Hypoxia-inducible factors: cancer progression and clinical translation

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(11)

Published: May 31, 2022

Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each the 50 trillion cells in adult human body. Cancer co-opt this homeostatic system to drive cancer progression. HIFs activate transcription thousands genes mediate angiogenesis, stem cell specification, motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose lipid metabolism, immune evasion, invasion, metastasis. In Review, mechanisms consequences HIF activation presented. The current status future prospects small-molecule inhibitors use as therapeutics discussed.

Language: Английский

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Hypoxia signaling in human health and diseases: implications and prospects for therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 7, 2022

Abstract Molecular oxygen (O 2 ) is essential for most biological reactions in mammalian cells. When the intracellular content decreases, it called hypoxia. The process of hypoxia linked to several processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, other stress responses. mechanism underlying cells respond changes mediate subsequent signal response central question during Hypoxia-inducible factors (HIFs) sense regulate expressions a series downstream genes expression, which participate multiple processes cell metabolism, growth/death, proliferation, glycolysis, immune response, tumorigenesis, metastasis. Importantly, signaling also interacts with cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) endoplasmic reticulum (ER) stress. This paper systematically reviews mechanisms activation, control HIF function human health diseases. In addition, therapeutic targets involved balance diseases are summarized highlighted, would provide novel strategies design development drugs.

Language: Английский

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Cancer stem cells: advances in knowledge and implications for cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: July 5, 2024

Abstract Cancer stem cells (CSCs), a small subset of in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, maintain tumor heterogeneity. continues be significant global disease burden. In the past, surgery, radiotherapy, chemotherapy were main cancer treatments. The technology treatments develop advance, emergence targeted therapy, immunotherapy provides more options for patients certain extent. However, limitations efficacy treatment resistance still inevitable. Our review begins with brief introduction historical discoveries, original hypotheses, pathways regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, their crosstalk. We focus on role CSCs various therapeutic outcomes resistance, including how affect content alteration related molecules, CSCs-mediated clinical value targeting refractory, progressed or advanced tumors. summary, efficacy, method is difficult determine. Clarifying regulatory mechanisms biomarkers currently mainstream idea.

Language: Английский

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USP7 - a crucial regulator of cancer hallmarks

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2023, Volume and Issue: 1878(3), P. 188903 - 188903

Published: April 30, 2023

Language: Английский

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Single‐cell transcriptome sequencing of B‐cell heterogeneity and tertiary lymphoid structure predicts breast cancer prognosis and neoadjuvant therapy efficacy

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(8)

Published: Aug. 1, 2023

Breast cancer (BC) is a highly heterogeneous disease, and although immunotherapy has recently increased patient survival in number of solid hematologic malignancies, most BC subtypes respond poorly to immune checkpoint blockade therapy (ICB). B cells, particularly those that congregate tertiary lymphoid structures (TLS), play significant role antitumour immunity. However, B-cell heterogeneity at single-cell resolution its clinical significance with TLS need be explored further.Primary tumour lesions surrounding normal tissues were taken from 14 patients, totaling 124,587 for transcriptome sequencing bioinformatics analysis.Based on the usual markers, profiles classified into various clusters. A thorough study was conducted focus tumour-infiltrating cells (TIL-B) tumour-associated neutrophils (TAN). TIL-B divided five clusters, unusual cell types, such as follicular which are strongly related efficacy, identified. In BC, TAN infiltration positively correlated, same time, compared TLS-high, TLS-low group significantly correlated.In conclusion, our highlights explains how contribute immunity both level, offers straightforward marker called CD23. These results will offer more pertinent information applicability effectiveness BC.

Language: Английский

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Biological functions and molecular interactions of Wnt/β-catenin in breast cancer: Revisiting signaling networks

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 232, P. 123377 - 123377

Published: Jan. 23, 2023

Language: Английский

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Targeting the metabolism of tumor-infiltrating regulatory T cells

Trends in Immunology, Journal Year: 2023, Volume and Issue: 44(8), P. 598 - 612

Published: July 11, 2023

Although targeting the tumor metabolism is performed in cooperation with immunotherapy era of precision oncology, ignorance immune cells' has resulted unstable antitumor responses. Tumor-infiltrating regulatory T cells (TI-Tregs) are unique, overcoming hypoxic, acidic, and nutrient-deficient microenvironments (TMEs) maintaining immunosuppressive functions. However, secondary autoimmunity caused by systemic Treg depletion remains 'Sword Damocles' for current Treg-targeted therapies. In this opinion piece, we propose that metabolically reprogrammed TI-Tregs might represent an obstacle to cancer Indeed, metabolism-based therapy provide higher selectivity clearing than traditional kinase/checkpoint inhibitors chemokine/chemokine receptor blockade; it also restore efficacy eliminate certain metabolic barriers immunotherapy.

Language: Английский

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Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cβ/store-operated calcium entry/calreticulin/scavenger receptor A pathways

European Heart Journal, Journal Year: 2023, Volume and Issue: 45(4), P. 268 - 283

Published: Nov. 30, 2023

Abstract Background and Aims Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as disease-causing factor in atherogenesis, but detailed mechanism remains unknown. This study aims to explore P2Y6R regulation macrophage foaming, its downstream pathways. Furthermore, present sought find potent antagonist investigate feasibility P2Y6R-targeting therapy for Methods The expression was examined human atherosclerotic plaques mouse artery. Atherosclerosis animal models were established whole-body or macrophage-specific knockout mice evaluate P2Y6R. RNA sequencing, DNA pull-down experiments, proteomic approaches performed mechanisms. High-throughput Glide docking pipeline from repurposing drug library antagonists. Results deficiency alleviated atherogenesis characterized by decreasing plaque formation lipid deposition aorta. Mechanically, deletion significantly inhibited uptake oxidized low-density lipoprotein through scavenger A mediated phospholipase Cβ/store-operated calcium entry More importantly, reduced binding CALR, accompanied dissociation calreticulin STIM1. Interestingly, thiamine pyrophosphate found with excellent antagonistic activity affinity, which pharmacodynamic effect on atherosclerosis verified. Conclusions Macrophage regulates entry/calreticulin signalling pathway increase protein level, thereby improving cell atherosclerosis, indicating that may be potential therapeutic target intervention diseases using antagonists including pyrophosphate.

Language: Английский

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Melatonin alleviates lung injury in H1N1-infected mice by mast cell inactivation and cytokine storm suppression

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(5), P. e1011406 - e1011406

Published: May 18, 2023

Influenza A virus (IAV) H1N1 infection is a constant threat to human health and it remains so due the lack of an effective treatment. Since melatonin potent antioxidant anti-inflammatory molecule with anti-viral action, in present study we used protect against under vitro vivo conditions. The death rate H1N1-infected mice was negatively associated nose lung tissue local levels but not serum concentrations. AANAT-/- melatonin-deficient had significantly higher than that WT administration reduced rate. All evidence confirmed protective effects infection. Further identified mast cells were primary targets i.e., suppresses cell activation caused by molecular mechanisms involved down-regulation gene expression for HIF-1 pathway inhibition proinflammatory cytokine release from cells; this resulted reduction migration macrophages neutrophils tissue. This mediated receptor 2 (MT2) since MT2 specific antagonist 4P-PDOT blocked on activation. Via targeting cells, suppressed apoptosis alveolar epithelial injury findings provide novel mechanism H1N1-induced pulmonary injury, which may better facilitate progress new strategies fight or other IAV viral infections.

Language: Английский

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Berberine inhibits breast carcinoma proliferation and metastasis under hypoxic microenvironment involving gut microbiota and endogenous metabolites

Pharmacological Research, Journal Year: 2023, Volume and Issue: 193, P. 106817 - 106817

Published: June 12, 2023

A potential role of berberine, a benzyl isoquinoline alkaloid, in cancer therapy is apparent. Its underlying mechanisms berberine against breast carcinoma under hypoxia have not been elucidated. We focused on the doubt how restrains vitro and vivo. molecular analysis microbiome via 16 S rDNA gene sequencing DNA from mouse faeces confirmed that abundances diversity gut microbiota were significantly altered 4T1/Luc mice with higher survival rate following treatment. metabolome liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS) revealed regulated various endogenous metabolites, especially L-palmitoylcarnitine. Furthermore, cytotoxicity was investigated MDA-MB-231, MCF-7, 4T1 cells. In to simulate hypoxic environment, MTT assay showed inhibited proliferation cells IC50 values 4.14 ± 0.35 μM, 26.53 3.12 μM 11.62 1.44 respectively. Wound healing trans-well invasion studies migration RT-qPCR shed light reduced expression hypoxia-inducible factor-1α (HIF-1α) gene. Immunofluorescence western blot demonstrated decreased E-cadherin HIF-1α protein. Taken together, these results provide evidence efficiently suppresses growth metastasis microenvironment, highlighting as promising anti-neoplastic agent combat carcinoma.

Language: Английский

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