellular components and eleven of the other fourteen Gene Ontology terms from biological processes were directly associated with lipid metabolism. In KEGG pathway analysis, the five enriched pathways were also significantly related with lipid metabolism (p < 0.05). Overall, Parkinson's disease is associated with plasma lipid metabolic disturbance, including an activated sphingolipid metabolism and decreased apolipoproteins.

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