Remodeling tumor microenvironment using prodrug nMOFs for synergistic cancer therapy

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 19, 2025

Metal–organic frameworks (MOFs) hold tremendous potential in cancer therapy due to their remarkable structural and functional adaptability, enabling them serve as nanocarriers for biopharmaceuticals nanoreactors organizing cascade bioreactions. Nevertheless, MOFs are predominantly utilized biologically inactive carriers most cases. Developing nanoscale prodrug suitable biomedical applications remains a huge challenge. In this study, we have designed novel nano-MOFs (nMOFs, named DCCMH) using metformin (Met) α-cyano-4-hydroxycinnamic acid (CHCA) ligands coordination self-assembly with CuCl2, followed by loading of doxorubicin (DOX) surface modification hyaluronic (HA). Upon internalization cells, DCCMH releases Cu2+/+, CHCA, Met, DOX response high levels glutathione (GSH) hydrogen peroxide (H2O2) within the tumor microenvironment (TME); Cu+ catalyzes conversion H2O2 ·OH via Fenton reaction while it was oxidized Cu2+, which subsequently further de-consumed GSH; CHCA induces decrease intracellular pH promotes reactions inhibiting lactate efflux; Met up-regulates tyrosine kinase activity enhances chemotherapy DOX. With ability synergistically combine chemo/chemodynamic (CT/CDT) remodel TME, NPs inhibit murine hepatoma effectively. This study presents feasible strategy fabricating nMOFs capable remodeling TME improve efficacy through synergistic therapy.

Language: Английский

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The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 29, 2024

Cancer, a disease that modern medicine has not fully understood and conquered, with its high incidence mortality, deprives countless patients of health even life. According to global cancer statistics, there were an estimated 19.3 million new cases nearly 10 deaths in 2020, the age-standardized mortality rates 201.0 100.7 per 100,000, respectively. Although remarkable advancements have been made therapeutic strategies recently, overall prognosis remains optimistic. Consequently, are still many severe challenges be faced difficult problems solved therapy today. Epigallocatechin gallate (EGCG), natural polyphenol extracted from tea leaves, received much attention for antitumor effects. Accumulating investigations confirmed EGCG can inhibit tumorigenesis progression by triggering apoptosis, suppressing proliferation, invasion, migration, altering tumor epigenetic modification, overcoming chemotherapy resistance. Nevertheless, regulatory roles biomolecular mechanisms immune microenvironment, metabolic immunotherapy remain obscure. In this article, we summarized most recent updates about effects on microenvironment (TME), reprogramming, anti-cancer immunotherapy. The results demonstrated promote response cytotoxic lymphocytes dendritic cells (DCs), attenuate immunosuppression myeloid-derived suppressor (MDSCs) T (Tregs), tumor-promoting functions tumor-associated macrophages (TAMs), neutrophils (TANs), various stromal including cancer-associated fibroblasts (CAFs), endothelial (ECs), stellate cells, mesenchymal stem/stromal (MSCs). Additionally, suppress multiple reprogramming pathways, glucose uptake, aerobic glycolysis, glutamine metabolism, fatty acid anabolism, nucleotide synthesis. Finally, EGCG, as immunomodulator checkpoint blockade, enhance immunotherapeutic efficacy may promising candidate conclusion, plays versatile TME which provides novel insights combined

Language: Английский

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N6-methyladenosine modified TGFB2 triggers lipid metabolism reprogramming to confer pancreatic ductal adenocarcinoma gemcitabine resistance

Oncogene, Journal Year: 2024, Volume and Issue: 43(31), P. 2405 - 2420

Published: June 24, 2024

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed sensitize cancer cells gemcitabine. Here, we constructed gemcitabine-resistant PDAC and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 identified as crucial gene significantly associated poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates gradual upregulation expression during gemcitabine-induced resistance. Silencing can enhance chemosensitivity against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, promote lipid accumulation enhanced triglyceride drives lipidomic profiling. upregulates lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 responsible for TGFB2-mediated Importantly, inhibitor imperatorin combined shows synergistic effects PDX model. This study sheds light on avenue mitigate targeting metabolism develops potential promising chemosensitizer clinical translation.

Language: Английский

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Intratumoral Collagen Deposition Supports Angiogenesis Suggesting Anti‐angiogenic Therapy in Armored and Cold Tumors

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract A previous study classifies solid tumors based on collagen deposition and immune infiltration abundance, identifying a refractory subtype termed armored & cold tumors, characterized by elevated diminished infiltration. Beyond its impact infiltration, also influences tumor angiogenesis. This systematically analyzes the association between immuno‐collagenic subtypes angiogenesis across diverse cancer types. As result, exhibit highest angiogenic activity in lung adenocarcinoma (LUAD). Single‐cell spatial transcriptomics reveal close interactions co‐localization of fibroblasts endothelial cells. In vitro experiments demonstrate that stimulates cells to express vascular growth factor (VEGFA) directly enhances vessel formation cell proliferation through sex determining region Y box 18 (SOX18) upregulation. Collagen inhibition via multiple approaches effectively suppresses vivo. addition, display superior responsiveness anti‐angiogenic therapy advanced LUAD cohorts. Post‐immunotherapy resistance, transformation into emerges as potential biomarker for selecting therapy. summary, is shown drive various cancers, providing novel actionable framework refine therapeutic strategies combining chemotherapy with treatments.

Language: Английский

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ID1high/activin Ahigh glioblastoma cells contribute to resistance to anti-angiogenesis therapy through malformed vasculature

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(4)

Published: April 24, 2024

Abstract Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as first-line treatment patients with glioblastoma (GBM), its efficacy notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, specific underlying yet be sufficiently ascertained. Here, we established that inhibitor differentiation 1 (ID1) high /activin A cell confers resistance BVZ. The bipotent effect activin during active phase was demonstrated reduce vasculature dependence in tumorigenesis. In response temporary exposure A, this cytokine found induce endothelial-to-mesenchymal transition via Smad3/Slug axis, whereas prolonged led endothelial apoptosis. ID1 tumors showing BVZ were characterized by hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using GBM mouse model, can overcome administering based on combination SB431542, Smad2/3 inhibitor, which contributed enhancing survival. These findings offer valuable insights could contribute development new strategies treating AAT-resistant GBM.

Language: Английский

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MicroRNA‐431‐5p inhibits angiogenesis, lymphangiogenesis, and lymph node metastasis by affecting TGF‐β1/SMAD2/3 signaling via ZEB1 in gastric cancer

Molecular Carcinogenesis, Journal Year: 2024, Volume and Issue: 63(7), P. 1378 - 1391

Published: April 24, 2024

Accumulating evidence suggests that lymphangiogenesis plays a crucial role in lymphatic metastasis, leading to tumor immune tolerance. However, the specific mechanism remains unclear. In this study, miR-431-5p was markedly downregulated both gastric cancer (GC) tissues and plasma exosomes, its expression were correlated negatively with LN metastasis poor prognosis. Mechanistically, weakens TGF-β1/SMAD2/3 signaling pathway by targeting ZEB1, thereby suppressing secretion of VEGF-A ANG2, which turn hinders angiogenesis, lymphangiogenesis, lymph node (LN) GC. Experiments using popliteal model BALB/c nude mice demonstrated significantly reduced metastasis. Additionally, enhances efficacy anti-PD1 treatment, particularly when combined galunisertib, treatment showing synergistic effect inhibiting GC progression C57BL/6 mice. Collectively, these findings suggest may modulate pathways ZEB1 impede progression, making it promising therapeutic target for management.

Language: Английский

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PKM2‐Driven Lactate Overproduction Triggers Endothelial‐To‐Mesenchymal Transition in Ischemic Flap via Mediating TWIST1 Lactylation

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 30, 2024

Abstract The accumulation of lactate is a rising risk factor for patients after flap transplantation. Endothelial‐to‐mesenchymal transition (EndoMT) plays critical role in skin fibrosis. Nevertheless, whether overproduction directly contributes to necrosis and its mechanism remain unknown. current study reveals that mice exhibit enhanced PKM2 fibrotic response. Endothelial‐specific deletion attenuates ameliorates fibrosis mice. Administration or overexpressing promotes dysfunction endothelial cells stimulates mesenchymal‐like phenotype following hypoxia. Mechanistically, glycolytic‐lactate induces correlation between Twist1 p300/CBP, leading lactylation lysine 150 (K150la). increase K150la phosphorylation nuclear translocation further regulates the transcription TGFB1 , hence inducing phenotype. Genetically endothelial‐specific diminishes lactylation, then EndoMT‐associated ischemia. serum levels transplantation are elevated predictive value prognosis. This findings suggested novel PKM2‐derived mediating exacerbates Inhibition reduces response might become potential therapeutic strategy

Language: Английский

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A tetrahedral DNA nanostructure-mediated miRNA inhibitor delivery system: Type H vessel-related bone healing during distraction osteogenesis

Chemical Engineering Journal, Journal Year: 2024, Volume and Issue: 496, P. 153863 - 153863

Published: July 20, 2024

Language: Английский

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Epigallocatechin-3-Gallate, an Active Green Tea Component to Support Anti-VEGFA Therapy in Wet Age-Related Macular Degeneration

Nutrients, Journal Year: 2023, Volume and Issue: 15(15), P. 3358 - 3358

Published: July 28, 2023

Age-related macular degeneration (AMD) is a largely incurable disease and an emerging problem in aging societies. It occurs two forms, dry wet (exudative, neovascular), which may cause legal blindness sight loss. Currently, there not any effective treatment for AMD. Meanwhile, repeated intravitreal injections with antibodies against vascular endothelial growth factor A (VEGFA) slow down AMD progression but are free from complications. (-)-Epigallocatechin-3-gallate (EGCG) active compound of green tea, exerts many beneficial effects the retinal pigment epithelium neural retina. has been reported to downregulate VEGFA gene by suppressing its activators. The inhibition mitogen-activated protein kinases 1 3 (MAPK1 MAPK3) lie behind antiangiogenic action EGCG mediated VEGFA. protective UV-induced damage cells improves dysfunctional autophagy. also interact mechanistic target rapamycin (MTOR) unc-51-like autophagy activating kinase (ULK1) modulate interplay between apoptosis. Several other studies report on retina that be related Therefore, controlled clinical trials needed verify whether diet supplementation or tea consumption improve results anti-VEGFA therapy

Language: Английский

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Negative Regulation of Lymphangiogenesis by Tenascin-C Delays the Resolution of Inflammation

iScience, Journal Year: 2025, Volume and Issue: 28(2), P. 111756 - 111756

Published: Jan. 7, 2025

Lymphatic vessels are required for the clearance of excess fluid and immune cells from inflamed tissue, making regulation lymphangiogenesis an important area research. Although positive regulatory mechanisms well known, negative observed during inflammation remain unclear. Here, we identify tenascin-C (TNC) as a spatiotemporal regulator inflammation. We found inverse correlation between TNC expression in mouse lymphedema model. Genetic deletion Tnc promotes improves lymphatic drainage function, thereby accelerating resolution Conversely, exogenous addition suppresses prolongs inhibits proliferation apoptosis endothelial cells. Mechanistically, facilitates integrin αvβ1 heterodimer formation, leading to activation non-canonical (TAK1/p38MAPK/ATF-2) TGFβ signaling suppress lymphangiogenesis. Our study highlights importance modulating responses.

Language: Английский

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