NF-κB in biology and targeted therapy: new insights and translational implications

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Март 4, 2024

Abstract NF-κB signaling has been discovered for nearly 40 years. Initially, was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have that its role can be expanded to variety of mechanisms, biological processes, human diseases, treatment options. In this review, we first scrutinize the research process signaling, summarize composition, activation, regulatory mechanism signaling. We investigate interaction other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, TLR The physiological pathological states well intricate involvement inflammation, immune regulation, tumor microenvironment, are also explicated. Additionally, illustrate how is involved cancers, autoimmune cardiovascular metabolic neurological COVID-19. Further, discuss therapeutic approaches targeting IKK inhibitors, monoclonal antibodies, proteasome nuclear translocation DNA binding TKIs, non-coding RNAs, immunotherapy, CAR-T. Finally, provide an outlook field hope present stereoscopic, comprehensive will inform future clinical practice.

Язык: Английский

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Advances in Nanotechnology for Biofilm Inhibition

ACS Omega, Год журнала: 2023, Номер 8(24), С. 21391 - 21409

Опубликована: Июнь 7, 2023

Biofilm-associated infections have emerged as a significant public health challenge due to their persistent nature and increased resistance conventional treatment methods. The indiscriminate usage of antibiotics has made us susceptible range multidrug-resistant pathogens. These pathogens show reduced susceptibility intracellular survival. However, current methods for treating biofilms, such smart materials targeted drug delivery systems, not been found effective in preventing biofilm formation. To address this challenge, nanotechnology provided innovative solutions formation by clinically relevant Recent advances nanotechnological strategies, including metallic nanoparticles, functionalized dendrimers, polymeric cyclodextrin-based delivery, solid lipid polymer conjugates, liposomes, may provide valuable technological against infectious diseases. Therefore, it is imperative conduct comprehensive review summarize the recent advancements limitations advanced nanotechnologies. present Review encompasses summary agents, mechanisms that lead formation, impact on human health. In nutshell, offers survey managing infections. A detailed presentation how these strategies improve control prevent key objective mechanisms, applications, prospects nanotechnologies better understanding

Язык: Английский

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Macrophage phenotypes and functions: resolving inflammation and restoring homeostasis

Trends in Immunology, Год журнала: 2023, Номер 44(12), С. 986 - 998

Опубликована: Ноя. 6, 2023

Язык: Английский

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IL-4 and IL-13: Regulators and Effectors of Wound Repair

Annual Review of Immunology, Год журнала: 2023, Номер 41(1), С. 229 - 254

Опубликована: Фев. 4, 2023

Type 2 immunity mediates protective responses to helminths and pathological allergens, but it also has broad roles in the maintenance of tissue integrity, including wound repair. cytokines are known promote fibrosis, an overzealous repair response, their contribution healthy is less well understood. This review discusses evidence that canonical type cytokines, IL-4 IL-13, integral process through two main pathways. First, essential for progression effective repair, IL-13 suppress initial inflammatory response injury. Second, these regulate how extracellular matrix modified, broken down, rebuilt and/or amplifies multiple aspects many pathways highly redundant can be induced by other signals. Therefore, exact IL-4Rα signaling remains difficult unravel.

Язык: Английский

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Distinct molecular profiles of skull bone marrow in health and neurological disorders

Cell, Год журнала: 2023, Номер 186(17), С. 3706 - 3725.e29

Опубликована: Авг. 1, 2023

The bone marrow in the skull is important for shaping immune responses brain and meninges, but its molecular makeup among bones relevance human diseases remain unclear. Here, we show that mouse has most distinct transcriptomic profile compared with other states of health injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals distinct, differentially expressed neutrophil-related pathways unique synaptic protein signature. 3D imaging demonstrates structural cellular details skull-meninges connections (SMCs) veins. Last, using translocator positron emission tomography (TSPO-PET) imaging, reflects inflammatory disease-specific spatial distribution patients various neurological disorders. anatomical functional potential as site diagnosing, monitoring, treating diseases.

Язык: Английский

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Defining blood-induced microglia functions in neurodegeneration through multiomic profiling

Nature Immunology, Год журнала: 2023, Номер 24(7), С. 1173 - 1187

Опубликована: Июнь 8, 2023

Abstract Blood protein extravasation through a disrupted blood–brain barrier and innate immune activation are hallmarks of neurological diseases emerging therapeutic targets. However, how blood proteins polarize cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic genetic loss-of-function pipeline to define the transcriptome global phosphoproteome blood-induced polarization its role in microglia neurotoxicity. induced widespread microglial transcriptional changes, including changes involving oxidative stress neurodegenerative genes. Comparative functional multiomics showed that induce distinct receptor-mediated programs macrophages, such as redox, type I interferon lymphocyte recruitment. Deletion coagulation factor fibrinogen reversed signatures. Genetic elimination fibrinogen-binding motif CD11b Alzheimer’s disease mice reduced lipid metabolism signatures were shared with autoimmune-driven neuroinflammation multiple sclerosis mice. Our data provide interactive resource for investigation immunology could support targeting by vascular signals.

Язык: Английский

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Immunology of human fibrosis

Nature Immunology, Год журнала: 2023, Номер 24(9), С. 1423 - 1433

Опубликована: Июль 20, 2023

Язык: Английский

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Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts

ACS Nano, Год журнала: 2024, Номер 18(13), С. 9713 - 9735

Опубликована: Март 20, 2024

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve immunotherapy for fibrotic BRCA. FPC@S combines tumor ECM-targeting peptide, photosensitizer (protoporphyrin IX) an antifibrotic drug (SIS3). After anchoring causes ECM remodeling BRCA cell death generating reactive oxygen species (ROS) situ. Interestingly, ROS-mediated can normalize blood vessel hypoxia turn facilitate more ROS production. Besides, upon acidic microenvironment, will release SIS3 reprograming CAFs reduce their activity but not kill them, thus inhibiting fibrosis while preventing metastasis. The natural physical barrier formed dense is consequently eliminated BRCA, allowing drugs cells penetrate deep into tumors have better efficacy. Furthermore, stimulate system effectively suppress primary, distant metastatic combining with checkpoint blockade therapy. This study provides different insights development targeted delivery systems exploration synergistic immunotherapeutic mechanisms against aggressive

Язык: Английский

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An oncolytic vaccinia virus encoding hyaluronidase reshapes the extracellular matrix to enhance cancer chemotherapy and immunotherapy

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(3), С. e008431 - e008431

Опубликована: Март 1, 2024

Background The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding soluble version hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA investigated its effects combination chemo drugs, polypeptide, immune cells, antibodies. Methods We constructed oncolytic hyaluronidase, function remodeling ECM TME, efficacy both vitro several murine solid tumors alone, drugs including doxorubicin gemcitabine, polypeptide liraglutide, therapeutics PD-L1/PD-1 blockade, CD47 antibody, CAR-T cells. Results Compared control OVV, injection OVV-Hyal1 showed superior efficacies series mouse subcutaneous models. Moreover, degradation by resulted increased infiltration T NK macrophages, activation CD8 + When was combined some therapeutics, example, doxorubicin, anti-PD-1, anti-CD47 more profound therapeutic outcomes were obtained. Conclusions effectively degrades reshape therefore overcoming major hurdles current therapy, limited OVs spread, unfavored polypeptides, antibodies, insufficient effector holds promise improve therapeutics.

Язык: Английский

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Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases

Bioactive Materials, Год журнала: 2024, Номер 39, С. 14 - 24

Опубликована: Май 14, 2024

Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment (TME). Herein, elevated neutrophil extracellular traps (NETs) cancer-associated neurotransmitters (CANTs, e.g., catecholamines) are firstly identified as two of the dominant inducements. Further, an injectable fibrin-alginate hydrogel high tissue adhesion has been constructed specifically co-deliver NETs inhibitor (DNase I)-encapsulated PLGA nanoparticles unselective β-adrenergic receptor blocker (propranolol). The components (i.e., fibrin alginate) respond triggers (thrombin Ca2+, respectively) in postoperative bleeding gelate, shaping into interpenetrating network (IPN) featuring strength. continuous release DNase I PR wreck antagonize catecholamines decrease microvessel density, blockade myeloid-derived suppressor cells, secrete various proinflammatory cytokines, potentiate natural killer cell function hamper cytotoxic T exhaustion. reprogrammed TME significantly suppress locally residual tumors, induce strong immune memory effects thus inhibit lung metastasis. Thus, targetedly degrading blocking CANTs enabled by this in-situ IPN-based drug depot provides a simple efficient approach against SR-induced cancer recurrence

Язык: Английский

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