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1.
Neurotox Res ; 42(4): 35, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39008165

RESUMO

This study elucidates the molecular mechanisms by which FABP3 regulates neuronal apoptosis via mitochondrial autophagy in the context of cerebral ischemia-reperfusion (I/R). Employing a transient mouse model of middle cerebral artery occlusion (MCAO) established using the filament method, brain tissue samples were procured from I/R mice. High-throughput transcriptome sequencing on the Illumina CN500 platform was performed to identify differentially expressed mRNAs. Critical genes were selected by intersecting I/R-related genes from the GeneCards database with the differentially expressed mRNAs. The in vivo mechanism was explored by infecting I/R mice with lentivirus. Brain tissue injury, infarct volume ratio in the ischemic penumbra, neurologic deficits, behavioral abilities, neuronal apoptosis, apoptotic factors, inflammatory factors, and lipid peroxidation markers were assessed using H&E staining, TTC staining, Longa scoring, rotation experiments, immunofluorescence staining, and Western blot. For in vitro validation, an OGD/R model was established using primary neuron cells. Cell viability, apoptosis rate, mitochondrial oxidative stress, morphology, autophagosome formation, membrane potential, LC3 protein levels, and colocalization of autophagosomes and mitochondria were evaluated using MTT assay, LDH release assay, flow cytometry, ROS/MDA/GSH-Px measurement, transmission electron microscopy, MitoTracker staining, JC-1 method, Western blot, and immunofluorescence staining. FABP3 was identified as a critical gene in I/R through integrated transcriptome sequencing and bioinformatics analysis. In vivo experiments revealed that FABP3 silencing mitigated brain tissue damage, reduced infarct volume ratio, improved neurologic deficits, restored behavioral abilities, and attenuated neuronal apoptosis, inflammation, and mitochondrial oxidative stress in I/R mice. In vitro experiments demonstrated that FABP3 silencing restored OGD/R cell viability, reduced neuronal apoptosis, and decreased mitochondrial oxidative stress. Moreover, FABP3 induced mitochondrial autophagy through ROS, which was inhibited by the free radical scavenger NAC. Blocking mitochondrial autophagy with sh-ATG5 lentivirus confirmed that FABP3 induces mitochondrial dysfunction and neuronal apoptosis by activating mitochondrial autophagy. In conclusion, FABP3 activates mitochondrial autophagy through ROS, leading to mitochondrial dysfunction and neuronal apoptosis, thereby promoting cerebral ischemia-reperfusion injury.


Assuntos
Apoptose , Autofagia , Proteína 3 Ligante de Ácido Graxo , Mitocôndrias , Neurônios , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Apoptose/fisiologia , Autofagia/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Camundongos , Mitocôndrias/metabolismo , Masculino , Proteína 3 Ligante de Ácido Graxo/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Camundongos Endogâmicos C57BL , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Estresse Oxidativo/fisiologia
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1403-1410, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627417

RESUMO

OBJECTIVE: To establish cytarabine-resistant acute lymphoblastic leukemia (ALL) cell lines and investigate its possible resistant mechanism. METHODS: Low-concentration cytarabine (Ara-C) continuously induced and cultured Jurkat and Nalm-6 cells to construct cytarabine-resistant cell lines Jurkat/Ara-C and Nalm-6/Ara-C. The cell viability was detected by CCK-8 assay, and the distribution of cell cycle was detected by flow cytometry. Real-time fluorescence quantitative PCR was used to detect the mRNA expression levels of multidrug resistant gene and Ara-C metabolic enzymes. The expression levels of cyclin were detected by Western blot. RESULTS: Jurkat/Ara-C and Nalm-6/Ara-C drug-resistant cell lines were successfully established, the resistance index of which was 1 973.908±161.163 and 7 231.643± 1 190.624, respectively. Drug-resistant cell lines had no cross-resistance to commonly used chemotherapeutic drugs, such as doxorubicin. Flow cytometry showed that the ratio of G0/G1 phase in Jurkat/Ara-C cells increased but G2/M phase decreased (P<0.05), while the cell cycle distribution of Nalm-6/Ara-C cells did not change in comparison with Nalm-6 cells. The results of real-time quantitative PCR showed that the expression of deoxycytidine kinase (DCK) and cytidine deaminase (CDA) were significantly down-regulated in drug-resistant cells (P<0.05), MRP was up-regulated in Nalm-6/Ara-C cells (P<0.05), while MDR1, LRP and BCRP did not increase in comparison with parental cells. Western blot analysis revealed that cyclinB1 was significantly under-expressed in drug-resistant cells (P<0.05), while cyclinD1 did not change, when compared with parental cells. CONCLUSION: Cytarabine-resistant ALL cell lines are successfully established by using low concentration continuous induction method, and its drug-resistant mechanism may be related to the deficiencies of DCK and cyclinB1.


Assuntos
Citarabina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Linhagem Celular , Citarabina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Proteínas de Neoplasias
4.
Exp Ther Med ; 21(6): 636, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33968167

RESUMO

The aim of the present study was to analyze whether the use of salidroside (SAL) could overcome dexamethasone (DEX) resistance in T-acute lymphocytic leukemia cells. The human T-ALL DEX-resistant cell line, CEM-C1 and the DEX-sensitive cell line, CEM-C7 were used in the current study. The proliferation inhibition rates in these cells, treated with SAL and DEX alone, and in combination were detected using a Cell Counting Kit-8 assay, while the morphological changes of the cells were observed using an inverted microscope. Reverse transcription-quantitative PCR was used to detect the mRNA expression levels of the c-Myc and LC3 genes, while flow cytometry was used to detect the cell cycle distribution and the rate of apoptosis. In addition, western blot analysis was used to detect the protein expression levels of c-Myc, BCL-2, Bax, cleaved PARP and LC3. and acridine orange staining was used to detect the changes in acidic autophagy vesicles. It was found that SAL could effectively inhibit cell proliferation and induce apoptosis in the CEM-C1 and CEM-C7 cells. In addition, SAL promoted the induction of autophagy. The protein expression levels of c-Myc in the CEM-C1 cells were significantly higher compared with that in the CEM-C7 cells. SAL downregulated the mRNA expression levels of the c-Myc gene and protein in a dose-dependent manner. This suggested that SAL could inhibit the proliferation of the CEM-C1 and CEM-C7 cells, induce apoptosis and autophagy and overcome DEX resistance in the CEM-C1 cells. The mechanism may be associated with the downregulation of c-Myc.

5.
Acta Pharmacol Sin ; 42(11): 1875-1887, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33608672

RESUMO

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth. However, monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness. Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation. In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation) on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo. A combination of lovastatin (>3.75 µM) and 2-deoxy-D-glucose (>1.25 mM) synergistically reduced cell viability, arrested cells in the G2/M phase, and induced apoptosis. The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate, resulting in decreased production of ATP and lower steady-state ATP levels. Energy depletion markedly activated AMPK, inhibited mTOR and RAS signaling pathways, eventually inducing autophagy, the cellular pro-survival process under metabolic stress, whereas inhibition of autophagy by chloroquine (6.25 µM) enhanced the cytotoxic effect of the combination of lovastatin and 2-deoxy-D-glucose. These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells. Our findings suggest that concurrently targeting glycolysis, oxidative phosphorylation, and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers.


Assuntos
Autofagia/fisiologia , Neoplasias Colorretais/genética , Desoxiglucose/administração & dosagem , Lovastatina/administração & dosagem , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Antimetabólitos/administração & dosagem , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cloroquina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Células HCT116 , Células HEK293 , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Zhongguo Dang Dai Er Ke Za Zhi ; 18(12): 1264-1268, 2016 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-27974119

RESUMO

OBJECTIVE: To explore the relationship between polymorphisms of interleukin-17A (IL-17A) gene promoter (-197G/A and -692C/T) and the susceptibility to childhood asthma, to further identify the candidate genes for asthma, and to provide a basis for early prevention of asthma in high-risk children. METHODS: Sixty-five outpatients or inpatients with childhood asthma between August 2013 and August 2015 were assigned to asthma group. Seventy healthy children within the same period were assigned to control group. Using peripheral venous blood from the two groups, PCR with sequence-specific primers was carried out to determine single nucleotide polymorphisms at positions -197G/A and -692C/T in IL-17A gene promoter. A statistical analysis was used to evaluate differences in genotype and allele frequencies between the two groups. RESULTS: Compared with the control group, the asthma group had significantly higher frequencies of TT genotype (29% vs 16%; P=0.012) and T allele (52% vs 42%; P=0.039) at position -692C/T of IL-17A gene. Children with T allele had 1.413-fold higher risk of childhood asthma than those with C allele (OR=1.413, 95%CI: 1.015-1.917). There were no significant differences in genotype and allele frequencies at position -197G/A in IL-17A gene between the two groups (p>0.05). CONCLUSIONS: Polymorphisms at position -692C/T in IL-17A gene promoter is associated with the susceptibility to childhood asthma. Children with -692T allele are more susceptible to childhood asthma. There is no significant relationship between polymorphisms at position -197G/A in IL-17A gene promoter and the susceptibility to childhood asthma.


Assuntos
Asma/genética , Predisposição Genética para Doença , Interleucina-17/genética , Polimorfismo de Nucleotídeo Único , Feminino , Genótipo , Humanos , Masculino
7.
Artigo em Chinês | MEDLINE | ID: mdl-23302158

RESUMO

OBJECTIVE: To compare the efficacy and recurrence rates of modified Epley maneuver, modified Semont maneuver and Brandt-Daroff maneuver in patients with posterior canal benign paroxysmal positional vertigo (PC-BPPV). METHODS: One hundred and sixty-eight patients with unilateral PC-BPPV were included in the study, which were divided into four groups randomly, 45 with modified Epley maneuver (group 1), 43 with modified Semont maneuver (group 2), and 40 with Brandt-Daroff maneuver (group 3). There were 40 controls without physical therapy technique (group 4) included. The efficacy after one week and one month, the time to recovery, the frequency of side effects and recurrence rates among the four groups were evaluated. RESULTS: The efficacy of modified Epley maneuver was superior to the other three groups after one week (χ(2)(1, 2) = 8.55, P < 0.05; χ(2)(1, 3) = 23.23, P < 0.01;χ(2)(1, 4) = 44.00, P < 0.01) and to the Brandt-Daroff maneuver at follow-up evaluation after one month (χ(2) = 8.42, P < 0.05). The efficacy of modified Semont maneuver was superior to the control groups after one week (χ(2) = 14.49, P < 0.01), but there was no difference between the two groups after one month (χ(2) = 0.01, P > 0.05). The efficacy of Brandt-Daroff maneuver was not different with the control group at one week and one month follow-up evaluation (χ(2) = 3.35, P > 0.05;χ(2) = 0.18, P > 0.05). Kaplan-Meier testing showed that the time to recovery was significantly shorter in the modified Epley group. The frequency of side effects was not significantly different among the three physical therapy groups. There was no difference in the frequency of recurrence among the four groups (χ(2) = 4.076, P = 0.253). Duration of illness before self-treatment and age were the independent predictors of recurrence. CONCLUSIONS: The modified Epley maneuver is more effective for self treatment of PC-BPPV than modified Semont maneuver and Brandt-Daroff maneuver. Daily routine of self-treatment does not prevent the recurrence of PC-BPPV.


Assuntos
Modalidades de Fisioterapia , Vertigem/terapia , Idoso , Vertigem Posicional Paroxística Benigna , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canais Semicirculares , Resultado do Tratamento , Vertigem/etiologia
8.
Molecules ; 15(10): 7438-49, 2010 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-20966883

RESUMO

Garcinia xanthochymus has been widely used in traditional Chinese medicine for expelling worms and removing food toxins. Bioassay-guided fractionation of an EtOAc-soluble extract of G. xanthochymus stem bark led to the isolation of six new xanthones. Their structures were elucidated by spectroscopic methods, especially 2D-NMR techniques. Free-radical-scavenging activities of the isolated compounds were elucidated through DPPH method. Most of the isolated compounds showed considerable free radical scavenging activity on DPPH assay. Compound 1 exhibited effective antioxidant scavenging activity against DPPH radical with an IC50 value of 19.64 µM, and compound 6 showed the lowest activity among all the tested molecules, with an IC50 value of 66.88 µM. These findings support the notion that the plant genus Garcinia is a good source of bioactive compounds.


Assuntos
Compostos de Bifenilo/química , Sequestradores de Radicais Livres/química , Garcinia , Indicadores e Reagentes/química , Picratos/química , Casca de Planta/química , Xantonas/química , Radicais Livres/química , Garcinia/anatomia & histologia , Garcinia/química , Humanos , Medicina Tradicional Chinesa , Estrutura Molecular , Extratos Vegetais/química , Prenilação
9.
Yao Xue Xue Bao ; 43(9): 938-41, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19048786

RESUMO

To study xanthones from the barks of Garcinia xanthochymus, the constituents were isolated by normal-phase and reverse-phase silica gel column chromatography from the EtOAc extract. Their structures were elucidated by spectral analysis. Three new xanthones were purified and identified as 1,2,5-trihydroxy-6-methoxyxanthone (1), 1,4,6-trihydroxy-5-methoxyxanthone (2), 1,2,7-trihydroxy-4-(1,1-dimethylallyl) xanthone (3).


Assuntos
Garcinia/química , Xantonas/química , Estrutura Molecular , Casca de Planta/química , Plantas Medicinais/química , Xantonas/isolamento & purificação
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