Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 47.322
Filtrar
1.
J Nat Med ; 78(2): 342-354, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38324123

RESUMO

Evodiamine, a novel alkaloid, was isolated from the fruit of tetradium. It exerts a diversity of pharmacological effects and has been used to treat gastropathy, hypertension, and eczema. Several studies reported that evodiamine has various biological effects, including anti-nociceptive, anti-bacterial, anti-obesity, and anti-cancer activities. However, there is no research regarding its effects on drug-resistant cancer. This study aimed to investigate the effect of evodiamine on human vemurafenib-resistant melanoma cells (A375/R cells) proliferation ability and its mechanism. Cell activity was assessed using the cell counting kit-8 (CCK-8) method. Flow cytometry assay was used to assess cell apoptosis and cell cycle. A xenograft model was used to analyze the inhibitory effects of evodiamine on tumor growth. Bioinformatics analyses, network pharmacology, and molecular docking were used to explore the potential mechanism of evodiamine in vemurafenib-resistant melanoma. RT-qPCR and Western blotting were performed to reveal the molecular mechanism. The alkaloid extract of the fruit of tetradium, evodiamine showed the strongest tumor inhibitory effect on vemurafenib-resistant melanoma cells compared to treatment with vemurafenib alone. Evodiamine inhibited vemurafenib-resistant melanoma cell growth, proliferation, and induced apoptosis, conforming to a dose-effect relationship and time-effect relationship. Results from network pharmacology and molecular docking suggested that evodiamine might interact with IRS4 to suppress growth of human vemurafenib-resistant melanoma cells. Interestingly, evodiamine suppressed IRS4 expression and then inhibited PI3K/AKT signaling pathway, and thus had the therapeutic action on vemurafenib-resistant melanoma.


Assuntos
Alcaloides , Antineoplásicos , Melanoma , Quinazolinas , Humanos , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Simulação de Acoplamento Molecular , Transdução de Sinais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Proliferação de Células , Alcaloides/farmacologia , Linhagem Celular Tumoral , Proteínas Substratos do Receptor de Insulina/metabolismo
2.
Int J Oncol ; 64(4)2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38334171

RESUMO

Chemoresistance is a major challenge in treating triple­negative breast cancer (TNBC); chemotherapy remains the primary approach. The present study aimed to elucidate the role of guanylate­binding protein 2 (GBP2) in activating autophagy in TNBC and its impact on the sensitivity of TNBC cells to paclitaxel (PTX). Transfection with lentivirus was performed to establish TNBC cell lines with stable, high GBP2 expression. The mRNA and protein levels of GBP2 expression were evaluated utilizing reverse transcription­quantitative PCR and western blotting, respectively. Autophagy in TNBC cells was evaluated using immunoblotting, transmission electron microscopy and fluorescence microscopy. The PI3K/AKT/mTOR pathway proteins and their phosphorylation were detected by immunoblotting, and fluorescence co­localization analysis was performed to evaluate the association between GBP2 and autophagy­related protein 2 (ATG2). BALB/c NUDE mice were subcutaneously injected with GBP2 wild­type/overexpressing MDA­MB­231 cells. Low GBP2 expression was detected in TNBC, which was associated with a poor prognosis. Overexpression of GBP2 suppressed cell growth, and especially enhanced autophagy in TNBC. Forced expression of GBP2 significantly increased the PTX sensitivity of TNBC cells, and the addition of autophagy inhibitors reversed this effect. GBP2 serves as a prognostic marker and exerts a notable inhibitory impact on TNBC. It functions as a critical regulator of activated autophagy by co­acting with ATG2 and inhibiting the PI3K/AKT/mTOR pathway, which contributes to increasing sensitivity of TNBC cells to PTX. Therefore, GBP2 is a promising therapeutic target for enhancing TNBC treatment.


Assuntos
Transdução de Sinais , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Camundongos Nus , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Proteínas de Ligação ao GTP/metabolismo
3.
Eur J Med Chem ; 267: 116179, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38340509

RESUMO

The structural motif of coumarins is related with various biological activities and pharmacological properties. Both natural coumarin extracted from various plants or a new coumarin derivative synthesized by modification of the basic structure of coumarin, in vitro experiments showed that coumarins are a promising class of anti-tumor agents with high selectivity. Cancer is a complex and multifaceted group of diseases characterized by the uncontrolled and abnormal growth of cells in the body. This review focuses on the anticancer mechanism of various coumarins synthesized and isolated in more than a decade. Isopentenyloxycoumarins inhibit angiogenesis by reducing CCl2 chemokine levels. Ferulin C is a potent colchicine-binding agent that destabilizes microtubules, exhibiting antiproliferative and anti-metastatic effects in breast cancer cells through PAK1 and PAK2-mediated signaling. Trimers of triphenylethylene-coumarin hybrids demonstrated significant proliferation inhibition in HeLa, A549, K562, and MCF-7 cell lines. Platinum(IV) complexes with 4-hydroxycoumarin have the potential for high genotoxicity against tumor cells, inducing apoptosis in SKOV-3 cells by up-regulating caspase 3 and caspase 9 expression. Derivatives of 3-benzyl coumarin seco-B-ring induce apoptosis, mediated through the PI3K/Akt/mTOR signaling pathway. Sesquiterpene coumarins inhibit the efflux pump of multidrug resistance-associated protein. Coumarin imidazolyl derivatives inhibit the aromatase enzyme, a major contributor to estrogen overproduction in estrogen-dependent breast cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Feminino , Humanos , Antineoplásicos/química , Apoptose , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cumarínicos/química , Estrogênios/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo
4.
Mol Cancer ; 23(1): 33, 2024 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355583

RESUMO

BACKGROUND: Circular RNAs are highly stable regulatory RNAs that have been increasingly associated with tumorigenesis and progression. However, the role of many circRNAs in triple-negative breast cancer (TNBC) and the related mechanisms have not been elucidated. METHODS: In this study, we screened circRNAs with significant expression differences in the RNA sequencing datasets of TNBC and normal breast tissues and then detected the expression level of circRPPH1 by qRT‒PCR. The biological role of circRPPH1 in TNBC was then verified by in vivo and in vitro experiments. Mechanistically, we verified the regulatory effects between circRPPH1 and ZNF460 and between circRPPH1 and miR-326 by chromatin immunoprecipitation (ChIP), fluorescence in situ hybridization assay, dual luciferase reporter gene assay and RNA pull-down assay. In addition, to determine the expression of associated proteins, we performed immunohistochemistry, immunofluorescence, and western blotting. RESULTS: The upregulation of circRPPH1 in TNBC was positively linked with a poor prognosis. Additionally, both in vivo and in vitro, circRPPH1 promoted the biologically malignant behavior of TNBC cells. Additionally, circRPPH1 may function as a molecular sponge for miR-326 to control integrin subunit alpha 5 (ITGA5) expression and activate the focal adhesion kinase (FAK)/PI3K/AKT pathway. CONCLUSION: Our research showed that ZNF460 could promote circRPPH1 expression and that the circRPPH1/miR-326/ITGA5 axis could activate the FAK/PI3K/AKT pathway to promote the progression of TNBC. Therefore, circRPPH1 can be used as a therapeutic or diagnostic target for TNBC.


Assuntos
MicroRNAs , Fatores de Transcrição , Neoplasias de Mama Triplo Negativas , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , RNA Circular/genética , Hibridização in Situ Fluorescente , Linhagem Celular Tumoral , Integrinas/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Proteínas de Ligação a DNA/metabolismo
5.
J Agric Food Chem ; 72(8): 4100-4115, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38373195

RESUMO

Wound healing is a multiphase process with a complex repair mechanism; trauma-repairing products with safety and high efficiency have a great market demand. Egg white peptides (EWP) have various physiological regulatory functions and have been proven efficient in ameliorating skin damage. However, their underlying regulation mechanism has not been revealed. This study further evaluated the EWP ameliorating mechanism by conducting a full-thickness skin wound model. Results demonstrated that EWP administration significantly inhibited the expression of pro-inflammatory and shortened the inflammatory phase. Besides, EWP can accelerate the secretion of growth factors (PDGF, VEGF, and TGF-ß1) in skin tissue, significantly increasing the regeneration of granulation tissue and endothelium in the proliferation phase, thereby promoting wound healing. After 400 mg/kg EWP interventions for 13 days postoperation, the wound healing rate reached 90%. The combination of transcriptomic and proteomic analyses demonstrated the ameliorating efficiency effects of EWP on wound healing. EWP mainly participates in the functional network with the PI3K-AKT signaling pathway as the core to accelerate wound healing. These findings suggest a promising EWP-based strategy for accelerating wound healing.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Cicatrização , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteômica , Clara de Ovo , Proliferação de Células , Movimento Celular , Peptídeos/farmacologia , Perfilação da Expressão Gênica
6.
Invest Ophthalmol Vis Sci ; 65(2): 34, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38393716

RESUMO

Purpose: The purpose of this study was to investigate the antitumor effects of GSK-J4 on retinoblastoma, as well as its related biological functions and molecular mechanisms. Methods: The antitumor effect of GSK-J4 on retinoblastoma was evaluated by in vitro and in vivo assays. CCK-8, EdU incorporation, and soft agar colony formation assays were performed to examine the effect of GSK-J4 on cell proliferation. Flow cytometry was used to evaluate the effect of GSK-J4 on the cell cycle and apoptosis. RNA-seq and Western blotting were conducted to explore the molecular mechanisms of GSK-J4. An orthotopic xenograft model was established to determine the effect of GSK-J4 on tumor growth. Results: GSK-J4 significantly inhibited retinoblastoma cell proliferation both in vitro and in vivo, arrested the cell cycle at G2/M phase, and induced apoptosis. Mechanistically, GSK-J4 may suppress retinoblastoma cell growth by regulating the PI3K/AKT/NF-κB signaling pathway. Conclusions: The antitumor effects of GSK-J4 were noticeable in retinoblastoma and were at least partially mediated by PI3K/AKT/NF-κB pathway suppression. Our study provides a novel strategy for the treatment of retinoblastoma.


Assuntos
Benzazepinas , Pirimidinas , Neoplasias da Retina , Retinoblastoma , Humanos , Histona Desmetilases/metabolismo , NF-kappa B , Retinoblastoma/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Proliferação de Células , Neoplasias da Retina/tratamento farmacológico , Linhagem Celular Tumoral , Apoptose
7.
Int J Mol Sci ; 25(4)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38396988

RESUMO

Alzheimer's disease (AD) is a representative cause of dementia and is caused by neuronal loss, leading to the accumulation of aberrant neuritic plaques and the formation of neurofibrillary tangles. Oxidative stress is involved in the impaired clearance of amyloid beta (Aß), and Aß-induced oxidative stress causes AD by inducing the formation of neurofibrillary tangles. Hwangryunhaedok-tang (HHT, Kracie K-09®), a traditional herbal medicine prescription, has shown therapeutic effects on various diseases. However, the studies of HHT as a potential treatment for AD are insufficient. Therefore, our study identified the neurological effects and mechanisms of HHT and its key bioactive compounds against Alzheimer's disease in vivo and in vitro. In a 5xFAD mouse model, our study confirmed that HHT attenuated cognitive impairments in the Morris water maze (MWM) test and passive avoidance (PA) test. In addition, the prevention of neuron impairment, reduction in the protein levels of Aß, and inhibition of cell apoptosis were confirmed with brain tissue staining. In HT-22 cells, HHT attenuates tBHP-induced cytotoxicity, ROS generation, and mitochondrial dysfunction. It was verified that HHT exerts a neuroprotective effect by activating signaling pathways interacting with Nrf2, such as MAPK/ERK, PI3K/Akt, and LKB1/AMPK. Among the components, baicalein, a bioavailable compound of HHT, exhibited neuroprotective properties and activated the Akt, AMPK, and Nrf2/HO-1 pathways. Our findings indicate a mechanism for HHT and its major bioavailable compounds to treat and prevent AD and suggest its potential.


Assuntos
Doença de Alzheimer , Antioxidantes , Extratos Vegetais , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
8.
Int J Mol Sci ; 25(4)2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38397033

RESUMO

In female mammals, the proliferation and apoptosis of granulosa cells (GCs) are critical in determining the fate of follicles and are influenced by various factors, including brain-derived neurotrophic factor (BDNF). Previous research has shown that BDNF primarily regulates GC proliferation through the PI3K/AKT, NF-kB, and CREB tumour pathways; however, the role of other molecular mechanisms in mediating BDNF-induced GC proliferation remains unclear. In this study, we investigated the involvement of the m6A reader YTH domain-containing family member 2 (YTHDF2) in BDNF-stimulated GC proliferation and its underlying mechanism. GCs were cultured in DMEM medium supplemented with varying BDNF concentrations (0, 10, 30, 75, and 150 ng/mL) for 24 h. The viability, number, and cell cycle of GCs were assessed using the CCK-8 assay, cell counting, and flow cytometry, respectively. Further exploration into YTHDF2's role in BDNF-stimulated GC proliferation was conducted using RT-qPCR, Western blotting, and sequencing. Our findings indicate that YTHDF2 mediates the effect of BDNF on GC proliferation. Additionally, this study suggests for the first time that BDNF promotes YTHDF2 expression by increasing the phosphorylation level of the ERK1/2 signalling pathway. This study offers a new perspective and foundation for further elucidating the mechanism by which BDNF regulates GC proliferation.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Fosfatidilinositol 3-Quinases , Feminino , Suínos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Células da Granulosa/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Proliferação de Células , Mamíferos/metabolismo
9.
Int J Mol Sci ; 25(4)2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38397050

RESUMO

Complement component 4 binding protein α (C4BPA) is an immune gene which is responsible for the complement regulation function of C4BP by binding and inactivating the Complement component C4b (C4b) component of the classical Complement 3 (C3) invertase pathway. Our previous findings revealed that C4BPA was differentially expressed by comparing the transcriptome in high-fat and low-fat bovine mammary epithelial cell lines (BMECs) from Chinese Holstein dairy cows. In this study, a C4BPA gene knockout BMECs line model was constructed via using a CRISPR/Cas9 system to investigate the function of C4BPA in lipid metabolism. The results showed that levels of triglyceride (TG) were increased, while levels of cholesterol (CHOL) and free fatty acid (FFA) were decreased (p < 0.05) after knocking out C4BPA in BMECs. Additionally, most kinds of fatty acids were found to be mainly enriched in the pathway of the biosynthesis of unsaturated fatty acids, linoleic acid metabolism, fatty acid biosynthesis, and regulation of lipolysis in adipocyte. Meanwhile, the RNA-seq showed that most of the differentially expressed genes (DEGs) are related to PI3K-Akt signaling pathway. The expressions of 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 (HMGCS1), Carnitine Palmitoyltransferase 1A (CPT1A), Fatty Acid Desaturase 1 (FADS1), and Stearoyl-Coenzyme A desaturase 1 (SCD1) significantly changed when the C4BPA gene was knocked out. Collectively, C4BPA gene, which is an immune gene, played an important role in lipid metabolism in BMECs. These findings provide a new avenue for animal breeders: this gene, with multiple functions, should be reasonably utilized.


Assuntos
Complemento C4 , Metabolismo dos Lipídeos , Fosfatidilinositol 3-Quinases , Animais , Bovinos , Feminino , Complemento C4/metabolismo , Células Epiteliais/metabolismo , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transcriptoma
10.
Genes (Basel) ; 15(2)2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38397192

RESUMO

Malignant melanomas (MMs) are the abnormal proliferation of melanocytes and are one of the lethal skin cancers in humans, equines, and canines. Accordingly, MMs in companion animals can serve as naturally occurring animal models, completing conventional cancer models. The common constitutive activation of the MAPK and PI3K pathways in MMs has been described in all three species. Targeting the related pathways is considered a potential option in comparative oncologic approaches. Herein, we present a cross-species comparative analysis exposing a set of ten melanoma cell lines (one human, three equine, and six canine) derived from primary tumors or metastasis to a pan-RAF and RAF dimer inhibitor (LY3009120). Cellular response (proliferation, biomass, metabolism, early and late apoptosis/necrosis, and morphology) and the presence of pathogenic single-nucleotide variants (SNVs) within the mutational hotspot genes BRAF exon 11 and 15, NRAS exon 2 and 3, KRAS exon 2, and KIT exon 11 were analyzed. This study showed that equine malignant melanoma (EMM) cells (MelDuWi) harbor the KRAS p.Q61H mutation, while canine malignant melanoma (CMM) cells (cRGO1 and cRGO1.2) carry NRAS p.G13R. Except for EMM metastasis cells eRGO6 (wild type of the above-mentioned hotspot genes), all melanoma cell lines exhibited a decrease in dose dependence after 48 and 72 h of exposure to LY3009120, independent of the mutation hotspot landscape. Furthermore, LY3009120 caused significant early apoptosis and late apoptosis/necrosis in all melanoma cell lines except for eRGO6. The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the NRAS p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology.


Assuntos
Antineoplásicos , Melanoma , Compostos de Fenilureia , Pirimidinas , Neoplasias Cutâneas , Animais , Cães , Humanos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cavalos , Melanoma/tratamento farmacológico , Melanoma/genética , Necrose , Compostos de Fenilureia/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Pirimidinas/farmacologia
11.
PLoS One ; 19(2): e0297875, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38408058

RESUMO

Omentin (ITLN1) is a novel adipokine mainly expressed in the white adipose tissue. It plays a crucial role in the metabolic homeostasis and insulin sensitivity. Our last study documented that ITLN1 levels in the adipose tissue and plasma are lower in fat Meishan (MS) compared to normal weight Large White (LW) pigs. The aim of this study was to investigate transcript and protein concentrations of ITLN1 as well as its immunolocalisation in the ovarian follicles and examine the molecular mechanism involved in the regulation of its expression in response to gonadotropins (FSH, LH) and steroids (P4, T, E2). Ovarian follicles were collected from LW and MS sows on days 2-3, 10-12, and 14-16 of the oestrous. We found the elevated ITLN1 expression in the ovarian follicles and the increase of concentrations in follicular fluid (FF) of LW pigs vs MS pigs; in both breeds of pigs, the levels of ITLN1 increased with the oestrous progression. We noted ITLN1 signals in oocyte, granulosa and theca cells. Gonadotropins and steroids increased ITLN1 levels in the ovarian follicle cells of LW pigs, while in MS pigs, we observed only the stimulatory effect of LH and T. Both extracellular signal-regulated kinase (ERK1/2) and phosphatidylinositol 3'-kinase (PI3K) were involved in the regulation of ITLN1. Our study demonstrated the levels and regulation of ITLN1 in the porcine ovarian follicles through ERK1/2 and PI3K signaling pathways.


Assuntos
Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases , Feminino , Suínos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Folículo Ovariano/metabolismo , Esteroides/metabolismo , Gonadotropinas/farmacologia , Estradiol/metabolismo , Hormônio Foliculoestimulante/metabolismo
12.
Asian Pac J Cancer Prev ; 25(2): 473-483, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38415533

RESUMO

BACKGROUND: In the majority of cancers, metastasis of tumor cells is the main cause of treatment failure. This study intended to investigate the effectiveness of basic fibroblast growth factor (bFGF) peptide designed to inhibit tumor growth in 4T1 metastatic breast cancer through the PI3K/AKT and ERK/MAPK signal transduction pathways. METHODS: The tumor was induced through 4T1 tumor graft in BALB/c mice. The designed peptide was injected intraperitoneal at three selected doses after two weeks for 14 days. The PBS and doxorubicin were used as the negative and positive control groups, respectively. Tumor size was measured and after the treatment period, the mice underwent a surgery and tumors were used for the western blot examinations. RESULTS: the peptide injection was effective in reducing or inhibiting tumor growth in mice model and in vitro. The western blot analysis results showed that the p-AKT and p-ERK levels in peptide treated tumors were reduced (p<0.05). CONCLUSION: The peptide injection was effective in mice model. Findings showed that in the two signal transduction pathways, the p-AKT and p-ERK levels were significantly different from the negative control group.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Crescimento de Fibroblastos , Transdução de Sinais , Modelos Animais de Doenças , Linhagem Celular Tumoral
13.
Nutrients ; 16(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38398890

RESUMO

The utilization of food as a therapeutic measure for various ailments has been a prevalent practice throughout history and across different cultures. This is exemplified in societies where substances like Hibiscus sabdariffa have been employed to manage health conditions like hypertension and elevated blood glucose levels. The inherent bioactive compounds found in this plant, namely, delphinidin-3-sambubioside (DS3), quercetin (QRC), and hibiscus acid (HA), have been linked to various health benefits. Despite receiving individual attention, the specific molecular targets for these compounds remain unclear. In this study, computational analysis was conducted using bioinformatics tools such as Swiss Target Prediction, ShinnyGo 0.77, KEGG, and Stringdb to identify the molecular targets, pathways, and hub genes. Supplementary results were obtained through a thorough literature search in PubMed. DS3 analysis revealed potential genetic alterations related to the metabolism of nitrogen and glucose, inflammation, angiogenesis, and cell proliferation, particularly impacting the PI3K-AKT signaling pathway. QRC analysis demonstrated interconnected targets spanning multiple pathways, with some overlap with DS3 analysis and a particular focus on pathways related to cancer. HA analysis revealed distinct targets, especially those associated with pathways related to the nervous system. These findings emphasize the necessity for focused research on the molecular effects of DS3, QRC, and HA, thereby providing valuable insights into potential therapeutic pathways.


Assuntos
Antocianinas , Citratos , Hibiscus , Quercetina , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/análise , Fosfatidilinositol 3-Quinases
14.
Ann Biol Clin (Paris) ; 81(6): 591-601, 2024 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-38391164

RESUMO

This study was conducted to evaluate the diagnostic and prognostic values of LINC00623 in patients with lung adenocarcinoma (LUAD), as well as the promoting role in LUAD progression. LINC00623 levels were identified by RT-qPCR. Using ROC curve analysis, the discrimination value of LINC00623 for LUAD from lung squamous cell carcinoma (LUSC) and the health was assessed. Recurrence-free and overall survival were estimated using the Kaplan-Meier method and multivariate survival analysis. Cell biological properties were analyzed by growth curves, transwell migration, and invasion assays. The downstream miRNA and genes were retrieved and annotated by online databases. LINC00623 was significantly upregulated in the LUAD tissues and cell lines compared to LUSC tissues and the noncancerous tissues. LINC00623 showed a discriminating power for predicting LUAD. LUAD patients with a high level of LINC00623 tend to have poor overall survival and recurrence-free survival. Downregulation of LINC00623 reduced the proliferation, migration, and invasion of LUAD cells. MiR-1207-5p was a target of LINC00623 and its target genes were related to PI3K/Akt signaling pathway. The subtypes, recurrence-free survival, and overall survival of patients with LUAD might be well discriminated by LINC00623 levels. LINC00623 promoted LUAD progression through sponging miR-1207-5p.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , MicroRNAs , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Prognóstico , Fosfatidilinositol 3-Quinases , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia
15.
Cells ; 13(4)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38391958

RESUMO

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Feminino , Humanos , Proteína BRCA1/genética , Proteína Supressora de Tumor p53/genética , Proteínas Proto-Oncogênicas B-raf/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Carcinogênese , Transformação Celular Neoplásica , Cistadenocarcinoma Seroso/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Patrimônio Genético
16.
Cells ; 13(4)2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38391968

RESUMO

In this study, we investigated the beneficial effects of grapefruit IntegroPectin, derived from industrial waste grapefruit peels via hydrodynamic cavitation, on microglia cells exposed to oxidative stress conditions. Grapefruit IntegroPectin fully counteracted cell death and the apoptotic process induced by cell exposure to tert-butyl hydroperoxide (TBH), a powerful hydroperoxide. The protective effects of the grapefruit IntegroPectin were accompanied with a decrease in the amount of ROS, and were strictly dependent on the activation of the phosphoinositide 3-kinase (PI3K)/Akt cascade. Finally, IntegroPectin treatment inhibited the neuroinflammatory response and the basal microglia activation by down-regulating the PI3K- nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)- inducible nitric oxide synthase (iNOS) cascade. These data strongly support further investigations aimed at exploring IntegroPectin's therapeutic role in in vivo models of neurodegenerative disorders, characterized by a combination of chronic neurodegeneration, oxidative stress and neuroinflammation.


Assuntos
Citrus paradisi , Microglia , Humanos , Microglia/metabolismo , Citrus paradisi/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Linhagem Celular
17.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(1): 31-38, 2024 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-38322519

RESUMO

Alveolar bone, the protruding portion of the maxilla and the mandible that surrounds the roots of teeth, plays an important role in tooth development, eruption, and masticatory performance. In oral inflammatory diseases, including apical periodontitis, periodontitis, and peri-implantitis, alveolar bone defects cause the loosening or loss of teeth, impair the masticatory function, and endanger the physical and mental health of patients. However, alveolar bone restoration is confronted with great clinical challenges due to the the complicated effect of the biological, mechanical, and chemical factors in the oral microenvironment. An in-depth understanding of the underlying molecular regulatory mechanisms will contribute to the exploration of new targets for alveolar bone restoration. Recent studies have shown that Notch, Wnt, Toll-like receptor (TLR), and nuclear factor-κB (NF-κB) signaling pathways regulate the proliferation, differentiation, apoptosis, and autophagy of osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, and adaptive immune cells, modulate the expression of inflammatory mediators, affect the balance of the receptor activator for nuclear factor-κB ligand/receptor activator for nuclear factor-κB/osteoprotegerin (RANKL/RANK/OPG) system, and ultimately participate in alveolar bone restoration. Additionally, alveolar bone restoration involves AMP-activated protein kinase (AMPK), phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT), Hippo/YAP, Janus kinase/signal transducer and activator of transcription (JAK/STAT), and transforming growth factor ß (TGF-ß) signaling pathways. However, current studies have failed to construct mature molecular regulatory networks for alveolar bone restoration. There is an urgent need for further research on the molecular regulatory mechanisms of alveolar bone restoration by using new technologies such as single-cell transcriptome sequencing and spatial transcriptome sequencing.


Assuntos
NF-kappa B , Fosfatidilinositol 3-Quinases , Humanos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Osteoprotegerina/metabolismo , Osteoprotegerina/farmacologia , Osso e Ossos/metabolismo , Transdução de Sinais , Osteoclastos/metabolismo , Ligante RANK/metabolismo , Ligante RANK/farmacologia
18.
Appl Microbiol Biotechnol ; 108(1): 218, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38372808

RESUMO

Ovarian cancer poses a significant threat to women's health, with conventional treatment methods encountering numerous limitations, and the emerging engineered bacterial anti-tumor strategies offer newfound hope for ovarian cancer treatment. In this study, we constructed the VNP20009-Abvec-Igκ-MIIP (VM) engineered strain and conducted initial assessments of its in vitro growth performance and the expression capability of migration/invasion inhibitory protein (MIIP). Subsequently, ID8 ovarian cancer cells and mouse cancer models were conducted to investigate the impact of VM on ovarian cancer. Our results revealed that the VM strain demonstrated superior growth performance, successfully invaded ID8 ovarian cancer cells, and expressed MIIP, consequently suppressing cell proliferation and migration. Moreover, VM specifically targeted tumor sites and expressed MIIP which further reduced the tumor volume of ovarian cancer mice (p < 0.01), via the downregulation of epidermal growth factor receptor (EGFR), Ras, p-MEK, and p-ERK. The downregulation of the PI3K/AKT signaling pathway and the decrease in Bcl-2/Bax levels also indicated VM's apoptotic potency on ovarian cancer cells. In summary, our research demonstrated that VM exhibits promising anti-tumor effects both in vitro and in vivo, underscoring its potential for clinical treatment of ovarian cancer. KEY POINTS: • This study has constructed an engineered strain of Salmonella typhimurium capable of expressing anticancer proteins • The engineered bacteria can target and colonize tumor sites in vivo • VM can inhibit the proliferation, migration, and invasion of ovarian cancer cells.


Assuntos
Vacinas Bacterianas , Neoplasias Ovarianas , Fosfatidilinositol 3-Quinases , Humanos , Feminino , Animais , Camundongos , Neoplasias Ovarianas/terapia , Transdução de Sinais , Modelos Animais de Doenças , Quinases de Proteína Quinase Ativadas por Mitógeno
19.
Medicine (Baltimore) ; 103(7): e36970, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363936

RESUMO

To explore the mechanism of the Zhenbao pill (ZBP) in treating spinal cord injury (SCI). The TCMSP Database, HERB Database and literature search were used to screen the effective ingredients and targets of ZBP; SCI-related genes were searched in GeneCards, OMIM, PharmGkb, TTD and DrugBank databases; the potential targets of ZBP for treating SCI were predicted and Venn diagrams were drawn, and the "herb-ingredient-target" network was constructed by Cytoscape software. The PPI network was constructed by STRING software, and the core targets were screened by cytoNCA plug-in; GO enrichment and KEGG pathway analysis were performed on the predicted targets using the DAVID Platform, and visualized with the Microbiology Network Platform. The molecular docking between the key ingredients and the core target was carried out by AutoDockVina software. 391 active ingredients and 836 action targets were obtained from ZBP and there are 1557 SCI related genes in 5 disease databases. The top 5 active ingredients were Quercetin, Camptothecin, Kaempferol, Ethyl iso-allocholate, and Ethyl linoleate, and 5 core genes were SRC, CTNNB1, TP53, AKT1, and STAT3. GO enrichment analysis showed that the core targets were involved in 1206 biological processes, 120 cellular components and 160 molecular functions; KEGG enrichment analysis showed that the core targets involved 183 pathways, including PI3K-Akt signaling pathway and other signaling pathways. Molecular docking indicated that CTNNB1, SRC, TP53, AKT1 and STAT3 showed good binding ability with the active ingredients quercetin, kaempferol and ethyl isobutyric acid. ZBP improves SCI through multi-components, multi-targets and multi-pathways.


Assuntos
Medicamentos de Ervas Chinesas , Farmacologia em Rede , Humanos , Simulação de Acoplamento Molecular , Quempferóis , Fosfatidilinositol 3-Quinases , Quercetina , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
20.
J Transl Med ; 22(1): 170, 2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38368381

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by aggressive progression and elevated mortality rates. This study aimed to investigate the regulatory effects of RBBP7 on HCC pathogenesis and the underlying mechanisms. METHODS: The expression and clinical feature of RBBP7 were evaluated using bioinformatics analysis and the assessment of clinical HCC samples. CCK8 and colony formation were employed to estimate cell proliferation function of RBBP7. Aerobic glycolysis levels of RBBP7 were evaluated by measuring ATP levels, lactic acid production, glucose uptake capacity, and the expression of relevant enzymes (PFKM, PKM2, and LDHA). The phosphorylation levels in PI3K/AKT signaling were measured by western blotting. The regulatory effect of transcription factors of specificity protein 1 (SP1) on RBBP7 mRNA expression was confirmed in dual-luciferase reporter assays and chromatin immunoprecipitation experiments. The proliferation- and glycolysis-associated proteins were assessed using immunofluorescence staining in vivo. RESULTS: We found that RBBP7 is expressed at high levels in HCC and predicts poor survival. Functional assays showed that RBBP7 promoted HCC proliferation and glycolysis. Mechanistically, it was demonstrated that RBBP7 activates the PI3K/AKT pathway, a crucial pathway in glycolysis, contributing to the progression of HCC. The outcomes of the dual-luciferase assay further confirmed that SP1 is capable of activating the promoter of RBBP7. CONCLUSIONS: RBBP7, which is up-regulated by SP1, promotes HCC cell proliferation and glycolysis through the PI3K/AKT pathway. The findings of this study suggest that RBBP7 is a potential biomarker for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Luciferases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína 7 de Ligação ao Retinoblastoma/genética , Proteína 7 de Ligação ao Retinoblastoma/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...