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1.
Food Chem ; 367: 130658, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343808

RESUMO

Camel milk is rich in nutrients and its impact on human medicine and nutrition cannot be ignored. We conducted an in-depth analysis of milk proteins obtained from two camel breed (Camelus bactrianus, CB and Camelus dromedarius, CD). Label-free proteomic technology was performed to analysis the MFGM and whey proteomes of CB and CD milk. In total, 1133 MFGM proteins and 627 whey proteins were identified from camel milk. Results revealed that 216 MFGM proteins and 109 whey proteins were significantly different between them. In addition, the cellular process, cell and binding were the predominately GO annotations of milk proteins. KEGG analysis shown that most proteins were involved in metabolic pathways. Furthermore, many proteins were found to be involved in PI3K/AKT signaling pathway, which could be the possible reason for hypoglycemic effect of camel milk. These results could provide a further understanding for unique biological characteristics of camel milk proteins.


Assuntos
Camelus , Proteoma , Animais , Glicolipídeos , Glicoproteínas , Gotículas Lipídicas , Proteínas do Leite , Fosfatidilinositol 3-Quinases , Proteômica , Soro do Leite , Proteínas do Soro do Leite
2.
Neoplasma ; 68(5): 938-946, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34619972

RESUMO

Breast cancer is the most common malignancy in females. The emergence of endocrine resistance is frustrating for estrogen receptor (ER)-positive breast cancer patients even the efficacy of endocrine therapy is acceptable. Our previous study has shown that tumor-associated macrophages (TAMs) are associated with endocrine resistance, yet the mechanism remains unclear. This article is dedicated to discuss the role of TAMs in the endocrine resistance of breast cancer. It was found that tamoxifen-resistant MCF-7 cells induced more macrophages polarized into TAMs. Conversely, TAMs increased the expression of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), which promoted tamoxifen resistance through the activation of the PI3K/Akt/mTOR signaling pathway in MCF-7 cells. Furthermore, clinical analysis supported that five-year progression-free survival (PFS) of breast cancer patients with abundant COX-2 expression in TAMs was shorter (p<0.05). Therefore, these results show a positive feedback loop between TAMs and breast cancer cells, suggesting that TAMs and COX-2 may be new therapeutic targets for breast cancer patients suffering from endocrine resistance.


Assuntos
Neoplasias da Mama , Ciclo-Oxigenase 2/genética , Transdução de Sinais , Macrófagos Associados a Tumor , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(5): 759-766, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34622589

RESUMO

Objective: To explore the efficacy and mechanism of using 3-n-butylphthalide (NBP) in combination with bone marrow mesenchymal stem cells (BMSCs) in the treatment of experimental autoimmune encephalomyelitis (EAE) in mice. Methods: Myelin oligodendrocyte glycoprotein (MOG35-55) was used for the induction and establishment of the EAE model in C57BL/6 mice. The mice were randomly assigned to the EAE group, which received intraperitoneal injection of phosphate-buffered saline (PBS), the NBP-treated EAE group, or the NBP group, which received intraperitoneal injection of NBP, the BMSCs transplantion EAE group, or the BMSCs group, which received BMSCs injected into the lateral ventricle and intraperitoneal injection of PBS, and the BMSCs and NBP combination treatment EAE group, or the BMSCs+NBP group, which received BMSCs injected into the lateral ventricle and intraperitoneal injection of NBP. Each group had 10 mice, while ten normal mice were used as the blank control group receiving intraperitoneal injection of PBS. The neurological function scores were documented daily. The mice were sacrificed 22 days after EAE induction, and the demyelination state of of the spinal cords was observed through Luxol fast blue (LFB) staining. In addition, the levels of serum interleukin-6 (IL-6), IL-10, IL-17, IL-22 and transforming growth factor-ß (TGF-ß) were examined with ELISA. The levels of glial fibrillary acidic protein (GFAP), microtubule associated protein-2 (MAP-2) and myelin basic protein (MBP) in the brain were examined with immunofluorescence staining. Western blot was used to check the expressions of nuclear factor (NF)-κB pathway, phosphoinositide-3 kinase (PI3K)/protein kinase B (PKB or Akt) pathway, IL-17 and forkhead box P3 (Foxp3) in the spinal cords. Results: The neurological function scores and average scores of each treatment group were significantly lower than those of the EAE group ( P<0.05). The scores of the BMSCs+NBP group decreased more significantly than those of the single treatment groups (the NBP group and the BMSCs group) ( P<0.05). LFB staining results of the spinal cords were consistent with the neurological function scores and the average scores. Compared with the EAE group, the levels of pro-inflammatory cytokines, including IL-6, IL-17 and IL-22, significantly decreased ( P<0.05), and the levels of anti-inflammatory cytokines IL-10 and TGF-ß significantly increased ( P<0.05). The change in cytokine expression was more significant in the BMSCs+NBP group ( P<0.05). The expressions of GFAP, MAP-2 and MBP in the BMSCs+NBP group were significantly higher than those of the BMSCs group ( P<0.05). Compared with the EAE group, the p-NF-κB/NF-κB ratio and the IL-17/Foxp3 ratio in NBP group, BMSCs group and BMSCs+NBP group decreased, while P-IκBα/IκBα, p-pI3k/PI3K and P-Akt/Akt ratios increased, especially in the BMSCs+NBP group( P<0.05). Conclusion: The combined treatment of NBP and BMSCs can help alleviate the symptoms of EAE model mice, showing better efficacy than treatment with NBP or BMSCs alone. The mechanism is related to the inhibition of the NF-κB pathway to regulate Th17/Foxp3 ratio and the activation of the PI3K/Akt pathway to promote the neurogenic differentiation of BMSCs.


Assuntos
Encefalomielite Autoimune Experimental , Células-Tronco Mesenquimais , Animais , Benzofuranos , Encefalomielite Autoimune Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases
4.
Gen Physiol Biophys ; 40(5): 351-363, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34602449

RESUMO

Successful implantation requires endometrial receptivity. To investigate the mechanisms of miR-494-3p on endometrial receptivity, GnRHa's superovulation scheme was designed to reduce endometrial receptivity, and the pregnant mice were injected with miR-494-3p antagomir. The regulatory role of miR-494-3p was identified by RT-qPCR, uterine blastocyst count, scanning electron microscopy, hematoxylin-eosin (HE) staining, and Western blot. Results indicated that miR-494-3p antagomir increased uterine blastocysts numbers, promoted the pinocytosis expressions, and increased endometrial thickness. Besides, miR-494-3p antagomir significantly increased leukemia inhibitory factor (LIF), Ang-2 and VEGF protein expressions, and up-regulated p-AKT/AKT and p-mTOR/mTOR protein ratios in endometrium. Luciferase assay confirmed that LIF was a potential target of miR-494-3p. Subsequently, human endometrial epithelial cells (hEECs) were transfected with miR-494-3p inhibitor and PI3K inhibitor (LY294002). The role of miR-494-3p was identified by RT-qPCR, CCK-8 assay, transwell assay and flow cytometry. Results indicated that miR-494-3p inhibitor significantly increased proliferation and invasion, and significantly inhibited apoptosis in hEECs, while LY294002 reversed its biological function. Overall, these results suggested that miR-494-3p is the key regulator of endometrial receptivity in mice, regulating this complex process through the PI3K/AKT/mTOR pathway. Understanding the role of miR-494-3p in endometrial receptivity is of great significance for exploring new targets for the diagnosis and treatment of early pregnancy failure, and improving the success rates of artificial reproduction.


Assuntos
MicroRNAs/genética , Fosfatidilinositol 3-Quinases , Animais , Endométrio , Feminino , Camundongos , Gravidez , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR
5.
Anal Chim Acta ; 1182: 338943, 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34602188

RESUMO

PIK3CA H1047R gene plays an important role in the PI3K/Akt/mTOR signaling pathway, and its mutation is closely related to the occurrence and development of breast cancer and Lipoblastoma. Therefore, it is of great value to detect the PIK3CA H1047R mutant gene. Here, an analytical method coupled CRISPR/Cas12a with rolling circle amplification (RCA) technology was constructed for ultra-sensitive and specific detection of the single-nucleotide variant (SNV) of the PIK3CA H1047R gene. With efficient amplification of RCA and CRISPR/Cas12a, the detection limit of the mutant target and mixture of the mutant with wild-type target were as low as 10 aM and 0.036%, respectively. The detection limit of the RCA-CRISPR/Cas12a method was lower than that of allelic specific PCR (AS-PCR) for detecting SNV of the PIK3CA H1047R gene. Hence, this RCA-CRISPR/Cas12a method is sensitive and specific for the detection of SNV. What's more, this strategy provides a new idea for medical diagnosis and lays a technical foundation for the research of PI3K/Akt/mTOR signaling pathways.


Assuntos
Sistemas CRISPR-Cas , Fosfatidilinositol 3-Quinases , Sistemas CRISPR-Cas/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Humanos , Mutação , Nucleotídeos , Fosfatidilinositol 3-Quinases/genética
6.
Gen Physiol Biophys ; 40(5): 397-407, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34602453

RESUMO

The present study was conducted to explore the anti-acute myeloid leukaemia (AML) effects of leonurine. HL-60 and U-937 cells were used to assess the antileukaemia effect of leonurine in vitro, and HL-60 and U-937 xenograft nude mice were used to evaluate its antitumour effect in vivo. Leonurine inhibited the proliferation of HL-60 and U-937 cells in a time- and dose-dependent manner. Moreover, leonurine therapy prevented the growth of tumours in both xenograft animal models. Leonurine could induce apoptosis in HL-60 and U-937 cells. The cytotoxic effects of leonurine on HL-60 and U-937 cells were associated with an increased ratio of Bax/Bcl-2, activation of caspase-3, caspase-8 and caspase-9, and increased expression of cytochrome c in the cytoplasm. Leonurine inhibited activation of the PI3K/Akt pathway in HL-60 and U-937 cells by lowering the phosphorylation levels of PI3K and Akt. Our results indicate that leonurine is a potential anti-AML agent, and this activity may be associated with its repression of the phosphorylation of PI3K and Akt.


Assuntos
Leucemia , Fosfatidilinositol 3-Quinases , Animais , Ácido Gálico/análogos & derivados , Células HL-60 , Humanos , Camundongos , Camundongos Nus
7.
Folia Biol (Praha) ; 67(2): 49-61, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34624937

RESUMO

This study investigated the impact of exogenous replacement therapy with acylated ghrelin (AG) post sleeve gastrectomy (SG) on the memory function in rats. In addition, we investigated the possible underlying mechanisms, including the effects on markers of oxidative stress, tau phosphorylation, and apoptosis. Adult male Wistar rats were divided into four groups (N = 18/group) as follows: sham (control), SG, SG+AG (100 µM), and SG+AG+LY294002 (0.25 µg/100 g). We continued all treatments daily for four weeks post-surgery. SG impaired the spatial, retention, and recognition memories as tested by the Morris water maze test, passive avoidance test, and novel object recognition test, respectively. Also, it enhanced the levels of reactive oxygen species and lipid peroxides, reduced glutathione and protein levels of Bcl-2, and increased the levels of Bax and cleaved caspase-3 in the hippocampus. In addition, SG reduced the hippocampal levels of acetylcholine and brain-derived neurotrophic factor. Concomitantly, it inhibited the hippocampal activity of Akt and increased the activity of glycogen synthase kinase 3ß and tau protein phosphorylation. Exogenous administration of acylated ghrelin to rats that had undergone SG prevented memory deficits. Also, it prevented the alteration in the above-mentioned biochemical parameters, an effect that was abolished by co-administration of LY294002 (phosphoinositide 3-kinase inhibitor). In conclusion, AG replacement therapy after SG in rats protects them against memory deficits and hippocampal damage by suppressing tau protein phosphorylation, mediated by activating PI3K/Aktinduced inhibition of glycogen synthase kinase 3ß.


Assuntos
Grelina , Proteínas tau , Animais , Apoptose , Gastrectomia , Grelina/metabolismo , Grelina/farmacologia , Hipocampo/metabolismo , Masculino , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Proteínas tau/metabolismo
8.
Artigo em Chinês | MEDLINE | ID: mdl-34624962

RESUMO

Endocrine disrupting chemicals (EDCs) are a kind of exogenous chemicals widely existing in the environment, which cause serious harm to the environment and human health. At present, the impact of this type of substance on the thyroid has attracted much attention.This review summarized the effects of EDCs on thyroid hormones, and phosphatidylinositol 3-kinase (PI3K) /protein kinase B (Akt) /mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) signaling pathway and its role in thyroid diseases, and explore the role of PI3K/Akt/mTOR signaling pathway in EDCs-induced apoptosis and autophagy of thyroid follicular epithelial cells.This paper could provide further understandings for thyroid diseases induced by the autophagy and apoptosis of thyroid follicular epithelial cells.


Assuntos
Disruptores Endócrinos , Células Epiteliais da Tireoide , Apoptose , Autofagia , Disruptores Endócrinos/toxicidade , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Células Epiteliais da Tireoide/metabolismo
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1394-1402, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627416

RESUMO

OBJECTIVE: To investigate the effect of glycolytic enzyme pyruvate kinase type 2 (PKM2) on the proliferation and apoptosis of human leukemia HL-60 cells. METHODS: si-PKM2 plasmid was transfected into HL-60 cells (set as si-PKM2 group), and blank vector transfected cells were set as control group (si-Ctl group). The expression levels of PKM2 mRNA and protein in si-Ctl group and si-PKM2 group were detected by RT-qPCR and Western blot. CCK-8 cell detection kit was used to detect the proliferation ability of the cells in the two groups. Flow cytometry was used to detect the changes of cell cycle and apoptosis. Western blot and RT-qPCR were used to detect the changes of p-Akt and p-mTOR protein levels in PI3K/Akt/mTOR signaling pathway and the changes of glycolysis-related mRNA levels of the cells in the two groups. The changes in glucose consumption and lactic acid production of the cells were assayed. Over expressed PKM2, HL-60 cells were treated with PI3K inhibitor LY294002 or galactose, the changes in cell proliferation ability, cell cycle and apoptosis, as well as changes in glucose consumption and lactic acid production were detected. RESULTS: Interfered by si-PKM2, mRNA and protein levels of PKM2 in si-PKM2 group significantly decreased, and proliferation ability of the cells was also reduced (P<0.05). After PKM2 knockdown, the cells were significantly blocked at G1 phase, and cell apoptosis was obviously induced (P<0.05). p-Akt and p-mTOR levels were lower in si-PKM2 group than those in si-Ctl group. The glucose consumption and lactic acid production significantly decreased in si-PKM2 cells. Overexpressed PKM2, HL-60 cells were treated with PI3K inhibitor LY294002. The glucose consumption and lactate acid production induced by overexpressed PKM2 were reduced. Overexpressed PKM2, HL-60 cells showed no significant changes in cell proliferation, cycle and apoptosis when cultured with galactose. CONCLUSION: PKM2 knockdown can inhibit the proliferation and induce apoptosis of HL-60 cells, and its molecular mechanism may be related to the PKM2-mediated PI3K/Akt/mTOR-glycolysis, which suggesting that PKM2 may serve as a molecular target for the prevention and treatment of leukemia.


Assuntos
Apoptose , Fosfatidilinositol 3-Quinases , Proliferação de Células , Glicólise , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Piruvato Quinase
10.
Arch Oral Biol ; 131: 105265, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34601318

RESUMO

OBJECTIVE: Sodium fluoride (NaF) plays an important role in preventing dental caries. However, the regulatory effect of NaF on the committed differentiation of DPSCs is not fully understood. In this study, we characterized the impact of micromolar levels of NaF on the osteo/odontogenic differentiation of DPSCs. DESIGN: DPSCs were isolated from healthy human third molars and were cultured in conditioned media with different concentrations of NaF. RNA sequencing (RNA-seq) combined with Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was used to assess the pathways regulated by NaF. Alkaline phosphatase activity, Alizarin red staining, Western blotting, and real-time qRT-PCR were used to determine the osteo/odontogenic differentiation in DPSCs treated with NaF. RESULTS: NaF significantly promoted the osteo/odontogenic differentiation of DPSCs at micromolar levels. Furthermore, RNA-seq and KEGG pathway enrichment analysis indicated that the PI3K/AKT pathway was involved in the pro-osteoclastogenesis effect of NaF. Western blotting analysis exhibited that the phosphorylation of AKT was decreased in NaF-treated DPSCs. Chemical inhibition of the PI3K/AKT pathway abrogated the NaF-promoted DPSCs osteo/odontogenic differentiation. CONCLUSION: Micromolar NaF can promote the osteo/odontogenic differentiation of DPSCs by inhibiting the PI3K/AKT pathway. DATA AVAILABILITY: The data used to support the findings of this study are available from the corresponding author upon request.


Assuntos
Cárie Dentária , Polpa Dentária , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Odontogênese , Osteogênese , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Fluoreto de Sódio/farmacologia , Células-Tronco
11.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3934-3942, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472270

RESUMO

The present study aimed to explore the effect of Erxian Decoction on proteomics of osteoblasts stimulated by hydrogen peroxide(H_2O_2) and its protective mechanism with the H_2O_2-induced cell model of oxidative stress. The primary osteoblasts were cultured from the skulls of newborn rats(within 24 hours) and divided into a control group, a model group, a Fosamax group, and an Erxian Decoction group. Blank serum was added in the control group and model group, and the drug-containing serum was added correspondingly to the remaining two groups. After 45 hours, H_2O_(2 )stimulation was conducted for three hours except for the control group, followed by protein extraction. Nano-LC-LTQ-Orbitrap system was used for protein detection, Protein Discovery for protein identification, and SIEVE for quantitative and qualitative analysis. Furthermore, following the blocking of PI3 K signaling pathway by LY294002(10 µmol·L~(-1)), a control group, a model group, an LY294002 group, an Erxian Decoction group, and an Erxian Decoction + LY294002 group were set up to observe the effect of Erxian Decoction on cell proliferation, alkaline phosphatase(ALP) activity, and the relative expression of BMP-2, OPG, p-Akt, p-FoxO1 of osteoblasts stimulated by H_2O_2 under LY294002 intervention. The results revealed that 78 differential proteins were discovered between the Erxian Decoction group and model group, which were involved in the regulation of PI3 K/Akt, glucagon, estrogen, insulin, and other signaling pathways. LY294002 blunted the promoting effect of Erxian Decoction on osteoblast proliferation and significantly down-regulated the expression of OPG and p-FoxO1, whereas its down-regulation on the expression of BMP-2 and p-Akt was not significant. Both LY294002 and Erxian Decoction increased the ALP activity of osteoblasts, which may be related to the cell state and the cell differentiation. The above results suggest that Erxian Decoction can protect osteoblasts stimulated by H_2O_2, with the PI3 K/Akt signaling pathway as one of the internal mechanisms.


Assuntos
Peróxido de Hidrogênio , Fosfatidilinositol 3-Quinases , Animais , Medicamentos de Ervas Chinesas , Osteoblastos/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais
12.
Food Res Int ; 148: 110594, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507739

RESUMO

Diabetes and its related metabolic disorders are worldwide public health issues. Many studies have shown that changes in the structure and composition of the intestinal flora are closely related to the host's physiological and pathological processes. In this study, we aim to explore the effect of Liubao tea (LBT) extract on hyperglycemic mice with metabolic disorders and intestinal flora dysbiosis and to further study its regulatory effect on insulin resistance and its potential regulatory mechanism. Our results show that LBT had a good hypoglycemic effect and could significantly alleviate the metabolic disorder evoked by hyperglycemia. The gut microbial sequencing showed that LBT treatment increased the diversity of intestinal flora, increased the abundance of beneficial bacteria, and reduced the abundance of harmful or conditional pathogenic bacteria, as well as significantly altered 39 of the top 50 OTUs with abundance. Besides, LBT could activate the PI3K-Akt-PPARs-GLUT2 cascade signaling pathway to improve metabolic disorders, thereby alleviating insulin resistance. These results suggest that LBT has excellent potential to become a natural functional food for the prevention of hyperglycemia and insulin resistance.


Assuntos
Microbioma Gastrointestinal , Resistência à Insulina , Doenças Metabólicas , Animais , Glicemia , Doenças Metabólicas/tratamento farmacológico , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Chá
13.
Can J Gastroenterol Hepatol ; 2021: 9990338, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557456

RESUMO

Long noncoding RNAs (lncRNAs) have been substantially reported to have critical roles in regulating tumorigenesis in recent years. However, the expression pattern and biological function of SNHG17 in hepatocellular carcinoma (HCC) remain unclear. Bioinformatics analysis and qRT-PCR were performed to detect the expression pattern of SNHG17 in HCC tissues, adjacent nontumorous tissues, and cell lines. The effect of SNHG17 on proliferation, migration, and apoptosis of HCC was investigated by knockdown and overexpressing SNHG17 in HCC cell lines. RNA sequencing was utilized to explore the underlying mechanism. Utilizing publicly available TCGA-LIHC, GSE102079 HCC datasets, and qRT-PCR, we found SNHG17 was significantly upregulated in HCC tissues and cell lines and was notably associated with larger tumor size, poorly differentiation, presence of vascular invasion, and advanced TNM stage. Furthermore, gain- and loss-of-function studies demonstrated that SNHG17 promoted cell proliferation and migration and inhibited apoptosis of HCC. By employing RNA sequencing, we found knockdown of SNHG17 caused 1037 differentially expressed genes, highly enriched in several pathways, including metabolic, PI3K-Akt, cell adhesion, regulation of cell proliferation, and apoptotic pathway; among them, 92 were overlapped with SNHG17-related genes in the TCGA-LIHC dataset. Furthermore, ERH, TBCA, TDO2, and PDK4 were successfully validated and found significantly dysregulated in HCC tissues. Moreover, HCC patients with higher SNHG17 expression had a relatively poor overall survival and disease-free survival, and ERH and PDK4 also played a marked role in the prognosis of HCC. Broadly, our findings illustrate that SNHG17 acts as a noncoding oncogene in HCC progression, suggesting its potential value as a novel target for HCC therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , RNA Longo não Codificante/genética
14.
BMC Cancer ; 21(1): 1061, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34565342

RESUMO

BACKGROUND: Neuroblastoma (NB) patients with MYCN amplification or overexpression respond poorly to current therapies and exhibit extremely poor clinical outcomes. PI3K-mTOR signaling-driven deregulation of protein synthesis is very common in NB and various other cancers that promote MYCN stabilization. In addition, both the MYCN and mTOR signaling axes can directly regulate a common translation pathway that leads to increased protein synthesis and cell proliferation. However, a strategy of concurrently targeting MYCN and mTOR signaling in NB remains unexplored. This study aimed to investigate the therapeutic potential of targeting dysregulated protein synthesis pathways by inhibiting the MYCN and mTOR pathways together in NB. METHODS: Using small molecule/pharmacologic approaches, we evaluated the effects of combined inhibition of MYCN transcription and mTOR signaling on NB cell growth/survival and associated molecular mechanism(s) in NB cell lines. We used two well-established BET (bromodomain extra-terminal) protein inhibitors (JQ1, OTX-015), and a clinically relevant mTOR inhibitor, temsirolimus, to target MYCN transcription and mTOR signaling, respectively. The single agent and combined efficacies of these inhibitors on NB cell growth, apoptosis, cell cycle and neurospheres were assessed using MTT, Annexin-V, propidium-iodide staining and sphere assays, respectively. Effects of inhibitors on global protein synthesis were quantified using a fluorescence-based (FamAzide)-based protein synthesis assay. Further, we investigated the specificities of these inhibitors in targeting the associated pathways/molecules using western blot analyses. RESULTS: Co-treatment of JQ1 or OTX-015 with temsirolimus synergistically suppressed NB cell growth/survival by inducing G1 cell cycle arrest and apoptosis with greatest efficacy in MYCN-amplified NB cells. Mechanistically, the co-treatment of JQ1 or OTX-015 with temsirolimus significantly downregulated the expression levels of phosphorylated 4EBP1/p70-S6K/eIF4E (mTOR components) and BRD4 (BET protein)/MYCN proteins. Further, this combination significantly inhibited global protein synthesis, compared to single agents. Our findings also demonstrated that both JQ1 and temsirolimus chemosensitized NB cells when tested in combination with cisplatin chemotherapy. CONCLUSIONS: Together, our findings demonstrate synergistic efficacy of JQ1 or OTX-015 and temsirolimus against MYCN-driven NB, by dual-inhibition of MYCN (targeting transcription) and mTOR (targeting translation). Additional preclinical evaluation is warranted to determine the clinical utility of targeted therapy for high-risk NB patients.


Assuntos
Acetanilidas/farmacologia , Azepinas/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazóis/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Regulação para Baixo , Sinergismo Farmacológico , Fator de Iniciação 4E em Eucariotos/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Esferoides Celulares/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo
15.
Chem Biol Interact ; 348: 109644, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508709

RESUMO

Photoactivated chemotherapy (PACT) is an emerging strategy for targeted cancer therapy. Strained Ru complexes with pseudo-octahedral geometry may undergo photo-induced ligand dissociation, forming aquated photoproducts that are significantly more cytotoxic compared to the precursor complex. The complexes investigated were the strained complex [Ru(bpy)2BC]Cl2 (where bpy = 2,2'-bipyridine and BC = bathocuproine) and its unstrained control [Ru(bpy)2phen]Cl2 (where phen = 1,10-phenanthroline). The uptake of [Ru(bpy)2BC]Cl2, assessed by ICP/MS, started immediately post-incubation and plateaued after 24 h. Active transport was found as the main mode of intracellular transport. Cell viability assays on A375 cells indicated a mean phototoxicity index of 340-fold, and the effect was shown to be primarily mediated by the aquated photoproducts rather than the dissociating ligands. A significant increase in ROS production and DNA damage was also observed. Flow cytometry confirmed the induction of early apoptosis at 48 h that proceeds to late apoptosis/necrosis by 72 h post-treatment. Western blot analysis of pro- and anti-apoptotic proteins revealed that apoptosis was mediated through an interplay between the intrinsic and extrinsic pathways, as well as autophagy and via inhibition of the MAPK and PI3K pathways. In conclusion, this study demonstrates that [Ru(bpy)2BC]Cl2 is a multi-mechanistic PACT drug which exhibits promising anticancer potential.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Melanoma/patologia , Fenantrolinas/química , Rutênio/química , Linhagem Celular Tumoral , Humanos , Ligantes , Fosfatidilinositol 3-Quinases/metabolismo
16.
Nanoscale ; 13(37): 15598-15610, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34529749

RESUMO

The facial nerve is a crucial nerve in the maxillofacial region and is vulnerable to damage. As a consequence of the complications during nerve restoration, existing remedies have certain limitations, thus the treatment of facial nerve injury is always a perplexing task for people. Regulation of Schwann cells is always the breakpoint of neurorestoration since Schwann cells count a great deal in injured nerve repair. In this study, we presented proof that tetrahedral framework nucleic acids (tFNAs), a kind of nucleic acid nanomaterial, were capable of regulating the neurorestorative pathway NGF/PI3 K/AKT, resulting in the activation of a series of cell behaviors related to injured nerve restoration such as proliferation and migration. In vivo experiments also proved that tFNAs enhanced the expressions of axon and myelin marker proteins, impelled histological recovery, promoted the efficient restoration of nerve conduction and muscle movement. Additionally, tFNAs possessed excellent biocompatibility and superior endocytosis ability. Thus, there is good potential for tFNAs to be applied in the therapy of facial nerve injury or even peripheral nerve injury.


Assuntos
Ácidos Nucleicos , Proteínas Proto-Oncogênicas c-akt , Nervo Facial , Humanos , Fator de Crescimento Neural , Fosfatidilinositol 3-Quinases
17.
J Int Med Res ; 49(9): 300060520973137, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34528496

RESUMO

OBJECTIVE: The objective was to explore the expression and potential functions of long noncoding RNA (lncRNA) and mRNAs in human breast cancer (BC). METHODS: Differentially expressed lncRNAs and mRNAs were identified and annotated in BC tissues by using the Agilent human lncRNA assay (Agilent Technologies, Santa Clara, CA, USA) and RNA sequencing. After identification of lncRNAs and mRNAs through quantitative reverse transcription polymerase chain reaction, we conducted a series of functional experiments to confirm the effects of knockdown of one lncRNA, TCONS_00029809, on the progression of BC. RESULTS: We discovered 238 lncRNAs and 200 mRNAs that were differentially expressed in BC tissues and para-carcinoma tissue. We showed that differentially expressed mRNAs were related to biological adhesion and biological regulation and mainly enriched in cytokine-cytokine receptor interaction, metabolic pathways, and PI3K-Akt signaling pathway. We created a protein-protein interaction network to analyze the proteins enriched in these pathways. We demonstrated that silencing of TCONS_00029809 remarkably inhibited proliferation, invasion, and migration of BC cells, and accelerated their apoptosis. CONCLUSIONS: We identified a large number of differentially expressed lncRNAs and mRNAs, which provide data useful in understanding BC carcinogenesis. The lncRNA TCONS_00029809 may be involved in the development of BC.


Assuntos
Neoplasias da Mama , RNA Longo não Codificante , Apoptose , Neoplasias da Mama/genética , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Fosfatidilinositol 3-Quinases , RNA Longo não Codificante/genética , RNA Mensageiro/genética
18.
J Pharm Biomed Anal ; 205: 114357, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500237

RESUMO

This study aimed to demonstrate the pharmacological mechanism of total flavonoids extracted from Astragali Radix (AR) on cyclophosphamide (Cy)-induced leucopenia in mice. First, flow cytometry, network pharmacology and plasma metabolomics were integrated to investigate the pharmacological mechanism of total flavonoids, the targets from network pharmacology and metabolites from metabolomics were analyzed by DAVID. Then, the key cytokines were validated to confirm the predicted metabolic pathway results. The results showed that total flavonoids significantly increased body weight, routine blood indices, bone marrow DNA cells, and also markedly caused lymphocyte proliferation by increasing the percentages of CD4+ and CD8+. Using network pharmacology and metabolomics methods, the study identified 13 signal-related pathways regulated by total flavonoids including PI3K-Akt signaling pathway, Jak-STAT signaling pathway, Sphingolipid signaling pathway, and so on. Total flavonoids also reversed changes in serum cytokines IL-2, IL-6, and GM-CSF. Total flavonoids exhibits protective effects against leucopenia probably by modulating immunologic functions, promoting cell proliferation, and regulating related metabolic pathways at the system level.


Assuntos
Medicamentos de Ervas Chinesas , Flavonoides , Animais , Ciclofosfamida/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Camundongos , Fosfatidilinositol 3-Quinases , Biologia de Sistemas
19.
J Environ Pathol Toxicol Oncol ; 40(3): 51-61, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34587404

RESUMO

AIM: To investigate the anticancer mechanism of neferine on DMBA-prompted mammary tumorigenesis in animals. METHODS: Mammary cancer was prompted by the subcutaneous injection of 25 mg DMBA mixed in 1 ml of the vehicle (sunflower oil [0.5 ml] and saline [0.5 ml]). We analyzed the biochemical and molecular expression of cell-proliferation and apoptotic markers in normal and DMBA-induced rats. RESULTS: We detected low body weight, elevated quantities of lipid peroxidation, and low antioxidant enzyme activities in mammary tissues of DMBA-induced animals. We also found an invasive ductal carcinoma in DMBA-induced animals by histopathological assessment. Furthermore, western blotting findings displayed an augmented expression of PI3K, AKT, NF-κB, PCNA, cyclin D1, Ki-67, and Bcl-2, while reducing expression of p53, Bax, caspase-3, and caspase-9 in DMBA-induced cancer-bearing animals. RT-PCR results found upregulation of cyclin D1, PCNA, and Ki-67, and reduced expression of p53 in DMBA-prompted animals. The oral administration of neferine effectually inhibited mammary tumors via improved antioxidants and prevented lipid peroxidation activities when compared with tumor-bearing rats. Furthermore, neferine also modulated PI3K/AKT/NF-κB signaling through inhibiting cell proliferation and induced apoptosis in tumor-bearing rats. CONCLUSION: In our findings, we concluded that neferine has an anti-proliferative and enhancing apoptotic property against DMBA-induced mammary cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Apoptose/fisiologia , Peso Corporal/efeitos dos fármacos , Carcinógenos/toxicidade , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
20.
Int Heart J ; 62(5): 1124-1134, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34497168

RESUMO

Our study was aimed at exploring the roles of lncRNA RP11-400K9.4 (RP11-400K9.4) on hypoxia/reoxygenation (H/R) -induced cardiomyocytes apoptosis. H/R model was constructed in rat primary cardiomyocytes (PC) and H9c2 cells. In this study, the results showed that H/R significantly induced the apoptosis of PC and H9c2 cells. The expression of RP11-400K9.4 was upregulated in H/R-induced PC and H9c2 cells, but miR-423 expression was downregulated. Silencing RP11-400K9.4 could attenuate H/R-induced apoptosis in PC and H9c2 cells. We also found that miR-423 was a potential target of RP11-400K9.4. The effect of silencing RP11-400K9.4 on H/R-induced apoptosis of PC and H9c2 cells was significantly reversed by miR-423 inhibitor transfection. Furthermore, our data confirmed that silencing RP11-400K9.4 promoted the activation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) /extracellular signal-regulated kinase (ERK) pathways and these phenomena can be reversed by miR-423 inhibitor transfection. In conclusion, our study demonstrated that silencing RP11-400K9.4 could alleviate H/R-induced cardiomyocytes damages via suppressing apoptosis by targeting miR-423 with the activation of PI3K/AKT and MEK/ERK signaling pathways.


Assuntos
MicroRNAs/genética , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/genética , Animais , Apoptose/genética , Estudos de Casos e Controles , Regulação para Baixo , Inativação Gênica , Hipóxia/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Modelos Animais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Sprague-Dawley/genética , Transfecção/métodos , Regulação para Cima
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