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1.
ACS Nano ; 2024 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-39432819

RESUMEN

Lactate-enriched tumor microenvironment (TME) fosters an immunosuppressive milieu to hamper the functionality of tumor-associated macrophages (TAMs). However, tackling the immunosuppressive effects wrought by lactate accumulation is still a big challenge. Herein, we construct a dual enzyme-driven cascade reaction platform (ILH) with immunosuppressive TME modulation for photoacoustic (PA) imaging-guided catalytic therapy and immune activation. The ILH is composed of iridium (Ir) metallene nanozyme, lactate oxidase (LOx), and hyaluronic acid (HA). The combination of Ir nanozyme and LOx can not only efficiently consume lactate to reverse the immunosuppressive TME into an immunoreactive one by promoting the polarization of TAMs from the M2 to M1 phenotype, thus enhancing antitumor defense, but also alleviate tumor hypoxia as well as induce strong oxidative stress, thus triggering immunogenic cell death (ICD) and activating antitumor immunity. Furthermore, the photothermal performance of Ir nanozyme can strengthen the cascade catalytic ability and endow ILH with a PA response. Based on the changes in PA signals from endogenous molecules, three-dimensional multispectral PA imaging was utilized to track the process of cascade catalytic therapy in vivo. This work provides a nanoplatform for dual enzyme-driven cascade catalytic therapy and immune activation by regulating the immunosuppressive TME.

2.
FASEB J ; 38(19): e70074, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39340228

RESUMEN

Diabetes osteoporosis (DOP) is a chronic metabolic bone disease. This study aimed to identify potential biomarkers of DOP and explore their underlying mechanisms through bioinformatics methods and experimental verification. Bioinformatics methods were used to identify differentially expressed genes (DEGs) for DOP based on GEO data and the GeneCards database. GO and KEGG enrichment analyses were used to search the key pathways. The STRING website was used to construct a protein-protein interaction (PPI) network and identify key genes. Then, 50 mg/mL glucose was used to interveneosteoblasts (OBs).CCK-8 and Alizarin Red staining were used to investigate the proliferation and differentiation changes in OBs. Flowcytometry was used to investigate apoptosis. The membrane protein chip, WB, and RT-PCR were used to verify the expression of key targets or pathways about DOP. Forty-two common genes were screened between DOP-related targets and DEGs. GO and KEGG enrichment analysis showed that DOP was mainly associated with cytokine-cytokine receptor interactions, and apoptosis. PPI network analysis showed that TNF, IL1A, IL6, IL1B, IL2RA, Fas ligand (FASLG), and Fas cell surface death receptor (FAS) were key up-regulated genes in the occurrence of DOP. The experiment results show that 50 mg/mL glucose significantly inhibited OBs proliferation but presented an increase in apoptosis. Membrane protein chip, WB, and RT-PCR-verified a significantly active in the expression of TNF/FASLG/FAS pathway. High glucose activated the TNF-α/FAS/FASLG pathway and induced the inflammatory microenvironment and apoptosis, then impaired osteogenic differentiation of OBs. These may be an important mechanism for the occurrence and development of DOP.


Asunto(s)
Apoptosis , Biología Computacional , Inflamación , Osteoporosis , Mapas de Interacción de Proteínas , Osteoporosis/genética , Osteoporosis/patología , Osteoporosis/metabolismo , Biología Computacional/métodos , Inflamación/metabolismo , Inflamación/genética , Humanos , Osteoblastos/metabolismo , Animales , Diferenciación Celular , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Proliferación Celular , Complicaciones de la Diabetes/genética , Complicaciones de la Diabetes/metabolismo
3.
Sci Adv ; 10(35): eadn8274, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39213344

RESUMEN

Recent advancements in photoacoustic (PA) imaging have leveraged reversibly photoswitchable chromophores, known for their dual absorbance states, to enhance imaging sensitivity through differential techniques. Yet, their deployment in tumor imaging has faced obstacles in achieving targeted delivery with high efficiency and specificity. Addressing this challenge, we introduce innovative protein assemblies, DrBphP-CBD, by genetically fusing a photosensory module from Deinococcus radiodurans bacterial phytochrome (DrBphP) with a collagen-binding domain (CBD). These protein assemblies form sub-100-nanometer structures composed of 24 DrBphP dimers and 12 CBD trimers, presenting 24 protein subunits. Their affinity for collagens, combined with impressive photoswitching contrast, markedly improves PA imaging precision. In various tumor models, intravenous administration of DrBphP-CBD has demonstrated enhanced tumor targeting and retention, augmenting contrast in PA imaging by minimizing background noise. This strategy underscores the clinical potential of DrBphP-CBD as PA contrast agents, propelling photoswitchable chromoproteins to the forefront of precise cancer diagnosis.


Asunto(s)
Colágeno , Deinococcus , Neoplasias , Técnicas Fotoacústicas , Fitocromo , Técnicas Fotoacústicas/métodos , Colágeno/química , Colágeno/metabolismo , Animales , Humanos , Ratones , Fitocromo/química , Fitocromo/metabolismo , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Deinococcus/metabolismo , Deinococcus/química , Línea Celular Tumoral , Unión Proteica , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética
4.
5.
Biology (Basel) ; 13(8)2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39194571

RESUMEN

Hepatocellular carcinoma (HCC) is a prevalent malignant digestive tumor. Numerous genetic mutations have been documented in HCC, yet the clinical significance of these mutations remains largely unexplored. The objective of this study is to ascertain the clinical value and biological effects of xin actin binding repeat containing 2 (XIRP2) mutation in HCC. The gene mutation landscape of HCC was examined using data from the Cancer Genome Atlas and the International Cancer Genome Consortium databases. The prognostic significance of the XIRP2 mutation was assessed through KM plot analysis. The association between drug sensitivity and the XIRP2 mutation was investigated using the TIDE algorithm and CCK-8 experiments. The biological effects of the XIRP2 mutation were evaluated through qRT-PCR, protein stability experiments, and relevant biological experiments. The XIRP2 mutation is one of the high-frequency mutations in HCC, and is associated with poor prognosis. A total of 72 differentially expressed genes (DEGs) were observed in HCC tissues with the XIRP2 mutation as compared to those with the XIRP2 wildtype, and these DEGs were closely related to ion metabolic processes. The XIRP2 mutation was linked to alterations in the sensitivity of fludarabine, oxaliplatin, WEHI-539, and LCL-161. CCK-8 assays demonstrated that HCC cells carrying the XIRP2 mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the XIRP2 wildtype. The XIRP2 mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of XIRP2 resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the XIRP2 mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin.

6.
Angew Chem Int Ed Engl ; 63(43): e202408064, 2024 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-38853147

RESUMEN

Tumor-specific activatable long-wavelength (LW) photosensitizers (PSs) show promise in overcoming the limitations of traditional photodynamic therapy (PDT), such as systemic phototoxicity and shallow tissue penetration. However, their insufficient LW light absorption and low singlet oxygen quantum yield (Φ 1O2) usually require high laser power density to produce thermal energy and synergistically enhance PDT. The strong photothermal radiation causing acute pain significantly reduces patient compliance and hinders the broader clinical application of LW PDT. Through the exciton dynamics dissection strategy, we have developed a series of pH-activatable cyanine-based LW PSs (LET-R, R = H, Cl, Br, I), among which the activated LET-I exhibits strong light absorption at 808 nm and a remarkable 3.2-fold enhancement in Φ 1O2 compared to indocyanine green. Transient spectroscopic analysis and theoretical calculations confirmed its significantly promoted intersystem crossing and simultaneously enhanced LW fluorescence emission characteristics. These features enable the activatable fluorescence and photoacoustic dual-modal imaging-escorted complete photodynamic eradication of tumors by the folic acid (FA)-modified LET-I probe (LET-I-FA), under the ultralow 808 nm laser power density (0.2 W cm-2) for irradiation, without the need for photothermal energy synergy. This research presents a novel strategy of dissecting exciton dynamics to screen activatable LW PSs for traceable PDT.


Asunto(s)
Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Humanos , Concentración de Iones de Hidrógeno , Animales , Ratones , Estructura Molecular , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico
7.
J Cell Mol Med ; 28(10): e18395, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38774995

RESUMEN

Tumour-associated macrophages (TAMs), encompassing M1 and M2 subtypes, exert significant effects on osteosarcoma (OS) progression and immunosuppression. However, the impacts of TAM-derived biomarkers on the progression of OS remains limited. The GSE162454 profile was subjected to single-cell RNA (scRNA) sequencing analysis to identify crucial mediators between TAMs and OS cells. The clinical features, effects and mechanisms of these mediators on OS cells and tumour microenvironment were evaluated via biological function experiments and molecular biology experiments. Phosphodiesterase 4C (PDE4C) was identified as a pivotal mediator in the communication between M2 macrophages and OS cells. Elevated levels of PDE4C were detected in OS tissues, concomitant with M2 macrophage level, unfavourable prognosis and metastasis. The expression of PDE4C was observed to increase during the conversion process of THP-1 cells to M2 macrophages, which transferred the PDE4C mRNA to OS cells through exosome approach. PDE4C increased OS cell proliferation and mobility via upregulating the expression of collagens. Furthermore, a positive correlation was observed between elevated levels of PDE4C and increased TIDE score, decreased response rate following immune checkpoint therapy, reduced TMB and diminished PDL1 expression. Collectively, PDE4C derived from M2 macrophages has the potential to enhance the proliferation and mobility of OS cells by augmenting collagen expression. PDE4C may serve as a valuable biomarker for prognosticating patient outcomes and response rates following immunotherapy.


Asunto(s)
Neoplasias Óseas , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Inmunoterapia , Macrófagos , Osteosarcoma , Microambiente Tumoral , Humanos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodos , Macrófagos/metabolismo , Macrófagos/inmunología , Metástasis de la Neoplasia , Osteosarcoma/patología , Osteosarcoma/inmunología , Osteosarcoma/genética , Osteosarcoma/metabolismo , Osteosarcoma/terapia , Pronóstico , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo
8.
J Ethnopharmacol ; 332: 118385, 2024 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-38797379

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Sophora flavescens is often used in traditional Chinese medicine for skin issues, diarrhea, and vaginal itching (Plant names have been checked with http://www.the/plant/list.org on Feb 22nd, 2024). Oxymatrine (OY), a major bioactive compound from Sophora flavescens, is commonly used in China to treat ulcerative colitis, but its mechanisms are still unclear. AIM OF THE STUDY: Recent studies have found that the crosstalk between ferroptosis and inflammation is an important mechanism in the pathogenesis of UC. The aim of this study was to investigate the potential underlying mechanisms of OY treatment on DSS-induced ulcerative colitis, specifically focusing on the processes of ferroptosis and inflammation. MATERIALS AND METHODS: Bioinformatics methods were used to identify key targets of OY for ferroptosis and inflammation in ulcerative colitis, based on GEO data and FerrDb database. Then, 4% DSS solution was used to induce UC model. OY's impact on morphological changes was assessed using colon views, Hematoxylin and eosin (HE) staining, and transmission electron microscopy (TEM). Ferroptosis phenotype index and inflammations factors were detected by ELISA or chem-bio detection kits. The screen out hub related genes about ferroptosis and inflammation were verified by RT-PCR, immunohistochemistry (IHC), and western blotting (WB) respectively. RESULTS: Bioinformatics results show that there are 16 key target genes involved in ferroptosis and inflammation interaction of OY treatment for UC, such as IL6, NOS2, IDO1, SOCS1, and DUOX. The results of animal experiments show that OY could depress inflammatory factors (IL-1ß, IL-6, TNF-α, HMGB1, and NLRP3) and reduce iron deposition (Fe2+, GSH). Additionally, OY suppressed the hub genes or proteins expression involved in ferroptosis and inflammation, including IL-1ß, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2. CONCLUSION: This present study combines bioinformatics, molecular biology, and animal experimental research evidently demonstrated that OY attenuates UC by improving ferroptosis and inflammation, mainly target to the expression of IL-1ß, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2.


Asunto(s)
Alcaloides , Colitis Ulcerosa , Sulfato de Dextran , Ferroptosis , Quinolizinas , Sophora , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Quinolizinas/farmacología , Quinolizinas/uso terapéutico , Sophora/química , Ferroptosis/efectos de los fármacos , Animales , Alcaloides/farmacología , Alcaloides/uso terapéutico , Ratones , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Sophora flavescens , Matrinas
9.
Theranostics ; 14(6): 2345-2366, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38646645

RESUMEN

Rationale: Primordial follicles are limited in number and cannot be regenerated, dormant primordial follicles cannot be reversed once they enter a growth state. Therefore, the length of the female reproductive lifespan depends on the orderly progression and selective activation of primordial follicles, the mechanism of which remains unclear. Methods: We used human ovarian cortical biopsy specimens, granulosa cells from diminished ovarian reserve (DOR) patients, Hdac6-overexpressing transgenic mouse model, and RNA sequencing to analyze the crucial roles of histone deacetylase 6 (HDAC6) in fertility preservation and primordial follicle activation. Results: In the present study, we found that HDAC6 was highly expressed in most dormant primordial follicles. The HDAC6 expression was reduced accompanying reproductive senescence in human and mouse ovaries. Overexpression of Hdac6 delayed the rate of primordial follicle activation, thereby prolonging the mouse reproductive lifespan. Short-term inhibition of HDAC6 promoted primordial follicle activation and follicular development in humans and mice. Mechanism studies revealed that HDAC6 directly interacted with NGF, reducing acetylation modification of NGF and thereby accelerating its ubiquitination degradation. Consequently, the reduced NGF protein level maintained the dormancy of primordial follicles. Conclusions: The physiological significance of the high expression of HDAC6 in most primordial follicles is to reduce NGF expression and prevent primordial follicle activation to maintain female fertility. Reduced HDAC6 expression increases NGF expression in primordial follicles, activating their development and contributing to reproduction. Our study provides a clinical reference value for fertility preservation.


Asunto(s)
Histona Desacetilasa 6 , Ratones Transgénicos , Factor de Crecimiento Nervioso , Folículo Ovárico , Ubiquitinación , Animales , Femenino , Humanos , Ratones , Acetilación , Células de la Granulosa/metabolismo , Histona Desacetilasa 6/metabolismo , Histona Desacetilasa 6/genética , Factor de Crecimiento Nervioso/metabolismo , Folículo Ovárico/metabolismo
10.
Cell Death Dis ; 15(4): 239, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38561331

RESUMEN

The oncogenic properties of members belonging to the forkhead box (FOX) family have been extensively documented in different types of cancers. In this study, our objective was to investigate the impact of FOXP3 on glioblastoma multiforme (GBM) cells. By conducting a screen using a small hairpin RNA (shRNA) library, we discovered a significant association between FOXP3 and ferroptosis in GBM cells. Furthermore, we observed elevated levels of FOXP3 in both GBM tissues and cell lines, which correlated with a poorer prognosis. FOXP3 was found to promote the proliferation of GBM cells by inhibiting cell ferroptosis in vitro and in vivo. Mechanistically, FOXP3 not only directly upregulated the transcription of GPX4, but also attenuated the degradation of GPX4 mRNA through the linc00857/miR-1290 axis, thereby suppressing ferroptosis and promoting proliferation. Additionally, the FOXP3 inhibitor epirubicin exhibited the ability to impede proliferation and induce ferroptosis in GBM cells both in vitro and in vivo. In summary, our study provided evidences that FOXP3 facilitates the progression of glioblastoma by inhibiting ferroptosis via the linc00857/miR-1290/GPX4 axis, highlighting FOXP3 as a potential therapeutic target for GBM.


Asunto(s)
Ferroptosis , Glioblastoma , MicroARNs , Humanos , Glioblastoma/genética , Ferroptosis/genética , MicroARNs/genética , ARN Interferente Pequeño , Factores de Transcripción Forkhead/genética , Proliferación Celular/genética , Línea Celular Tumoral
11.
Molecules ; 29(7)2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38611789

RESUMEN

Natural chemicals derived from herbal plants have recently been recognized as potentially useful treatment alternatives owing to their ability to target a wide range of important biological molecules. Cynaroside is one of these natural compounds with promising anticancer activity for numerous tumor types. Nevertheless, the anticancer effects and molecular mechanisms of action of cynaroside on colorectal cancer (CRC) remain unclear. In this study, cynaroside was found to markedly inhibit CRC cell proliferation and colony formation in vitro. Cynaroside also inhibited cell proliferation in vivo and decreased the expression of KI67, a cell nuclear antigen. RNA sequencing revealed 144 differentially expressed genes (DEGs) in HCT116 cells and 493 DEGs in RKO cells that were enriched in the cell cycle signaling pathway. Cell division cycle 25A (CDC25A), a DEG widely enriched in the cell cycle signaling pathway, is considered a key target of cynaroside in CRC cells. Cynaroside also inhibited DNA replication and arrested cells in the G1/S phase in vitro. The expression levels of CDC25A and related G1-phase proteins were significantly elevated after CDC25A overexpression in CRC cells, which partially reversed the inhibitory effect of cynaroside on CRC cell proliferation and G1/S-phase arrest. In summary, cynaroside may be used to treat CRC as it inhibits CDC25A expression.


Asunto(s)
Neoplasias Colorrectales , Glucósidos , Humanos , Puntos de Control de la Fase G1 del Ciclo Celular , Luteolina , Neoplasias Colorrectales/tratamiento farmacológico
12.
Aging (Albany NY) ; 16(6): 5618-5633, 2024 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-38499392

RESUMEN

The telomerase reverse transcriptase promoter (TERTp) is frequently mutated in gliomas. This study sought to identify immune biomarkers of gliomas with TERTp mutations. Data from TCGA were used to identify and validate survival-associated gene signatures, and immune and stromal scores were calculated using the ESTIMATE algorithm. High stromal or immune scores in patients with TERTp-mutant gliomas correlated with shorter overall survival compared to cases with low stromal or immune scores. Among TERTp-mutant gliomas with both high immune and high stromal scores, 213 commonly shared DEGs were identified. Among 71 interacting DEGs representing candidate hub genes in a PPI network, HOXC6, WT1, CD70, and OTP showed significant ability in establishing subgroups of high- and low-risk patients. A risk model based on these 4 genes showed strong prognostic potential for gliomas with mutated TERTp, but was inapplicable for TERTp-wild-type gliomas. TERTp-mutant gliomas with high-risk scores displayed a greater percentage of naïve B cells, plasma cells, naïve CD4 T cells, and activated mast cells than low-risk score gliomas. TIDE analysis indicated that immune checkpoint blockade (ICB) therapy may benefit glioma patients with TERTp mutations. The present risk model can help predict prognosis of glioma patients with TERTp mutations and aid ICB treatment options.


Asunto(s)
Neoplasias Encefálicas , Glioma , Telomerasa , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Mutación , Glioma/tratamiento farmacológico , Glioma/genética , Pronóstico , Telomerasa/genética
13.
Front Oncol ; 14: 1294745, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38410098

RESUMEN

Introduction: The risk that a large polyp (≥10 mm) evolves into high-grade dysplasia (HGD) is relatively high compared with that of a small/diminutive polyp (<10 mm). Recently, the detection of small and diminutive polyps has been substantially improved with the advancement of endoscopy. However, further research is needed on the role of the incidence of HGD caused by the co-occurrence of small and diminutive polyps in the progression of HGD. In this study, we aim to investigate whether and how the small and diminutive polyps correlate with the incidence of HGD in the population. Methods: The pooled data were deeply analyzed from four published randomized controlled trials (RCTs) regarding colon polyp detection. All polyps detected were examined and confirmed by pathologists. The primary outcome was the composition ratio of the HGD polyps in each polyp size category. Results: Among a total of 3,179 patients with 2,730 polyps identified, there were 83 HGD polyps confirmed, and 68 patients had at least one polyp with HGD. The risk of development of HGD was lower for a single small and diminutive polyp than for one large polyp (2.18% vs. 22.22%, P < 0.0001). On the contrary, the composition ratio for HGD from small and diminutive polyps was significantly higher than that from the large ones (68.67% vs. 31.33%, P < 0.0001). The combined number of HGD presented a trend negatively correlated to size. Conclusions: Our data demonstrated that the absolute number of HGD significantly derives more from small and diminutive polyps than from the large ones, and the collective number of small and diminutive polyps per patient is indicative of his/her HGD exposure. These findings positively provide novel perspectives on the management of polyps and may further optimize the prevention of colorectal cancer. Systematic Review Registration: http://www.chictr.org.cn, identifier ChiCTR1900025235, ChiCTR1800017675, ChiCTR1800018058, and ChiCTR1900023086.

14.
J Ethnopharmacol ; 319(Pt 3): 117329, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-37879510

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Bone defects are difficult to treat and have a high incidence of nonunion. The Epimedii folium-Rhizoma drynariae herbal pair (EDP) is a traditional Chinese medicine (TCM) used for treating bone diseases. However, the mechanisms by which EDP promotes osteogenesis or bone formation remain largely unclear. AIM OF THE STUDY: This study aimed to investigate the mechanism of EDP promoted bone formation in bone defects using network pharmacology and experiments. MATERIALS AND METHODS: The chemical components of EDP were analyzed by UHPLC-MS. The hub target and pathway enrichment analysis was conducted using molecular docking or network pharmacology. The pharmacological actions of EDP were determined by µCT and histopathology examination using a bone defect rat model. The effects of EDP on the mRNA expression of Bmp2, Smad2/5, Runx2, and Alp genes were measured by RT-PCR, while changes in the protein expressions of BMP2, COL1A1, SPP1, ALP, and RUNX2in the tibia tissues of the rats in response to EDP were analyzed by immunohistochemical staining or Western blot. We also performed cell viability assays, Alizarin Red and ALP staining assays, and RT-PCR to better understand how EDP affected osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). RESULTS: Identified 14 key compounds and 47 hub targets of EDP that may be involved in promoting osteogenesis to repair bone defects. And the BMP/Smad/Runx2 pathway was likely the key pathway through which EDP promoted bone defects repairing. The results of in vivo rat experiments indicated that EDP effectively promoted tibia repair in the model rats and activated the BMP/Smad/Runx2 pathway in the tibia tissue, with upregulating Bmp2, Bmpr1α, Smad2/5, Runx2, and Alp genes, and increased the protein expression of BMP2, COL1A1, RUNX2, and ALP. In vitro, EDP was found to increase the proliferation, differentiation, and mineralization in BMSCs- and also up-regulated the expression of key genes in the BMP/Smad/Runx2 pathway. CONCLUSION: This study highlighted the ability of EDP to promote the osteogenic differentiation to enable bone repair by activating the BMP/Smad/Runx2 pathway.


Asunto(s)
Subunidad alfa 1 del Factor de Unión al Sitio Principal , Osteogénesis , Ratas , Animales , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Farmacología en Red , Simulación del Acoplamiento Molecular , Células Cultivadas , Diferenciación Celular
15.
Molecules ; 28(24)2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38138552

RESUMEN

Gastrodin, the primary bioactive compound found in Gastrodia elata, has been shown to exhibit neuroprotective properties in a range of neurological disorders. However, the precise mechanisms through which gastrodin influences glioma cells remain unclear, and there is a scarcity of data regarding its specific effects. To ascertain the viability of glioma cell lines LN229, U251, and T98, the CCK-8 assay, a colony formation assay, and a 3D culture model were employed, utilizing varying concentrations of gastrodin (0, 5, 10, and 20 µM). Gastrodin exhibited a notable inhibitory effect on the growth of glioma cells, as evidenced by its ability to suppress colony formation and spheroid formation. Additionally, gastrodin induced ferroptosis in glioma cells, as it can increase the levels of reactive oxygen species (ROS) and peroxidized lipids, and reduced the levels of glutathione. Using a subcutaneous tumor model, gastrodin was found to significantly inhibit the growth of the T98 glioma cell line in vivo. Using high-throughput sequencing, PPI analysis, and RT-qPCR, we successfully identified Homeobox D10 (HOXD10) as the principal target of gastrodin. Gastrodin administration significantly enhanced the expression of HOXD10 in glioma cells. Furthermore, treatment with gastrodin facilitated the transcription of ACSL4 via HOXD10. Notably, the inhibition of HOXD10 expression impeded ferroptosis in the cells, which was subsequently restored upon rescue with gastrodin treatment. Overall, our findings suggest that gastrodin acts as an anti-cancer agent by inducing ferroptosis and inhibiting cell proliferation in HOXD10/ACSL4-dependent pathways. As a prospective treatment for gliomas, gastrodin will hopefully be effective.


Asunto(s)
Ferroptosis , Glioma , Humanos , Ferroptosis/genética , Regulación hacia Arriba , Genes Homeobox , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/metabolismo , Línea Celular Tumoral
16.
Medicine (Baltimore) ; 102(44): e34683, 2023 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-37933071

RESUMEN

To explore the potential mechanism of Gegen Qinlian decoction (GGQL) in the treatment of COVID-19 comorbid with diabetes mellitus (DM) through network pharmacology and molecular docking, and to provide theoretical guidance for clinical transformation research. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform was used to screen the active compounds and targets of GGQL, the targets of COVID-19 comorbid with DM were searched based on Genecards database. Protein-protein interaction network was constructed using String data platform for the intersection of compounds and disease targets, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the intersection targets was performed using DAVID database. Cytoscape software was used to construct the "compound target-pathway (C-T-P)" of GGQL in the treatment of COVID-19 comorbid with DM, the molecular docking platform was used to complete the simulated docking of key compounds and targets. We obtained 141 compounds from GGQL, revealed 127 bioactive compounds and 283 potential targets of GGQL. Quercetin, kaempferol and formononetin in GGQL play a role by modulating the targets (including AR, GSK3B, DPP4, F2, and NOS3). GGQL might affect diverse signaling pathways related to the pathogenesis of coronavirus disease - COVID-19, AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, human cytomegalovirus infection and Th17 cell differentiation. Meanwhile, molecular docking showed that the selected GGQL core active components had strong binding activity with the key targets. This study revealed that GGQL play a role in the treatment of COVID-19 comorbid with DM through multi-component, multi-target and multi-pathway mode of action, which provided good theoretical basis for further verification research.


Asunto(s)
COVID-19 , Diabetes Mellitus , Medicamentos Herbarios Chinos , Humanos , Simulación del Acoplamiento Molecular , Farmacología en Red , Medicina Tradicional China
17.
Biomed Pharmacother ; 169: 115893, 2023 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-37979377

RESUMEN

AIM: Diabetes osteoporosis (DOP) is a chronic bone metabolic disease induced by diabetes, whose morbidity continues to increase. Epimedium brevicornum Maxim (EB), a popular Chinese traditional medicine, has been used to treat bone diseases in China for thousands of years. But its material basis and specific mechanism of action are not clear. METHODS: Epimedium brevicornum crude polysaccharide (EPE) is the main component, in this research the characterized the structure of EBPC1 purified from EPE was detected and its effects on cell proliferation, differentiation, and cytoskeletal in osteoblasts induced by high glucose. RESULTS: The molecular weight of EBPC1 was 10.5 kDa. It was mainly comprised of glucose and galactose, and the backbone of EBPC1 was→4)-α-D-Galp-(1→4)-α-D-Galp-(1→6)-ß-D-Galp-(1→6)-ß-D-Galp-(1→4)-α-D-Glcp-(1→4)-α-D-Glcp-(1→. The results from in vitro experiments revealed that EBPC1 significantly increased alkaline phosphatase (ALP) activity and mineralized nodule formation in primary osteoblasts, also significantly up-regulated expression of Alp mRNA and Runx2 mRNA in the presence of EBPC1 pretreatment. Moreover, EBPC1 modulated apoptosis via the regulation of Bax/Bcl2. CONCLUSION: These results indicate that EBPC1 treatment can promote osteogenesis during DOP, which can ameliorate apoptosis by regulating Bax/Bcl2 and accelerating osteogenesis in osteoblasts.


Asunto(s)
Diabetes Mellitus , Epimedium , Osteoporosis , Humanos , Epimedium/química , Osteogénesis , Proteína X Asociada a bcl-2/metabolismo , Osteoporosis/metabolismo , Diferenciación Celular , Osteoblastos , Polisacáridos/química , ARN Mensajero/metabolismo , Diabetes Mellitus/metabolismo
18.
Aging (Albany NY) ; 15(19): 10453-10472, 2023 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-37812190

RESUMEN

Immune and stromal cells contribute to glioma progression by infiltrating the tumor microenvironment. We used clinical characteristics, RNA sequencing data and the ESTIMATE algorithm to obtain stromal and immune scores for alpha thalassemia retardation syndrome X-linked (ATRX)-mutation-type (ATRX-mt) and ATRX-wildtype (ATRX-wt) glioma tissues from The Cancer Genome Atlas. To identify specific immune biomarkers of glioma, we compared the gene expression profiles of ATRX-wt glioma tissues with high vs. low immune/stromal scores, and discovered 162 differentially expressed genes. The protein-protein interaction network based on these results contained 80 interacting genes, of which seven (HOXA5, PTPN2, WT1, HOXD10, POSTN, ADAMDEC1 and MYBPH) were identified as key prognostic genes via LASSO and Cox regression analyses. A risk model constructed using the expression of these seven genes could predict survival for ATRX-wt glioma patients, but was ineffective for ATRX-mt patients. T cells and macrophages were more prevalent in low-risk than in high-risk glioma tissues. Immune checkpoint blockade treatment was highly beneficial for patients with low risk scores. High-risk gliomas were predicted to be more sensitive to rapamycin, dasatinib, 5-fluorouracil and gemcitabine. Thus, our model can be used for the diagnosis, prognostic prediction and treatment planning of ATRX-wt glioma patients.


Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/metabolismo , Pronóstico , Microambiente Tumoral
19.
Biomolecules ; 13(10)2023 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-37892195

RESUMEN

tRNA-derived small RNAs (tDRs) are dysregulated in several diseases, including pancreatic cancer (PC). However, only a limited number of tDRs involved in PC progression are known. Herein, a novel tDR, 5'-tRF-19-Q1Q89PJZ (tRF-19-Q1Q89PJZ), was verified in PC plasma using RNA and Sanger sequencing. tRF-19-Q1Q89PJZ was downregulated in PC tissues and plasma, which was related to advanced clinical characteristics and poor prognosis. tRF-19-Q1Q89PJZ overexpression inhibited the malignant activity of PC cells in vitro, while tRF-19-Q1Q89PJZ inhibition produced an opposite effect. The differentially expressed genes induced by tRF-19-Q1Q89PJZ overexpression were enriched in "pathways in cancer" and "glycolysis". Mechanistically, tRF-19-Q1Q89PJZ directly sponged hexokinase 1 (HK1) mRNA and inhibited its expression, thereby suppressing glycolysis in PC cells. HK1 restoration relieved the inhibitory effect of tRF-19-Q1Q89PJZ on glycolysis in PC cells and on their proliferation and mobility in vitro. tRF-19-Q1Q89PJZ upregulation inhibited PC cell proliferation and metastasis in vivo and suppressed HK1 expression in tumor tissues. Furthermore, tRF-19-Q1Q89PJZ expression was attenuated under hypoxia. Collectively, these findings indicate that tRF-19-Q1Q89PJZ suppresses the malignant activity of PC cells by regulating HK1-mediated glycolysis. Thus, tRF-19-Q1Q89PJZ may serve as a key target for PC therapy.


Asunto(s)
Hexoquinasa , Neoplasias Pancreáticas , Humanos , Hexoquinasa/genética , Hexoquinasa/metabolismo , Línea Celular Tumoral , Neoplasias Pancreáticas/metabolismo , Glucólisis , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas
20.
Aging (Albany NY) ; 15(18): 9377-9390, 2023 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-37768200

RESUMEN

Ar-turmerone, a compound isolated from turmeric seeds, has exhibited anti-malignant, anti-aging and anti-inflammatory properties. Here, we assessed the effects of ar-turmerone on glioma cells. U251, U87 and LN229 glioma cell lines were treated with different concentrations of ar-turmerone (0, 50, 100 and 200 µM), and their viability and mobility were evaluated using Cell Counting Kit 8, colony formation, wound healing and Transwell assays. The effects of ar-turmerone on U251 glioma cell proliferation were also assessed using a subcutaneous implantation tumor model. High-throughput sequencing, bioinformatic analyses and quantitative real-time polymerase chain reactions were used to identify the key signaling pathways and targets of ar-turmerone. Ar-turmerone reduced the proliferation rate and mobility of glioma cells in vitro and arrested cell division at G1/S phase. Cathepsin B was identified as a key target of ar-turmerone in glioma cells. Ar-turmerone treatment reduced cathepsin B expression and inhibited the cleavage of its target protein P27 in glioma cells. On the other hand, cathepsin B overexpression reversed the inhibitory effects of ar-turmerone on glioma cell proliferation, mobility progression in vitro and in vivo. In conclusion, ar-turmerone suppressed cathepsin B expression and P27 cleavage, thereby inhibiting the proliferation and mobility of glioma cells.


Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Catepsina B , Línea Celular Tumoral , Glioma/patología , Proliferación Celular , Apoptosis , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología
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