This study explored the mechanism by which glucose transporter type 1 (GLUT1) promotes neutrophil extracellular trap (NET)-mediated macrophage phenotype conversion in a high-glucose environment, based on the interaction between fibroblasts and macrophages. We demonstrated that GLUT1 plays an important role in immune cell-fibroblast crosstalk. High glucose induces GLUT1 to upregulate high mobility group box 1 (HMGB1) levels, thereby promoting NET release and macrophage M1 polarization. Addition of a NET inhibitor promoted macrophage M2 polarization and alleviated the impaired macrophage phenotype conversion. Additionally, overexpression of Glut1 enhanced the expression of inflammatory factors tumor necrosis factor alpha (TNF-α) and interleukin beta (IL-1β), leading to inflammatory damage to fibroblasts, which was reversed significantly by inhibiting NETs . The results indicated that GLUT1 mediates the crosstalk between NETs, macrophage phenotype conversion impairment, and inflammatory damage in fibroblasts. This study emphasizes the importance of GLUT1 in the interaction between immune cells and fibroblasts, and its regulatory role in the impairment of NET-mediated macrophage phenotype conversion. These findings suggest that the regulatory mechanisms between HMGB1 and NETs in a high-glucose environment might provide potential therapeutic targets to treat diabetic wounds.

2025-06-01·JOURNAL OF CONTROLLED RELEASE

Lipid nanoparticles target neutrophils to reduce SARS-CoV-2-induced lung injury and inflammation

Article

作者: Jang, Hye Jung ; Park, Chun Gwon ; Park, Joo Dong ; Verma, Saguna ; Park, Wooram ; Shin, Ha Eun ; Murphy, Sean V ; Giannakopoulos, Stefanos ; Park, Juwon

The need to understand key players driving pulmonary inflammation and fibrosis in COVID-19 patients leading to effective preventive strategies is imminent. Excessive neutrophil activation, including extracellular trap (NET) formation, is associated with severe COVID-19 and long-term sequelae. However, the clinical applications of neutrophil-targeting therapies are challenging due to short bioavailability and lack of cell-type specificity. This study presents a lipid nanoparticle (LNP) platform designed to deliver two established NET inhibitors, DNase I and Sivelestat (Siv) referred to as DPNLNPs, specifically to lung neutrophils. In vitro and in vivo experiments demonstrate that DPNLNPs preferentially accumulate in the lung neutrophils and degrade NETs as efficiently as the free DNase I and Siv. Additionally, administration of DPNLNPs in K18-hACE2 mice significantly inhibited SARS-CoV-2-induced NETs at a much lower dose than the free drugs and correlated with reduced lung and systemic inflammation, lung epithelium injury, and collagen deposition. Importantly, DPNLNP treatment only during the symptomatic phase of infection improved SARS-CoV-2 outcome revealing the complex role of NETs in COVID-19 pathogenesis. Together, this study serves as a proof-of-concept for adapting the LNP platform to deliver more than one immunomodulatory drug in a cell-specific manner to manage NET-associated complications in COVID-19 and other respiratory diseases.

2025-03-01·Journal for ImmunoTherapy of Cancer

Immunosuppressive microenvironment of liver restrains chemotherapeutic efficacy in triple-negative breast cancer

Article

作者: Zhou, Wenbin ; Sun, Yue ; Yu, Muxin ; Mao, Xinrui ; Wang, Shui ; Pan, Hong ; Qi, Qi ; Ling, Peiwen ; Sun, Chang ; Tang, Xinyu ; Pang, Zheng ; Qian, Mengjia ; Sun, Xiaowei ; Zhang, Weiya ; Liu, Mingduo ; Sun, Wen ; Li, Wei

Background:

Patients with liver metastases of triple-negative breast cancer (TNBC) show poor prognosis compared with other metastases. Chemotherapy is the primary treatment for advanced TNBC. Tumor cell diversity and the tumor microenvironment could affect therapeutic effect. However, whether liver metastases of TNBC exhibit differential chemotherapy efficacy compared with the primary tumors remains inadequately understood. The specific mechanisms that modulate chemotherapy efficacy in liver metastases need further investigation.

Methods:

Single-cell RNA sequencing data from public databases were leveraged to contrast the immune profiles of liver metastases and primary tumors in TNBC. Murine models bearing liver tumors or primary tumors of TNBC were used to evaluate chemotherapy efficacy. Techniques such as immunohistochemistry, wound healing assays, and colony formation assays were employed to account for tumor heterogeneity. Intratumoral T lymphocytes and macrophages were quantified and characterized using RNA sequencing, immunohistochemistry, and flow cytometry. Antibody-mediated depletion of CD8+T cells or macrophages in mice substantiated their impact on chemotherapy responses.

Results:

Single-cell RNA sequencing data showed the immune microenvironments of liver metastases and primary tumors exhibited significant differences, which may critically influence chemotherapy outcomes. Mouse models confirmed that chemotherapy was less effective against liver tumors compared with subcutaneous tumors. After excluding the influence of tumor cell heterogeneity, the weaker responsiveness in liver tumors was mediated by the impeded infiltration of CD8+T cells, attributed to the decreased activation of macrophages. Augmenting macrophage activation can improve the chemotherapeutic efficacy in liver tumors. Moreover, chemotherapy drove the immune microenvironment towards increased suppression through distinct mechanisms, with neutrophil extracellular traps (NETs) accumulating in liver tumors and impaired functionality of macrophages at the primary site. The combination of NET inhibitors or macrophage activators with chemotherapy enhanced treatment effectiveness.

Conclusions:

These findings disclose the compromised chemotherapeutic efficacy in liver tumors of TNBC and elucidate the underlying immune-related mechanisms within the tumor microenvironment. Targeting the specific underpinnings of immune suppression at different tumor sites with selective drugs could optimize chemotherapeutic efficacy.

项与 NET INHIBITORS (Peel Therapeutics) 相关的新闻（医药）

2023-04-13

·BioSpace

Peel Therapeutics Describes Excessive NETosis Induction in Long COVID

Peer-reviewed study offers first description of ongoing NETosis induction in Long COVID; provides insights into pathogenesis and can serve as a surrogate marker for persistent pathology Research emphasizes need to explore neutrophil-targeted therapies in acute and chronic COVID-19 SALT LAKE CITY, April 13, 2023 /PRNewswire/ -- Peel Therapeutics, an evolutionary-inspired, clinical-stage biotech company, announced research conducted by the company has been published in The Journal of Thrombosis and Haemostasis. The study, NETosis Induction Reflects COVID-19 Severity and Long COVID: Insights from a Two-Center Patient Cohort Study in Israel, evaluated the ability of blood from Israeli patients with Long COVID to induce neutrophil extracellular traps (NETs) as a marker of ongoing inflammation. NETs are sticky webs of DNA released by activated immunes cells that contribute to immunothrombosis (mini-clots) and fibrosis. Peel scientists also correlated NETosis potential with acute disease severity in COVID-19. The study concluded that NET inhibitors may be a possible treatment approach for COVID-19 and recommended additional research to confirm findings. Peel Therapeutics is developing first-in-class Neutrophil Targeting Peptides (NTPs) – originating from natural NET inhibitors in newborns – to block inflammation leading to immunothrombosis and fibrosis. In this study, Peel researchers examined NETs among people with and without COVID-19 and measured NET induction during and after infection. The study concluded that increased NETosis induction can be detected in people with Long COVID, offering insight into the potential uses of NTPs and other NET inhibitors for the treatment of Long COVID. The study included 177 patients from 2 Israeli hospitals with acute COVID-19 infection (mild/moderate or severe/critical) or convalescent COVID-19 (recovered or Long COVID), along with 54 non-COVID controls. People who experienced symptoms of Long COVID maintained higher NETosis induction compared to recovered convalescent patients. Dr. Kimberly Martinod, Assistant Professor in Cardiovascular Sciences at KU Leuven, runs a NET research laboratory that studies clotting and fibrosis in heart failure and is co-author on the paper. Dr. Martinod remarked, "Measuring NETs in blood samples is challenging. The Peel team quantified the ability of patient blood to form NETs instead of measuring fragments of NETs which can be complicated by their rapid degradation – especially in COVID-19 where this is unbalanced. This study demonstrates the increased ability of blood from patients with acute and ongoing COVID-19 to induce NETs in healthy neutrophils. This reflects ongoing inflammation that may trigger excessive NET release, even weeks after the initial infection has cleared." Peel CEO and Co-founder, Dr. Joshua Schiffman, stated, "This study offers a new target for COVID patients suffering from ongoing inflammation. The potential use of our NTPs in acute and chronic COVID further validates Peel's ability to unlock evolutionary biology for cancer and inflammation. Our preclinical research lays the groundwork for scientists and clinicians to understand NTP's potential to treat inflammatory diseases, improve health outcomes, and in this case, offer hope to patients with Long COVID." The study can be accessed via the Journal of Thrombosis and Haemostasis. About Peel Therapeutics Peel Therapeutics is an evolutionary-inspired, clinical-stage biotech company that engineers nature better than evolution intended. Our scientists search for nature's super abilities where evolutionary biology accomplished the inconceivable in preventing or defeating disease. We then apply drug development expertise to rapidly translate this evolutionary biology into medicines. The company is advancing a therapeutic pipeline to treat a spectrum of devastating conditions, with a near-term focus on cancer and inflammation. At Peel Therapeutics, we push the limits of biology to develop highly effective and safe medicines for patients. "Peel" is the Hebrew word for elephant, our company originates from the natural cancer resistance found in elephants.

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100 项与 NET INHIBITORS (Peel Therapeutics) 相关的药物交易

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