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1.
Acta Pharmacol Sin ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34522005

RESUMO

Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34448599

RESUMO

Objective: The outbreak of Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens a surging number of community groups within society, including women actively breastfeeding. Breastfeeding involves intimate behaviors, a major transmission route of SARS-CoV-2, and is integral to the close mother-baby relationship highly correlated with maternal psychological status. Materials and Methods: Twenty-three pregnant women and puerperae with either confirmed or suspected diagnoses of COVID-19 were enrolled in the study. The clinical characteristics and outcomes of the mothers and neonates were recorded. The presence of SARS-CoV-2, IgG, and IgM in breast milk, maternal blood, and infant blood, together with feeding patterns, was assessed within 1 month after delivery. Feeding patterns and maternal psychological status were also recorded in the second follow-up. Results: No positive detection of SARS-CoV-2 was found in neonates. All breast milk samples were negative for the detection of SARS-CoV-2. The presence of IgM for SARS-CoV-2 in breast milk was correlated with IgM presence in the maternal blood. The results of IgG detection for SARS-CoV-2 were negative in all breast milk samples. All infants were in a healthy condition in two follow-ups, and antibody tests for SARS-CoV-2 were negative. The rate of breast milk feeding increased during two follow-ups. All mothers receiving a second follow-up experienced negative psychological factors and status. Conclusions: Our findings support the feasibility of breastfeeding in women infected with SARS-CoV-2. The additional negative psychological status of mothers due to COVID-19 should also be considered during the puerperium period.

3.
Acta Pharmacol Sin ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33850276

RESUMO

Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancer cell glucose metabolism and plays a crucial role in the activation of various types of immune cells. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzes the conversion of D-glyceraldehyde 3-phosphate to D-glycerate 1,3-bisphosphate in the 6th critical step in glycolysis. GAPDH exerts metabolic flux control during aerobic glycolysis and therefore is an attractive therapeutic target for cancer and autoimmune diseases. Recently, GAPDH inhibitors were reported to function through common suicide inactivation by covalent binding to the cysteine catalytic residue of GAPDH. Herein, by developing a high-throughput enzymatic screening assay, we discovered that the natural product 1,2,3,4,6-penta-O-galloyl-ß-D-glucopyranose (PGG) is an inhibitor of GAPDH with Ki = 0.5 µM. PGG blocks GAPDH activity by a reversible and NAD+ and Pi competitive mechanism, suggesting that it represents a novel class of GAPDH inhibitors. In-depth hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis revealed that PGG binds to a region that disrupts NAD+ and inorganic phosphate binding, resulting in a distal conformational change at the GAPDH tetramer interface. In addition, structural modeling analysis indicated that PGG probably reversibly binds to the center pocket of GAPDH. Moreover, PGG inhibits LPS-stimulated macrophage activation by specific downregulation of GAPDH-dependent glucose consumption and lactate production. In summary, PGG represents a novel class of GAPDH inhibitors that probably reversibly binds to the center pocket of GAPDH. Our study sheds new light on factors for designing a more potent and specific inhibitor of GAPDH for future therapeutic applications.

4.
EMBO Rep ; 22(4): e50128, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33605073

RESUMO

N6 -methyladenosine (m6 A) modification of mRNA mediates diverse cellular and viral functions. Infection with Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma (NPC), 10% of gastric carcinoma, and various B-cell lymphomas, in which the viral latent and lytic phases both play vital roles. Here, we show that EBV transcripts exhibit differential m6 A modification in human NPC biopsies, patient-derived xenograft tissues, and cells at different EBV infection stages. m6 A-modified EBV transcripts are recognized and destabilized by the YTHDF1 protein, which leads to the m6 A-dependent suppression of EBV infection and replication. Mechanistically, YTHDF1 hastens viral RNA decapping and mediates RNA decay by recruiting RNA degradation complexes, including ZAP, DDX17, and DCP2, thereby post-transcriptionally downregulating the expression of EBV genes. Taken together, our results reveal the critical roles of m6 A modifications and their reader YTHDF1 in EBV replication. These findings contribute novel targets for the treatment of EBV-associated cancers.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Adenosina/análogos & derivados , Proteínas de Transporte , Herpesvirus Humano 4/genética , Humanos , Estabilidade de RNA , Proteínas de Ligação a RNA/genética , Replicação Viral
5.
Toxicol Appl Pharmacol ; 414: 115428, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524449

RESUMO

Researches have shown that calcitonin gene-related peptide (CGRP) plays a pivotal role in pain modulation. Nociceptive information from the periphery is relayed from parabrachial nucleus (PBN) to brain regions implicated involved in pain. This study investigated the effects and mechanisms of CGRP and CGRP receptors in pain regulation in the PBN of naive and neuropathic pain rats. Chronic sciatic nerve ligation was used to model neuropathic pain, CGRP and CGRP 8-37 were injected into the PBN of the rats, and calcitonin receptor-like receptor (CLR), a main structure of CGRP receptor, was knocked down by lentivirus-coated CLR siRNA. The hot plate test (HPT) and the Randall Selitto Test (RST) was used to determine the latency of the rat hindpaw response. The expression of CLR was detected with RT-PCR and western blotting. We found that intra-PBN injecting of CGRP induced an obvious anti-nociceptive effect in naive and neuropathic pain rats in a dose-dependent manner, the CGRP-induced antinociception was significantly reduced after injection of CGRP 8-37, Moreover, the mRNA and protein levels of CLR, in PBN decreased significantly and the antinociception CGRP-induced was also significantly lower in neuropathic pain rats than that in naive rats. Knockdown CLR in PBN decreased the expression of CLR and the antinociception induced by CGRP was observably decreased. Our results demonstrate that CGRP induced antinociception in PBN of naive or neuropathic pain rats, CGRP receptor mediates this effect. Neuropathic pain induced decreases in the expression of CGRP receptor, as well as in CGRP-induced antinociception in PBN.


Assuntos
Analgésicos/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Proteína Semelhante a Receptor de Calcitonina/agonistas , Dor Nociceptiva/prevenção & controle , Limiar da Dor/efeitos dos fármacos , Núcleos Parabraquiais/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/agonistas , Ciática/prevenção & controle , Animais , Proteína Semelhante a Receptor de Calcitonina/genética , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Masculino , Dor Nociceptiva/genética , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Núcleos Parabraquiais/metabolismo , Núcleos Parabraquiais/fisiopatologia , Ratos Sprague-Dawley , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genética , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Ciática/genética , Ciática/metabolismo , Ciática/fisiopatologia
6.
Phys Chem Chem Phys ; 23(3): 2384-2391, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33458726

RESUMO

In this work, combining first-principles calculations with kinetic Monte Carlo (KMC) simulations, we constructed an irregular carbon bridge on the graphene surface and explored the process of H migration from the Pt catalyst to carbon bridge, and further migration to the graphene surface. The calculated reaction diagrams show that the hydrogen atoms can easily migrate from the Pt cluster to the carbon bridge with a low barrier of 0.22-0.86 eV, and KMC simulations indicate that the migration reactions can take place at intermediate temperatures (91.9-329.5 K). Our research clarified the role of the carbon bridge: (1) the close combination of Pt clusters and carbon bridges reduces H2 adsorption enthalpy, which facilitates the spillover of H atoms from the Pt cluster to the carbon bridges and (2) the unsaturated carbon atoms on the carbon bridges have radical character and tend to bind radical H atoms. The subsequent study shows that the F atoms decorated on graphene can greatly reduce the migration barrier of H atoms from the carbon bridge to graphene. With F atoms decorated, the carbon atoms are in an electron-deficient state, which have a strong ability to bind the hydrogen atoms, and it promotes the migration of H atoms to the graphene surface. The migration barrier and reaction temperature are reduced to 0.72 eV and 279 K, respectively.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33072159

RESUMO

Background: Vitamin D (VitD) can regulate immune responses and maternal VitD-deficiency can affect immune responses in the offspring. This study aimed at investigating the effects of maternal VitD-deficiency during pregnancy on Treg and Breg responses in offspring mice with house dust mite (HDM)-induced allergic airway inflammation. Methods: Female BALB/c mice were randomized and fed with normal chow or VitD-deficient diet until their offspring weaned. The offspring mice were fed with normal chow and injected with vehicle or HDM to induce allergic airway inflammation. The levels of serum 25(OH)D, cytokines and infiltrate numbers as well as percentages of Tregs and Bregs in the bronchoalveolar lavage fluid (BALF) were analyzed. The relative levels of VitD receptor (VDR), VitD-binding protein (VDBP), Cytochromes P450 (CYP) 27b1, and CYP24A1 mRNA transcripts in the lungs of different groups of mice were measured. Results: Maternal VitD-deficiency significantly reduced serum 25(OH)D levels in offspring mice. VitD-deficiency significantly increased the relative levels of VDR, VDBP and CYP27B1 mRNA transcripts, but decreased CYP24A1 expression in the lungs of mice. In comparison with the control mice, significantly elevated levels of pro-inflammatory cytokines, increased numbers of lymphocytes and eosinophils, but decreased levels of anti-inflammatory cytokines were detected in the BALF of VitD-deficient mice. VitD-deficiency significantly increased the frequency of Th1, Th2, Th9, Th17 cells, but decreased regulatory T (Tregs) and B cells (Bregs) in the BALF of mice with allergic airway inflammation. Conclusion: Maternal VitD-deficiency lowed serum 25(OH)D levels and enhanced HDM-induced allergic airway inflammation in the offspring by impairing Breg and Treg responses.

8.
Curr Med Sci ; 40(4): 597-601, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32767260

RESUMO

In late December 2019, COVID-19 was firstly recognized in Wuhan, China and spread rapidly to all of the provinces of China. The West Campus of Wuhan Union Hospital, the designated hospital to admit and treat the severe and critically ill COVID-19 cases, has treated a large number of such patients with great success and obtained lots of valuable experiences based on the Chinese guideline (V7.0). To standardize and share the treatment procedures of severe and critically ill cases, Wuhan Union Hospital has established a working group and formulated an operational recommendation, including the monitoring, early warning indicators, and several treatment principles for severe and critically ill cases. The treatment experiences may provide some constructive suggestions for treating the severe and critically ill COVID-19 cases all over the world.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , COVID-19 , Teste para COVID-19 , China/epidemiologia , Técnicas de Laboratório Clínico , Terapia Combinada , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Estado Terminal , Dexametasona/uso terapêutico , Hospitais , Humanos , Imunização Passiva , Medicina Tradicional Chinesa , Pandemias , Pneumonia Viral/epidemiologia , Terapia Respiratória/métodos , SARS-CoV-2
9.
Folia Histochem Cytobiol ; 58(2): 83-89, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32602552

RESUMO

INTRODUCTION: Preeclampsia (PE) is a major contributor to maternal and foetal morbidity and mortality worldwide. It manifests as high blood pressure and proteinuria in women at more than 20 weeks of gestation. Abnormal levels of anti- and pro-angiogenesis factors are known to be associated with PE. In the present study, we aimed to determine the localisation of angiogenic factor with G patch and FHA domains 1 (AGGF1) in the placenta and to compare the expression levels of AGGF1 in the third-trimester placentas of preeclamptic and normotensive pregnancies. MATERIALS AND METHODS: Placental tissue samples were collected from women with PE (n = 28) and without PE (n = 28). The normotensive controls without PE were matched for gestational age at delivery with the patients with PE. The expression levels of AGGF1 in the placental tissues were evaluated using immunohistochemistry, quantitative reverse transcription polymerase chain reaction and Western blot. RESULTS: The immunoexpression of AGGF1 was localised in the syncytiotrophoblast tissue. Notable, the mRNA and protein expression levels of AGGF1 were decreased in preeclamptic placentas as compared with the normotensive control group (P < 0.05). DISCUSSION: Our results suggest that the decreased AGGF1 in preeclamptic placentas may be related to the pathogenesis of preeclampsia.


Assuntos
Proteínas Angiogênicas/metabolismo , Pré-Eclâmpsia/metabolismo , Adulto , Proteínas Angiogênicas/genética , Feminino , Humanos , Placenta/patologia , Pré-Eclâmpsia/patologia , Gravidez , RNA Mensageiro/metabolismo , Trofoblastos/metabolismo
10.
Front Pharmacol ; 11: 928, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670060

RESUMO

It is known that calcitonin gene-related peptide (CGRP) plays a key role in pain modulation in the brain. There are high expressions of CGRP and CGRP receptor in anterior cingulate cortex (ACC), an important brain structure in pain modulation. The present study explored the role and mechanisms of CGRP and CGRP receptor in nociceptive modulation in ACC in naïve rats and inflammatory rats. Administration of different does of CGRP in ACC induced significant antinociception in a dose-dependent manner in both naïve rats and rats with inflammatory pain. The CGRP-induced antinociception was attenuated by injection of the CGRP receptor antagonist CGRP8-37 in ACC. Interestingly, both CGRP-induced antinociception and CGRP receptor expression decreased in ACC in rats with inflammatory pain compared with naïve rats. Knockdown of CGRP receptor in ACC by siRNA targeting to CGRP receptor attenuated both the CGRP receptor expression and the CGRP-induced antinociception significantly in rats. These findings demonstrate that CGRP and CGRP receptor participate in nociceptive modulation in ACC in rats, inhibiting CGRP receptor expression induces decrease in CGRP-induced antinociception in ACC.

11.
Angew Chem Int Ed Engl ; 59(40): 17461-17466, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32588510

RESUMO

Elucidating the effects of crystallization-induced blue-shift emission of a newly synthesized di-boron complex (DBC) by enhanced photoluminescence (PL) and electrochemiluminescence (ECL) in the annihilation pathway was realized for the first time. The 57 nm blue-shift and great enhancement in the crystalline lattice relative to the DBC solution were attributed to the restriction of intramolecular rotation (RIR) and confirmed by PL imaging, X-ray diffraction, as well as DFT calculations. It was discovered that ECL at crystalline film/solution interfaces can be further enhanced by means of both co-reactant route and RIR. The RIR contributions with co-reactant increased ECL up to 5 times more. Very interestingly, the co-reactant system was found to give off a red-shifted light emission. Mechanistic studies reveal that a difference between location of the ECL in the co-reactant route and that in the annihilation pathway leads to an alternative emission wavelength.

13.
Biochem Pharmacol ; 177: 113926, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32217098

RESUMO

BACKGROUND AND PURPOSE: Indoleamine 2, 3-dioxygenase 1 (IDO1) has been linked to neuropathic pain and IDO1 inhibitors have been shown to reduce pain in animals. Some studies have indicated that IDO1 expression increased after neuropathic pain in hippocampus and spinal cord, whether these changes existing in anterior cingulate cortex (ACC) and amygdala remains obscure and how IDO1 inhibition leads to analgesia is largely unknown. Here, we evaluated the antinociceptive effect of PCC0208009, an indirect IDO1 inhibitor, on neuropathic pain and examined the related neurobiological mechanisms. EXPERIMENTAL APPROACH: The effects of PCC0208009 on pain, cognition and anxiogenic behaviors were evaluated in a rat model of neuropathic pain. Motor disorder, sedation and somnolence were also assessed. Biochemical techniques were used to measure IDO1-mediated signaling changes in ACC and amygdala. KEY RESULTS: In rats receiving spinal nerve ligation (SNL), IDO1 expression level was increased in ACC and amygdala. PCC0208009 attenuated pain-related behaviors in the formalin test and SNL model and increased cognition and anxiogenic behaviors in SNL rats at doses that did not affect locomotor activity and sleeping. PCC0208009 inhibited IDO1 expression in ACC and amygdala by inhibiting the IL-6-JAK2/STAT3-IDO1-GCN2-IL-6 pathway. In addition, PCC0208009 reversed synaptic plasticity at the functional and structural levels by suppressing NMDA2B receptor and CDK5/MAP2 or CDK5/Tau pathway in ACC and amygdala. CONCLUSION AND IMPLICATIONS: These results support the role of IDO1-mediated molecular mechanisms in neuropathic pain and suggest that the IDO1 inhibitor PCC0208009 demonstrates selective pain suppression and could be a useful pharmacological therapy for neuropathic pain.


Assuntos
Tonsila do Cerebelo/metabolismo , Analgésicos/uso terapêutico , Giro do Cíngulo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Neuralgia/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Tetrazóis/uso terapêutico , Analgésicos/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Comorbidade , Modelos Animais de Doenças , Formaldeído/farmacologia , Hiperalgesia/tratamento farmacológico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Medição da Dor , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tetrazóis/farmacocinética
14.
Onco Targets Ther ; 12: 6927-6936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695408

RESUMO

Background: Activation of NLPR3 inflammasome is associated with the development and progression of some types of malignant tumors, but its role in endometrial cancer is unclear. This study aimed to investigate the expression and function of NLRP3 inflammasome in endometrial cancer. Materials and methods:  The expression levels of NLRP3, its inflammasome components and estrogen receptor ß in endometrial cancer and paired non-tumor tissues were detected. The effects of NLPR3 silencing or overexpression on the proliferation, migration, and invasion of Ishikawa and HEC-1A cells were determined. The impact of NLPR3 silencing on the growth of implanted tumors was determined in vivo. The effects of estrogen on NLPR3 inflammasome activation and Ishikawa cell proliferation were determined. Results: The upregulation of NLRP3, ASC, caspase-1, and IL-1ß was associated with the progression of endometrial cancer and poor survival. NLPR3 silencing inhibited the proliferation, migration, and invasion of endometrial cancer cells while NLPR3 overexpression had opposite effects. NLPR3 silencing reduced IL-1ß and caspase-1 expression and the growth of implanted endometrial tumors, accompanied by decreased pro-IL-1ß maturation. Estrogen enhanced NLPR3, ERß, pro-IL-1ß, IL-1ß expression, and endometrial cancer cell proliferation, which were mitigated by treatment with ERß inhibitor but not ERα inhibitor. Conclusion: Our results suggest that estrogen acts through ERß to enhance the activation of NLPR3 inflammasome and promote the progression of endometrial cancer. NLPR3 inflammasome may be a new therapeutic target for endometrial cancer.

15.
J Nat Prod ; 82(10): 2713-2720, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31599578

RESUMO

The new phthalideisoquinoline hemiacetal alkaloids (2-7) and the known analogues (1 and 8) were isolated from the bulbs of Corydalis decumbens. The new compounds were characterized by analysis of their NMR spectroscopic data, chemical degradation syntheses, X-ray crystallography, and comparison of experimental and calculated ECD data. All the isolates were screened in vitro for inhibitory activity of spontaneous calcium oscillations in primary cultured neocortical neurons. Compounds 1-3 and 5-7 were found to be active in the suppression of spontaneous calcium oscillations with IC50 values of 6.8, 5.6, 11.6, 10.2, 8.3, and 3.1 µM, respectively. It was also observed that the presence of hydroxy, methoxy, and ethoxy groups at the remote stereogenic center C-7' of some isolated phthalideisoquinoline hemiacetal alkaloids could alter the preferred conformation and invert the sign of optical rotation, rather than this resulting from configurational isomerism at C-1 or C-9, and that the 3J1,9 coupling constants of these analogues varied accordingly. For example, compounds 1 and 6 are levorotatory, despite these molecules having the same carbon skeleton and absolute configuration as (+)-egenine. This emphasizes the potential risk of incorrectly assigning absolute configuration based only on observed coupling constants or optical rotation when comparing the data of new compounds with literature values for known analogues, especially within this class of molecules.


Assuntos
Benzilisoquinolinas/isolamento & purificação , Sinalização do Cálcio/efeitos dos fármacos , Corydalis/química , Benzilisoquinolinas/química , Benzilisoquinolinas/farmacologia , Espectroscopia de Ressonância Magnética , Conformação Molecular
16.
Blood ; 134(2): 171-185, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31151983

RESUMO

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.


Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica/fisiologia , Linfoma Anaplásico de Células Grandes/metabolismo , Transdução de Sinais/fisiologia , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Linfoma Anaplásico de Células Grandes/genética , Regulação para Cima
17.
J Cell Physiol ; 234(10): 18587-18601, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30953349

RESUMO

Gastric cancer (GC) is a common heterogeneous disease. The critical roles of microRNA-340 (miR-340) in the development and progression of GC were emphasized in accumulating studies. This study aims to examine the regulatory mechanism of miR-340 in GC cellular processes. Initially, microarray technology was used to identify differentially expressed genes and regulatory miRs in GC. After that, the potential role of miR-340 in GC was determined via ectopic expression, depletion, and reporter assay experiments. Expression of secreted phosphoprotein 1 (SPP1), miR-340, phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and epithelial-mesenchymal transition (EMT)-related genes was measured. Moreover, to further explore the function of miR-340 in vivo and in vitro, proliferation, apoptosis, migration, invasion, and tumorigenic capacity were evaluated. SPP1 was a target gene of miR-340 which could then mediate the PI3K/AKT signaling pathway by targeting SPP1 in GC. Furthermore, miR-340 levels were reduced and SPP1 was enriched in GC tissues and cells, with the PI3K/AKT signaling pathway being activated. Inhibitory effects of upregulated miR-340 on SPP1 and the PI3K/AKT signaling pathway were confirmed in vivo and in vitro. Overexpression of miR-340 or the silencing of SPP1 inhibited GC cell proliferation, invasion, migration, and EMT process, but promoted apoptosis of GC cells. Typically, targeting of SPP1 by miR-340 may contribute to the inhibition of proliferation, migration, invasion, and EMT of GC cells via suppression of PI3K/AKT signaling pathway.


Assuntos
Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , Osteopontina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Animais , Apoptose/genética , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Camundongos Nus , MicroRNAs/genética , Modelos Biológicos , Invasividade Neoplásica , Osteopontina/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/genética
18.
Acta Pharmacol Sin ; 40(8): 991-998, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30728466

RESUMO

Olfactory bulb, as one of sensory organs opening to the outside, is susceptible to toxic environment and easy to deteriorate. Recent studies in Parkinson's disease (PD) patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that abnormal α-synuclein is accumulated in the olfactory glomeruli, suggesting that the lesions of PD are not only confined to the substantia nigra (SN) but also located in the olfactory bulb. Thus, olfactory bulb might be the region of onset in PD pathogenesis and a targeted region for diagnosis and treatment of PD. However, the relationship between olfactory bulb and pathogenesis of PD remains unclear. In the present study, we investigated the inflammatory pathological alterations in olfactory bulb and the underlying mechanisms in chronic MPTP mice. Mice were treated with MPTP/P, i.e., MPTP (25 mg/kg, s.c.) plus probenecid (250 mg/kg, i.p.) every 4 days, for ten times. The mice displayed typical parkinsonian syndrome. Then we examined their olfactory function and the pathologic changes in olfactory bulb. The mice showed obvious olfactory dysfunction in a buried pellet test. Immunohistochemical studies revealed that tyrosine hydroxylase (TH) protein levels were significantly decreased, whereas abnormal α-synuclein was significantly increased in the olfactory bulbs. Furthermore, the olfactory bulbs in MPTP/P-treated mice showed significantly increased levels of interleukin-1ß (IL-1ß), caspase-1, glial fibrillary acidic protein (GFAP), Toll receptor 4 (TLR4), phosphorylation of p65, as well as activated molecules of NOD-like receptor protein 3 (NLRP3) that were associated with neuroinflammation. Our results demonstrate that MPTP/P-caused olfactory bulb damage might be related to NLRP3-mediated inflammation.


Assuntos
Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Bulbo Olfatório/efeitos dos fármacos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Masculino , Camundongos Endogâmicos C57BL , Bulbo Olfatório/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/etiologia , Probenecid/farmacologia , Multimerização Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , alfa-Sinucleína/metabolismo
19.
Int Immunopharmacol ; 67: 458-464, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30594776

RESUMO

Parkinson's disease (PD) is a typical neurodegenerative disease and the pathological feature of which is the death of dopamine neurons in the substantia nigra region. At present, neuronal death caused by inflammatory cytokine-mediated neuroinflammation is being extensively studied. The nucleotide-binding oligomerization domain-, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome is an inflammatory complex existing in microglia. Its activation promotes the secretion of the inflammatory cytokine interleukin-1ß/18 (IL-1ß/18) and induces pyroptosis, a type of cell death that possesses the potential for inflammation, to rupture microglia to further release IL-1ß. In this review we focus on the mechanisms of activation of the NLRP3 inflammasome and pyroptosis and their inflammatory effects on the development of PD. In addition, we focus on some inhibitors of NLRP3 inflammatory pathways to alleviate the progression of PD by inhibiting central inflammation and provide new therapeutic strategies for the treatment of PD.


Assuntos
Inflamassomos/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Parkinson/metabolismo , Piroptose/fisiologia , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doença de Parkinson/fisiopatologia
20.
Eur J Med Chem ; 161: 364-377, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30384042

RESUMO

Hederagenin is a naturally occurring pentacyclic triterpenoids compound with multiple pharmacological activities. We recently showed that H6, a synthetic derivative of hederagenin, could enhance the anticancer activity of paclitaxel in drug-resistant cells in vitro and in vivo, but showed poor solubility. With the aim of improving the drug resistant reversal activity of H6, here we designed and synthesized a series of novel H6 analogues. Our results showed that compound 10 at the concentration of 5 µM significantly enhanced the cytotoxicity of paclitaxel to drug-resistant KBV cells and sensitized cells to paclitaxel in arresting cells in G2/M phase and inducing apoptosis. We found that compound 10 might block the drug efflux of P-gp via stimulating P-gp ATPase activity. Importantly, compound 10 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors. Finally, we summarized a preliminary structure-activity relationship of hederagenin by the drug resistant reversal activity of H6 analogues in vitro and compound 10 and H6in vivo. This study highlights the importance of nitrogen-containing derivatives of hederagenin C-28 in the development of novel drug resistance reversal agents.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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