作者: Jamir, Sungjemrenla I ; Khongwir, Larity Daniewkor ; Ahmed, Muskaan ; Gautam, Manish Kumar ; Islam, Aminul ; Mahajon, Bidhan ; Mondal, Sandip ; Mondal, Nur Shaid

Diabetic wounds are a class of chronic wounds that exhibit significant healing abnormalities due to dysregulated cytokines, growth factors, and unique cellular expressions, currently affecting an estimated 9.1-26.1 million people per year globally. Matrix metalloproteinases (MMPs), angiogenic factors, and inflammatory mediators remain the key determinants for managing diabetic wounds. Vascular endothelial growth factor (VEGF) is one of the most prominent types of growth factors induced during angiogenesis in general and cell proliferation pathways. Chronic hyperglycemia, neuropathy, and inflammation associated with diabetes disorders affect cellular responses, blood circulation, and immunological systems impair normal wound healing. This reduced effectiveness of current management strategies is reflected in the high number of delayed wounds among diabetic patients due to escalated oxidative stress and impaired signaling pathways, which prevent healing, calling for new therapies. MMPs are essential for tissue remodeling, but excess levels of MMPs predispose tissues to matrix degradation and interruption in cell signaling leading thereby prolonging inflammation seen in diabetic wounds. Efficient wound healing requires a balanced relationship regarding matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). New regenerative solutions, such as stem cells, platelet-rich plasma (PRP), gene therapies, and MMP inhibitors that can re-establish angiogenesis; decrease inflammation; and stimulate growth factor signaling, suggest promising strategies for improved diabetic wound healing. Hyperbaric oxygen therapy allows tissue regeneration and reduces the area of ulceration, bringing other benefits. In the future, therapeutics should focus on multifunctional and responsive strategies that include anti-inflammatory agents, cytokine modulators, and stem cell treatments that exhibit superior efficacy in comparison to conventional therapies when assessed clinically. Novel advanced combination strategies represent a realistic route to targeted therapies that meet clinical needs and have the potential capability for utilizing mechanistic insights, both creative in their implementation of recently developed techniques as well as applied on a broader scale through the evidence-based management across diabetic wounds offering better outcomes and quality of life amongst increasing diabetic commonalities.

2025-06-01·JOURNAL OF BIOLOGICAL CHEMISTRY

Directed evolution of metalloproteinase inhibitor TIMP-1 for selective inhibition of MMP-9 exploits catalytic and fibronectin domain interactions

Article

作者: Coban, Mathew A ; Raeeszadeh-Sarmazdeh, Maryam ; Dimesa, Alexandra M ; Rezhdo, Arlinda ; Radisky, Evette S ; Van Deventer, James A ; Hockla, Alexandra ; Shoari, Alireza

Matrix metalloproteinase-9 (MMP-9) is a critical enzyme involved in extracellular matrix degradation and is strongly implicated in many diseases, including triple-negative breast cancer and other poor prognosis cancers. Selective inhibition of MMP-9 is therefore a promising therapeutic strategy. However, development of MMP inhibitors has been hindered by challenges in achieving specificity, with past efforts failing in clinical trials due to off-target effects and associated toxicity. Here, we present a novel approach to overcoming these challenges by engineering tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural broad-spectrum MMP inhibitor, to achieve enhanced specificity and affinity for MMP-9. We demonstrate that TIMP-1 can be strategically engineered to selectively inhibit MMP-9 through modulating interactions not only with the catalytic domain but also with the unique fibronectin (FN) domains. By leveraging yeast surface display with strategic library design, we identified TIMP-1 variants that exploit multiple surface epitopes to optimize interactions with both the catalytic and FN domains of MMP-9. Molecular dynamics simulations further suggest how modifications in the N-terminal and C-terminal domains of TIMP-1 drive these selective interactions. The top engineered TIMP-1 variant exhibited significantly improved selectivity for MMP-9 in a manner dependent upon novel interactions with the FN domains, as validated through inhibition kinetics. This variant also demonstrated potent inhibition of MMP-9-driven triple-negative breast cancer cell invasiveness, underscoring the therapeutic potential of this approach. Our study highlights the versatility of TIMP-1 as a scaffold that can be optimized for highly selective MMP inhibition, providing new avenues for the development of targeted therapies.

2025-05-15·FASEB JOURNAL

Interleukin‐1β Stimulates Matrix Metalloproteinase 10 Secretion: A Possible Mechanism in Trophoblast‐Dependent Spiral Artery Remodeling

Article

作者: Whitley, Guy S. ; Aziz, Miriam ; Tryfonos, Zoe ; Ashton, Sandra ; Lagzouli, Nora ; Tinsley, Holly ; Longhurst, Charlotte ; Frick, Alexander ; Cartwright, Judith E.

ABSTRACT:

Maternal uterine spiral arteries (SpA) undergo significant structural changes in early pregnancy, resulting in increased blood flow to the developing fetus. Endothelial cells (EC) and vascular smooth muscle cells (VSMC) are lost from the SpA wall and are replaced by trophoblasts. We have previously shown that matrix metalloproteinase 10 (MMP‐10) and Heparin binding‐EGF like growth factor (HB‐EGF) gene expression is increased in a 3D EC/VSMC co‐culture system in response to trophoblast secreted factors. This study investigated trophoblast mediated MMP‐10 and HB‐EGF expression and determined if there was a relationship between the secretion of MMP‐10 and the release of soluble HB‐EGF (sHB‐EGF) from EC. MMP‐10 was widely expressed in first trimester decidual tissue including trophoblast, and EC, but not VSMC. MMP‐10 expression was significantly lower in decidual tissue from pregnancies at increased risk of developing pre‐eclampsia compared to low‐risk pregnancies. In vitro, SGHEC‐7 cells, a human EC line, but not SGHVMC‐9, a human VSMC cell line, secreted MMP‐10 in response to trophoblast conditioned medium (TCM). TCM contains several growth factors and cytokines, but only interleukin‐1β (IL1β) significantly stimulated MMP‐10 secretion by SGHEC‐7 cells. Interleukin‐1 receptor antagonist (IL‐1Ra) significantly inhibited TCM‐induced MMP‐10 secretion. Interrogation of intracellular pathways established the involvement of MEK and JNK in TCM and IL‐1β stimulated MMP‐10 secretion. Although IL‐1β also significantly increased sHB‐EGF, inhibition of MMP‐10 activity using a broad spectrum MMP inhibitor had no effect on sHB‐EGF. Western blot analysis indicated that MMP‐10 secreted by EC in response to IL‐1β stimulation was the enzymatically inactive pro form.

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