Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

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

Published: Jan. 8, 2024

Abstract Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of intricate mechanisms underlying I/R hinders development effective therapeutic interventions. Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system pathways involved in injury. This review article elucidates signaling, as well complex interplay between and including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca 2+ -Activin A, Hippo-Yes-associated toll-like receptor 4/toll-interleukine-1 domain-containing adapter-inducing interferon-β, hepatocyte factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, apoptosis, inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, blood-brain barrier damage Our comprehensive analysis reveals that activation canonical promotes organ recovery, while non-canonical exacerbates Moreover, explore novel approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, clinical trials. objective this is provide deeper insights roles its I/R-mediated processes dysfunction, facilitate innovative agents for

Language: Английский

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Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Oct. 2, 2023

Abstract Despite centuries since the discovery and study of cancer, cancer is still a lethal intractable health issue worldwide. Cancer-associated fibroblasts (CAFs) have gained much attention as pivotal component tumor microenvironment. The versatility sophisticated mechanisms CAFs in facilitating progression been elucidated extensively, including promoting angiogenesis metastasis, inducing drug resistance, reshaping extracellular matrix, developing an immunosuppressive Owing to their robust tumor-promoting function, are considered promising target for oncotherapy. However, highly heterogeneous group cells. Some subpopulations exert inhibitory role growth, which implies that CAF-targeting approaches must be more precise individualized. This review comprehensively summarize origin, phenotypical, functional heterogeneity CAFs. More importantly, we underscore advances strategies clinical trials CAF various cancers, also progressions immunotherapy.

Language: Английский

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Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies

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

Published: March 8, 2024

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in biological processes tumors. Intriguingly, mesenchymal dedifferentiated cancer cells, which are usually resistant to apoptosis traditional therapies, exquisitely vulnerable ferroptosis, further underscoring its potential treatment approach for cancers, especially refractory cancers. However, impact ferroptosis on extends beyond direct cytotoxic effect cells. induction not only inhibits but also promotes development due negative anticancer immunity. Thus, comprehensive understanding role crucial successful translation therapy from laboratory clinical applications. In this review, we provide overview recent advancements cancer, covering molecular mechanisms, functions, regulatory pathways, interactions with microenvironment. We summarize applications immunotherapy, radiotherapy, systemic therapy, well inhibition various conditions. finally discuss markers, current challenges future directions cancer.

Language: Английский

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Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 4004 - 4004

Published: Feb. 16, 2023

Most chronic inflammatory illnesses include fibrosis as a pathogenic characteristic. Extracellular matrix (ECM) components build up in excess to cause or scarring. The fibrotic process finally results organ malfunction and death if it is severely progressive. Fibrosis affects nearly all tissues of the body. associated with inflammation, metabolic homeostasis, transforming growth factor-β1 (TGF-β1) signaling, where balance between oxidant antioxidant systems appears be key modulator managing these processes. Virtually every system, including lungs, heart, kidney, liver, can affected by fibrosis, which characterized an excessive accumulation connective tissue components. Organ frequently caused remodeling, also linked high morbidity mortality. Up 45% fatalities industrialized world are damage any organ. Long believed persistently progressing irreversible, has now been revealed very dynamic preclinical models clinical studies variety systems. pathways from and/or main topics this review. Furthermore, different organs their effects was discussed. Finally, we highlight many principal mechanisms fibrosis. These could considered promising targets for development potential therapies important human diseases.

Language: Английский

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Anti-TGF-β/PD-L1 bispecific antibody promotes T cell infiltration and exhibits enhanced antitumor activity in triple-negative breast cancer

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(12), P. e005543 - e005543

Published: Dec. 1, 2022

Agents blocking programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have been approved for triple-negative breast cancer (TNBC). However, the response rate of anti-PD-1/PD-L1 is still unsatisfactory, partly due to immunosuppressive factors such as transforming growth factor-beta (TGF-β). In our previous pilot study, bispecific antibody targeting TGF-β and murine PD-L1 (termed YM101) showed potent antitumor effect. this work, we constructed a human BiTP) explored effect BiTP in TNBC.BiTP was developed using Check-BODYTM platform. The binding affinity measured by surface plasmon resonance, ELISA, flow cytometry. bioactivity assessed Smad NFAT luciferase reporter assays, immunofluorescence, western blotting, superantigen stimulation assays. activity humanized epithelial-mesenchymal transition-6-hPDL1 4T1-hPDL1 TNBC models. Immunohistochemical staining, cytometry, bulk RNA-seq were used investigate on immune infiltration.BiTP exhibited high dual targets. vitro experiments verified that effectively counteracted TGF-β-Smad PD-L1-PD-1-NFAT signaling. vivo animal demonstrated had superior relative anti-PD-L1 anti-TGF-β monotherapy. Mechanistically, decreased collagen deposition, enhanced CD8+ T penetration, increased tumor-infiltrating lymphocytes. This improved tumor microenvironment contributed BiTP.BiTP retains parent antibodies' bioactivity, with antibodies TNBC. Our data suggest might be promising agent treatment.

Language: Английский

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Challenges in developing personalized neoantigen cancer vaccines

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 24(3), P. 213 - 227

Published: Oct. 2, 2023

Language: Английский

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Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 22, 2023

Abstract The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define involved, here we treat established pancreatic with CAR cells directed fibroblast activation protein (FAP), an enzyme highly overexpressed subset of cancer-associated fibroblasts (CAFs). Depletion FAP + CAFs results loss structural integrity matrix. This renders these treatment-resistant cancers susceptible subsequent treatment tumor antigen (mesothelin)-targeted and anti-PD-1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving suppression, altering landscape by reducing myeloid accumulation increasing CD8 NK infiltration. These data provide strong rationale for combining stroma- malignant cell-targeted therapies be tested clinical trials.

Language: Английский

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Transforming growth factor-β signaling: From tissue fibrosis to therapeutic opportunities

Chemico-Biological Interactions, Journal Year: 2022, Volume and Issue: 369, P. 110289 - 110289

Published: Nov. 29, 2022

Language: Английский

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Exploiting innate immunity for cancer immunotherapy

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Nov. 27, 2023

Abstract Immunotherapies have revolutionized the treatment paradigms of various types cancers. However, most these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although agents already achieved great success, only a tiny percentage patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined multiple components in tumor microenvironment beyond immunity. Cells innate arm system, such as macrophages, dendritic cells, myeloid-derived suppressor neutrophils, natural killer unconventional also participate cancer evasion surveillance. Considering that cornerstone antitumor response, utilizing immunity provides potential therapeutic options for control. Up to now, exploiting agonists stimulator interferon genes, CAR-macrophage -natural therapies, metabolic regulators, novel exhibited potent activities preclinical clinical studies. Here, we summarize latest insights into roles cells discuss advances arm-targeted strategies.

Language: Английский

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Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 14, 2023

Abstract The ageing process is a systemic decline from cellular dysfunction to organ degeneration, with more predisposition deteriorated disorders. Rejuvenation refers giving aged cells or organisms youthful characteristics through various techniques, such as reprogramming and epigenetic regulation. great leaps in rejuvenation prove that not one-way street, many rejuvenative interventions have emerged delay even reverse the process. Defining mechanism by which roadblocks signaling inputs influence complex programs essential for understanding developing strategies. Here, we discuss intrinsic extrinsic factors counteract cell rejuvenation, targeted core mechanisms involved this Then, critically summarize latest advances state-of-art strategies of rejuvenation. Various methods also provide insights treating specific ageing-related diseases, including reprogramming, removal senescence (SCs) suppression senescence-associated secretory phenotype (SASP), metabolic manipulation, stem cells-associated therapy, dietary restriction, immune heterochronic transplantation, etc. potential applications therapy extend cancer treatment. Finally, analyze detail therapeutic opportunities challenges technology. Deciphering will further into anti-ageing disease treatment clinical settings.

Language: Английский

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