Stromal p53 Regulates Breast Cancer Development, the Immune Landscape, and Survival in an Oncogene-Specific Manner DOI Open Access

Jinghai Wu,

Xin Liu, Julie W. Reeser

et al.

Molecular Cancer Research, Journal Year: 2022, Volume and Issue: 20(8), P. 1233 - 1246

Published: May 9, 2022

Coevolution of tumor cells and adjacent stromal elements is a key feature during progression; however, the precise regulatory mechanisms this process remain unknown. Here, we show p53 loss enhances oncogenic KrasG12D, but not ErbB2, driven tumorigenesis in murine mammary epithelia. Stroma-specific deletion increases both epithelial fibroblast proliferation glands bearing KrasG12D oncogene epithelia, while concurrently increasing DNA damage and/or replication stress decreasing apoptosis proper. Normal epithelia was affected by deletion. Tumors with p53-null stroma had significant decrease total, cytotoxic, T cells; there increase myeloid-derived suppressor cells, total macrophages, M2-polarized tumor-associated no impact on angiogenesis or connective tissue deposition. reprogrammed gene expression fibroblasts epithelium, targets chemokine receptors/chemokine signaling pathways replication, repair, being most significantly impacted biological processes. A cluster p53-deficient mouse negatively associated patient survival when compared two independent datasets. In summary, stroma-specific promotes an oncogene-specific manner, influences immune landscape, ultimately impacts survival.Expression breast cancer regulates survival.

Language: Английский

Cuproptosis and cuproptosis–related genes in rheumatoid arthritis: Implication, prospects, and perspectives DOI Creative Commons
Jianan Zhao, Shicheng Guo, Steven J. Schrodi

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 4, 2022

Rheumatoid arthritis (RA) is an autoimmune disease that severely affects patients’ physical and mental health, leading to chronic synovitis destruction of bone joints. Although various available clinical treatment options exist, patients respond with varying efficacies due multiple factors, there urgent need discover new improve outcomes. Cuproptosis a newly characterized form cell death. Copper causes cuproptosis by binding lipid-acylated components the tricarboxylic acid cycle, protein aggregation, loss iron-sulfur cluster proteins, eventually proteotoxic stress. Targeting copper cytotoxicity are considered potential for treating oncological diseases. The synovial hypoxic environment presence excessive glycolysis in cells appear act as inhibitors cuproptosis, which can lead survival proliferation immune cells, such fibroblast-like synoviocytes, effector T macrophages, further mediating inflammation RA. Therefore, this study, we attempted elaborate summarize linkage key genes regulating pathological mechanisms RA their effects on variety cells. This study aimed provide theoretical basis support translating preclinical experimental results protocols.

Language: Английский

Citations

81
The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment DOI Creative Commons
Xing Wang, Danping Fan, Xiaoxue Cao

et al.

Antioxidants, Journal Year: 2022, Volume and Issue: 11(6), P. 1153 - 1153

Published: June 13, 2022

Rheumatoid arthritis (RA) is an inflammatory disease that begins with a loss of tolerance to modified self-antigens and immune system abnormalities, eventually leading synovitis bone cartilage degradation. Reactive oxygen species (ROS) are commonly used as destructive or modifying agents cellular components they act signaling molecules in the system. During development RA, hypoxic situation synovium maintains ROS generation, which can be sustained by increased DNA damage malfunctioning mitochondria feedback loop. Oxidative stress caused abundant production has also been shown associated RA. The goal this review examine functions related molecular mechanisms diverse cells synovial microenvironment strategies relying on regulating treat RA reviewed.

Language: Английский

Citations

75
Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects DOI Creative Commons

Qin Ru,

Yusheng Li,

Lin Chen

et al.

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

Published: Oct. 14, 2024

Iron, an essential mineral in the body, is involved numerous physiological processes, making maintenance of iron homeostasis crucial for overall health. Both overload and deficiency can cause various disorders human diseases. Ferroptosis, a form cell death dependent on iron, characterized by extensive peroxidation lipids. Unlike other kinds classical unprogrammed death, ferroptosis primarily linked to disruptions metabolism, lipid peroxidation, antioxidant system imbalance. Ferroptosis regulated through transcription, translation, post-translational modifications, which affect cellular sensitivity ferroptosis. Over past decade or so, diseases have been as part their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous cardiovascular musculoskeletal Ferroptosis-related proteins become attractive targets many major that are currently incurable, some regulators shown therapeutic effects clinical trials although further validation potential needed. Therefore, in-depth analysis its molecular mechanisms may offer additional strategies prevention treatment. In this review, we discuss significance contribution etiology development along with evidence supporting targeting approach. Importantly, evaluate recent promising interventions, providing guidance future targeted treatment therapies against

Language: Английский

Citations

42
Ferroptosis in inflammatory arthritis: A promising future DOI Creative Commons
Siyuan Chang, Mengshi Tang, Bikui Zhang

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 26, 2022

Ferroptosis is a kind of regulatory cell death (RCD) caused by iron accumulation and lipid peroxidation, which characterized mitochondrial morphological changes has complex network. been gradually emphasized in the pathogenesis inflammatory arthritis. In this review, we summarized relevant research on ferroptosis various arthritis including rheumatoid (RA), osteoarthritis, gout arthritis, ankylosing spondylitis, focused relationship between RA ferroptosis. patients with animal models RA, there was evidence overload as well dysfunction that may be associated inducers have shown good application prospects tumor therapy, some anti-rheumatic drugs such methotrexate sulfasalazine to modulating effects. These phenomena suggest role will worth further study. The development therapeutic strategies targeting for promising future.

Language: Английский

Citations

56
Ferroptosis as an emerging target in rheumatoid arthritis DOI Creative Commons
Hui Zhao, Cheng Tang, Miao Wang

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 19, 2023

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. Due to the rise in incidence rate RA and limitations existing therapies, search for new treatment strategies has become a global focus. Ferroptosis novel programmed cell death characterized by iron-dependent lipid peroxidation, with distinct differences from apoptosis, autophagy, necrosis. Under conditions iron accumulation glutathione peroxidase 4 (GPX4) activity loss, lethal peroxide direct cause ferroptosis. mediates inflammation, oxidative stress, damage processes, also participates occurrence pathological progression inflammatory joint diseases including RA. This review provides insight into role mechanism ferroptosis discusses potential challenges as therapeutic strategy RA, effort provide targets prevention treatment.

Language: Английский

Citations

21
P53 Alleviates the Progression of Periodontitis by Reducing M1-type Macrophage Differentiation DOI Creative Commons
Tingting Liu, Dongru Chen, Shanshan Tang

et al.

Inflammation, Journal Year: 2024, Volume and Issue: 47(4), P. 1170 - 1184

Published: Feb. 6, 2024

Our objective is to explore the effect of P53 on progression periodontitis by regulating macrophages differentiation both in vitro and vivo. Eighteen normal gingival tissues were collected for detecting expression infiltration immunofluorescence, real-time PCR (qPCR) western-blot. The inflammatory cytokines (TNF-α IL-6) THP-1, RAW264.7 bone marrow derived macrophage (BMDM) cells, treating with Pifithrin-α (P53 inhibitor) or Nutlin-3a activator) under lipopolysaccharide (LPS) stimulation, observed flow cytometry, qPCR ELISA. severity periodontitis, measured experimental wild-type mice p53 gene conditional knocked-out (p53-CKO) mice, which established ligation LPS injection. A higher number P53-positive was found infiltrated tissues. In experiments showed that compared Nutlin-3a, proportion M1-type TNF-α IL-6 treated cells stimulation. vivo intraperitoneal injection group greater alveolar loss, levels secretion more infiltration, while mild symptoms group. P53-CKO exhibited severe local mice. activation could alleviate reducing polarization. may serve as keeper providing new insights into treatment.

Language: Английский

Citations

6
Inhibition of ASIC1a reduces ferroptosis in rheumatoid arthritis articular chondrocytes via the p53/NRF2/SLC7A11 pathway DOI Creative Commons

Jie Tang,

Wenqiang Liu,

Zihan Li

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(1)

Published: Jan. 6, 2025

The activation of acid-sensing ion channel 1a (ASIC1a) in response to extracellular acidification leads an increase calcium influx, thereby exacerbating the degeneration articular chondrocytes rheumatoid arthritis (RA). It has been suggested that inhibition influx could potentially impede chondrocyte ferroptosis. cystine transporter, solute carrier family 7 member 11 (SLC7A11), is recognized as a key regulator Recent studies suggest tumor suppressor gene p53 facilitates induction ferroptosis by suppressing upregulation SLC7A11. This process mediated nuclear factor erythroid 2-related 2 (NRF2), transcription integral maintenance cellular redox homeostasis and regulation inflammatory responses. study aims investigate role ASIC1a RA determine involvement p53/NRF2/SLC7A11 pathway its underlying mechanism. In vitro experiments revealed acidosis induces reduces expression NRF2 SLC7A11 chondrocytes. Moreover, significantly increased protein levels Pifithrin-α (PFN-α), inhibitor, mitigated acidosis-induced restored diminished Furthermore, PcTx-1, inhibited acidification-induced ferroptosis, enhanced NRF2, reduced expression. vivo demonstrated ASIC1a-specific inhibitor PcTx-1 ameliorated histopathological characteristics ankle joints collagen-induced (CIA) mice, decreased expression, These findings may mitigate RA, via pathway.

Language: Английский

Citations

0
Exploring the impact of cuproptosis-related genes on immune infiltration in rheumatoid arthritis DOI
Fang Xu, Xinran Hu, Yuan Wang

et al.

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Language: Английский

Citations

0
Refining synovial inflammation assessment: A modified General Synovitis Score for active rheumatoid arthritis DOI Open Access

Dengfeng Wu,

Ying Deng,

Yiping Huang

et al.

Experimental and Therapeutic Medicine, Journal Year: 2025, Volume and Issue: 29(3)

Published: Jan. 24, 2025

The General Synovitis Score (GSS) is a well‑established method for scoring synovial inflammation. Despite its widespread use, the GSS does not fully capture inflammatory manifestations characteristic of synovium in rheumatoid arthritis (RA). To address this limitation, modified (mGSS) was developed. present study compared correlation mGSS and with clinical disease activity. aim to provide more precise histopathological system based on hematoxylin eosin (H&E) staining assessing inflammation patients active RA. In cross‑sectional study, tissues were obtained from 60 RA using novel biopsy device. Sections stained H&E, assessed mGSS. Neovascularization observed 56 (93.3%) significantly correlated activity score 28 joints‑C‑reactive protein (DAS28‑CRP) (ρ=0.49; P<0.001), erythrocyte sedimentation rate (ESR) (ρ=0.44; P<0.001) CRP (ρ=0.51; P<0.001). addition, severe neovascularization had higher DAS28‑CRP, ESR levels than those mild‑to‑moderate (P<0.05). Synoviocyte detachment, which occurred nine (15.0%), associated synoviocyte proliferation Furthermore, strongly DAS28‑CRP (ρ=0.62; (ρ=0.37; P=0.003). These findings indicated that are critical yet often overlooked aspects traditional GSS, important Incorporating these elements into may enhance assessment activity, providing accurate evaluation histopathology

Language: Английский

Citations

0
Iron metabolism in rheumatic diseases DOI Creative Commons

Aliakbar Givian,

Amin Azizan,

Ahmadreza Jamshidi

et al.

Journal of Translational Autoimmunity, Journal Year: 2025, Volume and Issue: 10, P. 100267 - 100267

Published: Jan. 5, 2025

Iron is a crucial element for living organism in terms of oxygen transport, hematopoiesis, enzymatic activity, mitochondrial respiratory chain function and also immune system function. The human being has evolved mechanism to regulate body iron. In some rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), sclerosis (SSc), ankylosing spondylitis (AS), gout, this balanced iron regulation impaired. Altered homeostasis can contribute disease progression through ROS production, fibrosis, inflammation, abnormal bone homeostasis, NETosis cell senescence. review, we have focused on the metabolism its role progression.

Language: Английский

Citations

0