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1.
J Ethnopharmacol ; 284: 114766, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34688798

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation induced by microglia is closely related to a variety of neurodegenerative diseases including Alzheimer's disease (AD). Previous study has found that aqueous extract of Epimedii Folium and Curculiginis Rhizoma (EX) had anti-inflammatory effect on AD by activating the NLRP3 inflammasome and inhibiting NF-κB/MAPK pathway. However, whether the anti-neuroinflammatory effect of EX is related to microglia or not remains unclear. AIM OF THE STUDY: The present study aimed to investigate the protective effect of EX on cognitive impairment induced by LPS and explore the underlying mechanism of EX. MATERIALS AND METHODS: High performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was performed to qualify the major components of EX, EX in the serum and cerebrospinal fluid. To evaluate the anti-inflammatory effects of EX in vivo, the mice were orally administrated with EX (2.34, 4.68 g kg-1•d-1) for 28 days before cotreatment with LPS (1 mg kg-1•d-1, i.p.). The leaning and memory abilities of mice were examined by Morris water maze test. The expression of inflammatory related proteins and the activation of microglia were detected by ELISA, immunofluorescence, real-time PCR and Western blotting. RESULTS: HPLC-MS analysis confirmed and quantified 9 components in EX, 5 components in the serum and 4 components in the cerebrospinal fluid. In a LPS-induced neuroinflammatory mouse model, EX was found to exert anti-inflammatory activity by reducing the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), regulating the expression of different phenotypes of microglia, and increasing the expression of proteins related with TREM2 in the hippocampus tissue. Moreover, LPS-induced microglia activation was markedly attenuated in the hippocampus. CONCLUSIONS: These findings demonstrate that EX exerts anti-neuroinflammatory effects via reducing the production of inflammatory mediators, regulating the conversion of microglia and activating the proteins related with TREM2. EX might become a novel herb pairs to treat neuroinflammatory diseases.

2.
Oral Dis ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34773344

RESUMO

Accumulated evidence indicates that immune cell populations play pivotal roles in the process of tumor initiation, progression, recurrence, metastasis, and immune escape. Ferroptosis is a form of regulating cell death in the nexus between metabolism, redox biology, and human health. Ferroptosis is considered as a vital important event in HNSCC, but the underling mechanism of regulating immune cell populations remains poorly understood. Our tissue microarray study showed that patients with high expression of GPX4 were related to poor survival. Moreover, the expression of GPX4 has been negatively associated with immunogenic cell death-related protein calreticulin in HNSCC tissue cohort. Further, RSL3 was used to induce ferroptosis in HNSCC xenograft of C3H/He mouse. We found that the occurrence of ferroptosis had significantly reduced the number of myeloid-derived suppressor cells (MDSCs) and tumor-associated M2-like macrophages (M2 TAMs) in tumor microenvironment. Meanwhile, the tumor-infiltrating CD4+ and CD8+ T cells were increased. And the calreticulin and HMGB1 may be potential candidate proteins improving the immunosuppressive tumor microenvironment. Taken together, our project suggests that ferroptosis can promote anti-tumor immune response by reversing immunosuppressive microenvironment, indicating that ferroptosis inducer is a promising therapeutic strategy in HNSCC.

3.
Ann Rheum Dis ; 80(12): 1604-1614, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34663597

RESUMO

Crystal structures activate innate immune cells, especially macrophages and initiate inflammatory responses. We aimed to understand the role of the mechanosensitive TRPV4 channel in crystal-induced inflammation. Real-time RT-PCR, RNAscope in situ hybridisation, and Trpv4eGFP mice were used to examine TRPV4 expression and whole-cell patch-clamp recording and live-cell Ca2+ imaging were used to study TRPV4 function in mouse synovial macrophages and human peripheral blood mononuclear cells (PBMCs). Both genetic deletion and pharmacological inhibition approaches were used to investigate the role of TRPV4 in NLRP3 inflammasome activation induced by diverse crystals in vitro and in mouse models of crystal-induced pain and inflammation in vivo. TRPV4 was functionally expressed by synovial macrophages and human PBMCs and TRPV4 expression was upregulated by stimulation with monosodium urate (MSU) crystals and in human PBMCs from patients with acute gout flares. MSU crystal-induced gouty arthritis were significantly reduced by either genetic ablation or pharmacological inhibition of TRPV4 function. Mechanistically, TRPV4 mediated the activation of NLRP3 inflammasome by diverse crystalline materials but not non-crystalline NLRP3 inflammasome activators, driving the production of inflammatory cytokine interleukin-1ß which elicited TRPV4-dependent inflammatory responses in vivo. Moreover, chemical ablation of the TRPV1-expressing nociceptors significantly attenuated the MSU crystal-induced gouty arthritis. In conclusion, TRPV4 is a common mediator of inflammatory responses induced by diverse crystals through NLRP3 inflammasome activation in macrophages. TRPV4-expressing resident macrophages are critically involved in MSU crystal-induced gouty arthritis. A neuroimmune interaction between the TRPV1-expressing nociceptors and the TRPV4-expressing synovial macrophages contributes to the generation of acute gout flares.

4.
Front Pharmacol ; 12: 679573, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34393775

RESUMO

Polygoni Multiflori Radix Praeparata (ZhiHeShouWu, PMRP) and Acori Tatarinowii Rhizoma (ShiChangPu, ATR) and their traditional combination (PA) are frequently used in traditional Chinese medicine to prevent and treat Alzheimer disease (AD) based on the theory that PMRP tonifies the kidney and ATR dissipates phlegm. However, the components of PA and their mechanisms of action are not known. The present study analyzed the active components of PA, and investigated the protective effect of PA against cognitive impairment induced by scopolamine in mice along with the underlying mechanism.The aqueous extract of PA was analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) and gas chromatography (GC)-MS in order to identify the major components. To evaluate the protective effect of PA against cognitive dysfunction, mice were orally administered PA, PMRP, or ATR for 30 days before treatment with scopolamine. Learning and memory were assessed in mice with the Morris water maze test; neurotransmitter levels in the hippocampus were analyzed by HPLC-MS; and the expression of synapse-related proteins in the hippocampus was detected by western blotting and immunohistochemistry. Eight active compounds in PA and rat plasma were identified by HPLC-MS and GC-MS. Plasma concentrations of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside, emodin, α-asarone, and asarylaldehyde were increased following PA administration; meanwhile, gallic acid, emodin-8-O-ß-d-glucopyranoside, ß-asarone, and cis-methyl isoeugenol concentrations were similar in rats treated with PA, PMRP, and ATR. In scopolamine-treated mice, PA increased the concentrations of neurotransmitters in the hippocampus, activated the brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) signaling pathway, and increased the expression of p90 ribosomal S6 kinase (p90RSK) and postsynaptic density (PSD)95 proteins. Thus, PA alleviates cognitive deficits by enhancing synaptic-related proteins, suggesting that it has therapeutic potential for the treatment of aging-related diseases such as AD.

5.
Cell Rep ; 35(3): 109025, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33882315

RESUMO

Ablation of Slc22a14 causes male infertility in mice, but the underlying mechanisms remain unknown. Here, we show that SLC22A14 is a riboflavin transporter localized at the inner mitochondrial membrane of the spermatozoa mid-piece and show by genetic, biochemical, multi-omic, and nutritional evidence that riboflavin transport deficiency suppresses the oxidative phosphorylation and reprograms spermatozoa energy metabolism by disrupting flavoenzyme functions. Specifically, we find that fatty acid ß-oxidation (FAO) is defective with significantly reduced levels of acyl-carnitines and metabolites from the TCA cycle (the citric acid cycle) but accumulated triglycerides and free fatty acids in Slc22a14 knockout spermatozoa. We demonstrate that Slc22a14-mediated FAO is essential for spermatozoa energy generation and motility. Furthermore, sperm from wild-type mice treated with a riboflavin-deficient diet mimics those in Slc22a14 knockout mice, confirming that an altered riboflavin level causes spermatozoa morphological and bioenergetic defects. Beyond substantially advancing our understanding of spermatozoa energy metabolism, our study provides an attractive target for the development of male contraceptives.

6.
Biometrics ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33569777

RESUMO

Geostatistical modeling for continuous point-referenced data has extensively been applied to neuroimaging because it produces efficient and valid statistical inference. However, diffusion tensor imaging (DTI), a neuroimaging technique characterizing the brain's anatomical structure, produces a positive-definite (p.d.) matrix for each voxel. Currently, only a few geostatistical models for p.d. matrices have been proposed because introducing spatial dependence among p.d. matrices properly is challenging. In this paper, we use the spatial Wishart process, a spatial stochastic process (random field), where each p.d. matrix-variate random variable marginally follows a Wishart distribution, and spatial dependence between random matrices is induced by latent Gaussian processes. This process is valid on an uncountable collection of spatial locations and is almost-surely continuous, leading to a reasonable way of modeling spatial dependence. Motivated by a DTI data set of cocaine users, we propose a spatial matrix-variate regression model based on the spatial Wishart process. A problematic issue is that the spatial Wishart process has no closed-form density function. Hence, we propose an approximation method to obtain a feasible Cholesky decomposition model, which we show to be asymptotically equivalent to the spatial Wishart process model. A local likelihood approximation method is also applied to achieve fast computation. The simulation studies and real data application demonstrate that the Cholesky decomposition process model produces reliable inference and improved performance, compared to other methods.

7.
Ecotoxicol Environ Saf ; 207: 111272, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32927162

RESUMO

Tobacco smoke is a common global environmental pollutant. Maternal tobacco smoke/nicotine exposure has long-term toxic effects on immune organs. We previously found that prenatal nicotine exposure (PNE)-induced programmed immune diseases caused by fetal thymic hypoplasia, but the mechanism still unknown. Autophagy has important functions in maintaining thymopoiesis, whether autophagy was involved in PNE-inhibited fetal thymocytes development is also obscure. Therefore, this study aimed to investigate how nicotine changed the development of fetal thymocytes from the perspective of autophagy in vivo and in vitro. PNE model was established by 3 mg/kg nicotine administration in Balb/c mice from gestational day 9 to 18. The results showed that PNE reduced the percentage and absolute number of CD69-CD4+SP cells, suggesting a block of fetal thymocytes mature. PNE promoted autophagosome formation, autophagy related proteins (Beclin1, LC3I/II) expression, and upregulated α7 nAChR as well as AMPK phosphorylation in fetal thymus. Moreover, PNE promoted Bcl10 degradation via autophagy-mediated proteolysis and inhibited p65 activation, blocking the transition of thymocytes between the DP to SP stage. Further, primary thymocytes were treated with nicotine in vitro and showed induced autophagy in a dose- and time-dependent manner. In addition, nicotine-inhibited CD69-CD4+SP cells and the Bcl10/p-p65 pathway have been reversed by an autophagy inhibitor. The α7 nAChR specific antagonist abrogated nicotine-induced AMPK phosphorylation and autophagy initiation. In conclusion, our findings showed that PNE repressed the Bcl10/p-p65 development pathway of CD4+SP cells by triggering autophagy, and illuminated the developmental origin mechanism of programmed immune diseases in PNE offspring.


Assuntos
Substâncias Perigosas/toxicidade , Nicotina/toxicidade , Timócitos/fisiologia , Animais , Autofagia/efeitos dos fármacos , Proteína 10 de Linfoma CCL de Células B , Proteína Beclina-1 , Feminino , Feto , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Timócitos/efeitos dos fármacos , Timócitos/imunologia , Vitaminas
8.
Front Pharmacol ; 12: 759040, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34987391

RESUMO

Hyperuricemia nephropathy (HN) is a form of chronic tubulointerstitial inflammation, caused by the deposition of monosodium urate crystals (MSU) in the distal collecting duct and medullary interstitium, associated with a secondary inflammatory reaction. Numerous published reports indicated that NLRP3 inflammasome pathway play crucial roles in HN symptoms. The present study aims to investigate the protective effects of methyl gallate on HN mice and the underlying mechanisms. An HN model was established by intraperitoneal injection of potassium oxide (PO) to assess the effect of methyl gallate on renal histopathological changes, renal function, cytokine levels and expressions of NLRP3-related protein in HN mice. Moreover, in vitro models of lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs) were established to explore the mechanism of methyl gallate on NLRP3 inflammasome activation. The results showed that methyl gallate significantly ameliorated HN by inhibiting uric acid production and promoting uric acid excretion as well as ameliorating renal injury induced by NLRP3 activation. Mechanistically, methyl gallate is a direct NLRP3 inhibitor that inhibits NLRP3 inflammasome activation but has no effect on the activation of AIM2 or NLRC4 inflammasomes in macrophages. Furthermore, methyl gallate inhibited the assembly of NLRP3 inflammasomes by blocking the ROS over-generation and oligomerization of NLRP3. Methyl gallate was also active ex vivo against ATP-treated PBMCs and synovial fluid mononuclear cells from patients with gout. In conclusion, methyl gallate has a nephroprotective effect against PO-induced HN through blocking the oligomerization of NLRP3 and then exerting anti-inflammatory activity in the NLRP3-driven diseases.

9.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-20095018

RESUMO

BackgroundCoronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has developed into a full-blown global pandemic. It has been reported that patients with COVID-19 meeting the criteria for hospital discharge (including two consecutive negative RT-PCR results) have experienced recurrent PCR positivity. However, the clinical course and risk factors for these patients have not been well described. MethodsIn this retrospective cohort study, consecutive patients with COVID-19 confirmed by RT-PCR from the Guanggu Branch of Hubei Province Maternity and Childcare Hospital from February 24, 2020 to March 31, 2020 were enrolled. All patients received follow-up to April 15, 2020 from discharge. The epidemiological, radiographic, laboratory, treatment, and outcome data were extracted from medical records. Univariate and multivariable logistic regression methods were used to elucidate risk factors for patients with recurrence of positive SARS-CoV-2 RNA. Results1087 COVID-19 patients were included in this study. Of these, 20 (1.8%) died and 1067 (98.2%) were discharged from the hospital. Among the discharged cases, there were 81 (7.6%) patients found to develop a repeat positive SARS-Cov-2 RNA result. Older age was obviously associated with death. For patients with recurrent RT-PCR positivity, the median duration from illness onset to onset of complete RNA negative was 33.0 days (range, 6.0-82.0 days; IQR, 20.0-41.0 days), while that from illness onset to recurrence was 50.0 days (range, 21.0-95.0 days; IQR, 36.5-59.5 days). Multivariate regression analysis identified recurrence of positive SARS-Cov-2 RNA was associated with elevated IL-6 levels (P=0.004, OR=3.050; 95% CI, 1.432-6.499), increased lymphocyte count (P=0.038, OR=2.321; 95% CI, 1.048-5.138) and CT imaging features of lung consolidation (P=0.038, OR=1.641; 95% CI, 1.028-2.620) during hospitalization. ConclusionElevated lymphocyte counts and IL-6 levels in blood, and consolidation features on CT imaging are useful risk factors for clinicians to identify patients at risk of developing recurrent positivity of SARS-CoV-2 RNA. This is speculated to be caused by a balance in immune regulation when fighting virus toxicity. For patients with a high risk of recurrent positivity, a prolonged observation and additional preventative measures should be implemented for at least 50 days after illness onset to prevent future outbreaks. Key PointsO_ST_ABSQuestionC_ST_ABSHow is the clinical course of patients with recurrence of positive SARS-CoV-2 RNA and what clinical characteristics are associated with that? FindingsIn this cohort involving 1067 COVID-19 patients discharged from the hospital, 81 (7.6%) patients found to develop a repeat positive SARS-Cov-2 RNA result. For patients with recurrent RT-PCR positivity, the median duration from illness onset to onset of complete RNA negative was 3.30 days (range, 6.0-82.0 days; IQR, 20.0-41.0 days), while that from illness onset to recurrence was 50.0 days (range, 21.0-95.0 days; IQR, 36.5-59.5 days). Risk factors associated with recurrence of positive SARS-Cov-2 RNA included elevated IL-6 levels, increased lymphocyte count and CT imaging features of lung consolidation during hospitalization. MeaningThe recurrence of positive SARS-Cov-2 RNA is speculated to be caused by a balance in immune regulation when fighting virus toxicity. For patients with a high risk of recurrent positivity, a prolonged observation and additional preventative measures should be implemented for at least 50 days after illness onset to prevent future outbreaks.

10.
Cell Stem Cell ; 26(2): 187-204.e10, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31956038

RESUMO

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvß5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvß5 inhibition. Collectively, our studies identify integrin αvß5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.


Assuntos
Glioblastoma , Células-Tronco Neurais , Infecção por Zika virus , Zika virus , Humanos , Receptores de Vitronectina , Fatores de Transcrição SOXB1/genética
11.
Eur J Med Chem ; 185: 111809, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683104

RESUMO

Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M double mutations. The IC50 value against EGFRL858R/T790M kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50 values were 0.057 µM, 0.104 µM and 0.916 µM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r2 = 0.965) and CoMSIA (q [2] = 0.875, r2 = 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Relação Quantitativa Estrutura-Atividade , Células A549 , Acrilamidas/síntese química , Acrilamidas/química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células Tumorais Cultivadas
12.
Toxicology ; 428: 152309, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629012

RESUMO

The recession of regulatory T cells (Tregs) contributes to development of autoimmune disease. Our previous study suggested that prenatal nicotine exposure (PNE) inhibited Tregs frequency in offspring, but the mechanisms are still uncertain. This study aimed to explore the molecular mechanisms of PNE-induced Tregs inhibition from the perspective of cellular cholesterol homeostasis both in vivo and in vitro. PNE mice model were established by 3 mg/kg/d nicotine administration in Balb/c strain from gestational day (GD) 9 to GD 18. The results showed that PNE significantly decreased thymic Tregs frequency in neonatal offspring. The activation of mTOR and downregulation of p-STAT5/Foxp3 pathway of Tregs were observed in PNE offspring. Mechanism study found that PNE elevated ATP-binding cassette transporter G1 (ABCG1) expression and decreased intracellular cholesterol content of Tregs in offspring, indicating impaired intracellular cholesterol homeostasis. Similar results were observed in 1 µM nicotine-treated primary thymocytes in vitro. Further, cholesterol-replenishment can abrogate nicotine-induced mTOR activation and the following suppression of p-STAT5/Foxp3 pathway and Tregs frequency. In addition, Abcg1 siRNA transfection can partly reverse the nicotine-decreased intracellular cholesterol content and cell frequency of Tregs. In conclusion, this study showed that PNE could suppress Tregs development in female mice by up-regulating ABCG1-dependent cholesterol efflux, and suggested that PNE-induced thymic Tregs recession of offspring at early life was the developmental origin mechanism of immune dysfunction in later life.


Assuntos
Colesterol/metabolismo , Nicotina/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Células Cultivadas , Feminino , Masculino , Troca Materno-Fetal , Camundongos Endogâmicos BALB C , Gravidez , Timo/citologia
13.
Neurochem Res ; 44(12): 2708-2722, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31612304

RESUMO

Macroautophagy, a sole pathway for dysfunctional organelles or aggregated proteins turnover, has been implicated in the early development of Alzheimer's disease (AD). Previous studies have found that reversal of autophagy dysfunction in APP transgenic mice ameliorates amyloid pathologies. Icariin (ICA), the main component from traditional Chinese herb Epimedium brevicornu Maxim., can reduce accumulations of amyloid-ß (Aß) peptide in vivo and in vitro, but the mechanism remains unclear. Here, we explored the effects of ICA on autophagy-lysosomal pathway in intracerebroventricular (icv) injection of human Aß1-42 peptide rats. We demonstrated that feeding the rats with ICA (30 mg/kg, 60 mg/kg and 90 mg/kg rat, per os) for 4 weeks rescued the Aß1-42-induced spatial memory impairments, reduced endogenous rat Aß42 tested by ELISA and decreased Aß accumulation using 6E10 antibody. Furthermore, Aß1-42 induced strong autophagy response, however ICA decreased the levels of microtubule-associated protein 1 light chain 3 (LC3) II/LC3I, Beclin1, Cathepsin D (Cat D) and brain lysosomal Cathepsin D activity. We also observed that ICA enhanced the phosphorylation of protein kinase B (PKB/AKT) and p70 ribosomal protein S6 kinase (p70S6K). In addition, ICA arrested Aß1-42-induced cells loss, mitochondrias damage, nuclear membranes unclear and abundant nucleas chromatin agglutinates in hippocampus, lessened the expression of Cleaved-caspase-3, brain oxidative stress, astroglial activation. These findings suggest that ICA can ameliorate amyloid pathologies with improving autophagy-lysosome function and Chinese materia medica may be potential for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Flavonoides/uso terapêutico , Homeostase/efeitos dos fármacos , Macroautofagia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/administração & dosagem , Animais , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Injeções , Lisossomos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos
14.
Cell Death Differ ; 26(10): 2015-2028, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30760873

RESUMO

Loss of either TSC1 or TSC2 causes tuberous sclerosis complex (TSC) via activation of mTOR signaling pathway. The two prominent features of TSC are skin lesions including hypomelanic macules and benign tumors in multiple organs, whose molecular alterations are largely unknown. We report here that Xc- cystine/glutamate antiporter (xCT) was elevated in Tsc2-/- or Pten-/- cells, Tsc1 knockout mouse tissues and TSC2-deficient human kidney tumor. xCT was transcriptionally boosted by mTOR-mediated Oct1 signaling cascade. Augmented xCT led to reduction of eumelanin and elevation of pheomelanin in Tsc1 skin knockout mice through mTOR signaling pathway. Disruption of xCT suppressed the proliferation and tumorigenesis of Pten-null cells and Tsc2-null cells. mTOR hyperactive cells were more sensitive to inhibitors of mTOR or xCT. Combined inhibition of mTOR and xCT synergistically blocked the propagation and oncogenesis of mTOR hyperactive cells. Therefore, oncogenic mTOR activation of xCT is a key connection between aberrant melanin synthesis and tumorigenesis. We suggest that xCT is a novel therapeutic target for TSC and other aberrant mTOR-related diseases.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Melaninas/biossíntese , Serina-Treonina Quinases TOR/metabolismo , Adolescente , Animais , Carcinogênese , Feminino , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Melaninas/metabolismo , Camundongos , Camundongos Knockout , Esclerose Tuberosa , Proteína 1 do Complexo Esclerose Tuberosa/deficiência , Proteína 2 do Complexo Esclerose Tuberosa/deficiência , Regulação para Cima
16.
Eur J Med Chem ; 163: 367-380, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530173

RESUMO

Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 µM, which makes it more valuable for potential lung cancer research.


Assuntos
Acrilamidas/síntese química , Compostos de Anilina/síntese química , Desenho de Fármacos , Acrilamidas/química , Acrilamidas/farmacologia , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Receptores ErbB/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Relação Estrutura-Atividade
17.
J Inorg Biochem ; 192: 17-24, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554070

RESUMO

Three new platinum(II) complexes with pendent morpholine were synthesized, namely complex 1 ([Pt(L)Cl]CF3SO3), complex 2 ([Pt(L)(NH3)](CF3SO3)2) and complex 3 ([Pt(L)(PPh3)](CF3SO3)2), where L = 4'-[4-(4-morpholinobutyloxy)phenyl]-2,2':6',2″-terpyridine and PPh3 = triphenylphosphine. The detailed molecular structures of complex 3, L and its precursor L' (1,4'-[4-(4-bromobutyloxy)phenyl]-2,2':6',2″-terpyridine) were determined by single crystal X-ray diffraction. An evaluation of in vitro cytotoxicity for both ligand and complexes was performed by methyl thiazolyl tetrazolium (MTT) assay in three cancer cell lines and normal cells as the control, respectively. IC50 values of complexes 1-3 were lower than those exhibited for the reference drug cisplatin, and selectivity of these complexes were greater than cisplatin. Among them, complex 3 with a leaving group PPh3 was found to be the most efficacious complex against certain cell lines, especially for cisplatin-resistant A549cisR cells. These complexes were found to bind DNA, induce efficient DNA unwinding. Meanwhile, topoisomerase (Topo) I inhibitory activities by three complexes were detected, and a minimum inhibitory concentration of 15 µM of complex 3 was found totally inhibit Topo I activity.


Assuntos
Antineoplásicos , DNA Topoisomerases Tipo I/metabolismo , Proteínas de Neoplasias , Neoplasias , Compostos Organoplatínicos , Inibidores da Topoisomerase I , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Células Hep G2 , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia
18.
Eur J Med Chem ; 154: 29-43, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29775935

RESUMO

Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.09 ±â€¯0.04 µM, 1.34 ±â€¯0.13 µM and 1.23 ±â€¯0.09 µM, respectively. Eight selected compounds were further selected to evaluated for the inhibitory activity against EGFR kinase. Three of them showed equal activity against EGFR kinase to positive control afatinib. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that the compound 13a could induce apoptosis of human lung cancer A549 cells.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Receptores ErbB/antagonistas & inibidores , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Quinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Indóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Quinolinas/química , Relação Estrutura-Atividade
19.
Arch Toxicol ; 92(1): 469-485, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28871336

RESUMO

Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFß pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 µM) as compared with those in controls. Zoledronate treatments in cells (50 µM) and mice (3 mg/kg) increased TGFß/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid ß-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy.


Assuntos
Ácidos Graxos/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Ácido Zoledrônico/efeitos adversos , Animais , Benzamidas/farmacologia , Linhagem Celular , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Dioxóis/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fenofibrato/farmacologia , Fibrose/induzido quimicamente , Humanos , Nefropatias/patologia , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Oxirredução/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
20.
Arch Pharm Res ; 41(12): 1190-1198, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28770537

RESUMO

Previous studies have shown that flavonoids (Fs) present in Linaria vulgaris inhibit lipid accumulation in vitro. This study was designed to evaluate the effects of Fs extracted from Linaria vulgaris ssp. sinensis (Bebeaux) Hong, on hyperlipidemia and hepatic steatosis induced by a western-type diet in mice. The major constituents of Fs were analyzed by LC-MS analysis. C57BL/6 mice were fed a western-type diet for 8 weeks to induce hyperlipidemia (model group), or fed a western-type diet followed by Fs treatment (90, 30 or 10 mg/kg/day) or atorvastatin treatment (1.0 mg/kg/day), for 8 weeks. It was found that Fs treatment resulted in significant reductions in serum levels of AST, ALT, TC, TG, LDL-C, free fatty acid and hepatic TC, and TG compared to those in model mice with hyperlipidemia (P < 0.05). The mice treated with Fs showed a relatively normal hepatic architecture compared to the hepatic steatosis shown in the model group. Moreover, the expressions of mature forms of sterol regulatory element-binding proteins (nuclear form of srebps, n-SREBPs) and 3-hydroxy-3-methylglutaryl coenzyme reductase (HMGCR) involved in lipid metabolism, were suppressed in the Fs-treated groups. Taken together, these results suggest Fs exert protective effects against hyperlipidemia and hepatic steatosis, which may involve the inhibition of mature SREBPs expressions.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Flavonoides/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Linaria/química , Obesidade/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Dieta/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Flavonoides/química , Flavonoides/isolamento & purificação , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/patologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação
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