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2.
J Inflamm (Lond) ; 18(1): 29, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732212

RESUMO

BACKGROUND: Excessive autophagic activity in alveolar epithelial cells is one of the main causes of acute lung injury (ALI), but the underlying molecular mechanism has not been fully elucidated. Previous studies have shown that microRNAs (miRs) are involved in regulating autophagy in several diseases. This study aimed to determine the role of miR-223 in excessive autophagic activity in alveolar epithelial cells and the underlying mechanism to identify a novel therapeutic targets for the development of new drugs to treat acute respiratory distress syndrome (ARDS). METHODS: A549 cells were treated with lipopolysaccharide (LPS) to establish an ALI in vitro model. The expression of miR-223 and its role of miR-223 in regulating oxidative stress and autophagy in the LPS-treated A549 cells, were examined using RT-PCR, flow cytometry and ELISA. A luciferase reporter assay was performed to verify the interaction between miR-223 and the high-mobility group box 2 (HMGB2) protein. RESULTS: The results showed that the LPS treatment downregulated miR-223 expression in alveolar epithelial cells. We further proved that miR-223 directly targeted the 3-untranslated region of the HMGB2 gene and the downregulation of miR-223 increased HMGB2 protein level, which activated the JNK signalling pathway and thus induced oxidative stress and autophagy in LPS-treated alveolar epithelial cells. Knockdown of HMGB2 protein deactivated the JNK signalling pathway and inhibited autophagy and oxidative stress in alveolar epithelial cells. CONCLUSIONS: The results of this study suggest that miR-223 regulates oxidative stress and autophagy in alveolar epithelial cells by targeting HMGB2 via the JNK signalling pathway.

3.
Transl Cancer Res ; 9(2): 937-948, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35117439

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 80% of the total lung cancer and gemcitabine (GEM)-based chemotherapy is the first-line therapeutic approach for NSCLC treatment. Owing to acquired chemo-resistance, the prognosis of NSCLC patients receiving GEM treatment is still poor. METHODS: Dysregulation of mRNAs in GEM-resistant (GR) NSCLC cells comparing to parental cells were profiled by analyzing GSEA6914 datasets from GEO database. Additionally, qRT-PCR were performed on clinically collected patient serum samples and transplanted tumor tissues and GEM-resistant (GR)/sensitive (GS) cell lines. In order to explore the functional role of tripartite motif protein 22 (TRIM22), gain and loss-of-function cell models were constructed in A549 and A549/GR respectively. MTT and Annexin V-FITC/propidium iodide (PI) staining assay were carried out to access the response to GEM of A549 and A549/GR cells. Observation of RFP-LC3 puncta and western blot detection of autophagy markers were used to evaluate autophagy. Bi-luciferase reporter assay was used to confirm the transcriptional regulatory relationship. Rescue experiments were carried out to confirm the FOXO3/TRIM22 regulatory axis in GEM susceptibility. RESULTS: TRIM22 was significantly upregulated in GR patient serum samples, transplanted tumor tissues and NSCLC cells which was negatively transcriptional regulated by FOXO3. TRIM22 overexpression attenuated the sensitivity of A549 to GEM and its depletion promoted the sensitivity of A549/GR to GEM. Additionally, TRIM22 promoted GEM-induced pro-survival autophagy to protected NSCLC cells from apoptosis. CONCLUSIONS: TRIM22 was significantly upregulated in GR lung adenocarcinoma cell line A549 which is negatively transcriptional regulated by FOXO3. Due to the enhancement of pro-survival autophagy induced by TRIM22, the A549 cells became less sensitive to GEM. This study may provide a basis for screening target of liquid biopsy for predicting GEM sensitivity in NSCLC.

4.
PLoS One ; 6(7): e21930, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21755010

RESUMO

BACKGROUND: Multiple myeloma (MM) is a disease of cell cycle dysregulation while cell cycle modulation can be a target for MM therapy. In this study we investigated the effects and mechanisms of action of a sesquiterpene lactone 6-O-angeloylplenolin (6-OAP) on MM cells. METHODOLOGY/PRINCIPAL FINDINGS: MM cells were exposed to 6-OAP and cell cycle distribution were analyzed. The role for cyclin B1 to play in 6-OAP-caused mitotic arrest was tested by specific siRNA analyses in U266 cells. MM.1S cells co-incubated with interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or bone marrow stromal cells (BMSCs) were treated with 6-OAP. The effects of 6-OAP plus other drugs on MM.1S cells were evaluated. The in vivo therapeutic efficacy and pharmacokinetic features of 6-OAP were tested in nude mice bearing U266 cells and Sprague-Dawley rats, respectively. We found that 6-OAP suppressed the proliferation of dexamethasone-sensitive and dexamethasone-resistant cell lines and primary CD138+ MM cells. 6-OAP caused mitotic arrest, accompanied by activation of spindle assembly checkpoint and blockage of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. Combined use of 6-OAP and bortezomib induced potentiated cytotoxicity with inactivation of ERK1/2 and activation of JNK1/2 and Casp-8/-3. 6-OAP overcame the protective effects of IL-6 and IGF-I on MM cells through inhibition of Jak2/Stat3 and Akt, respectively. 6-OAP inhibited BMSCs-facilitated MM cell expansion and TNF-α-induced NF-κB signal. Moreover, 6-OAP exhibited potent anti-MM activity in nude mice and favorable pharmacokinetics in rats. CONCLUSIONS/SIGNIFICANCE: These results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potentials for MM.


Assuntos
Lactonas/farmacologia , Lactonas/uso terapêutico , Mitose/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Animais , Células da Medula Óssea/citologia , Ácidos Borônicos/farmacologia , Bortezomib , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/metabolismo , Dexametasona/farmacologia , Doxorrubicina/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Fator de Crescimento Insulin-Like I/farmacologia , Interleucina-6/farmacologia , Lactonas/farmacocinética , Camundongos , Mieloma Múltiplo/patologia , Substâncias Protetoras/farmacologia , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/farmacocinética , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Yao Xue Xue Bao ; 44(1): 60-2, 2009 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-19350823

RESUMO

In order to find the compound basis of Phlomis younghusbandii Mukerjee that related to pharmacodynamic action, various chromatographic techniques were used to separate and purify the constituents of this plant, and physicochemical and spectral data were used to identify the structures of obtained compounds. A new furanolabdane diterpene glycoside, named as phlomisoside F, was isolated and identified, which was 15,16-epoxy-8(9),13(16), 14-labdatrien-7-ketone-19-oic acid-beta-D-glucopyranosyl ester.


Assuntos
Diterpenos/isolamento & purificação , Glucosídeos/isolamento & purificação , Glicosídeos/isolamento & purificação , Phlomis/química , Diterpenos/química , Glucosídeos/química , Glicosídeos/química , Estrutura Molecular , Tubérculos/química , Plantas Medicinais/química
6.
7.
Chem Biodivers ; 4(12): 2810-6, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18081091

RESUMO

Two new guaiane-type sesquiterpene lactones, compounds 1 and 2, along with three known guaianolide- or pseudoguaianolides, were isolated from Centipeda minima (whole plant). Their structures were identified by spectroscopic and mass-spectrometric analyses. The configuration at C5 of the guaiane framework of 1 was rationalized by quantum-mechanical calculations (Table 2). All compounds were found to be active against eight different microbial pathogens (Table 3), with MIC values in the range of 6.25-100 microg/ml.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Asteraceae/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular
8.
Chem Biodivers ; 4(12): 2948-52, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18081105

RESUMO

Two new alkaloids, brachystemidines F (1) and G (2), were isolated from the roots of Brachystemma calycinum. Their structures were established on the basis of detailed spectroscopic analyses, including extensive NMR and HR-MS techniques. Compound 2, which exhibits an unusual N-hydroxydiazenyl (HO-N=N) moiety, is a potent immunosuppressive agent, as demonstrated by inhibition of mouse T- and B-lymphocyte proliferation, with IC50 values of 6.33 and 5.60 microg/ml, resp.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Caryophyllaceae/química , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Alcaloides/isolamento & purificação , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular
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