AGEs-induced MMP-9 activation mediated by Notch1 signaling is involved in impaired wound healing in diabetic rats

Zhu, Ping; Chen, Chuping; Wu, Daoai; Chen, Guangshu; Tan, Rongshao; Ran, Jianmin

doi:10.1016/j.diabres.2022.109831

Cited by 21 publications

(10 citation statements)

References 40 publications

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“…Remarkably, the regulatory effect of Notch1 on MMP-9 relies on NF-kB activation, and suppression of Notch1 significantly prevents the nuclear translocation of NF-kB induced by AGEs-BSA in keratinocytes. Interestingly, inhibiting Notch1 signal with DAPT represses NICD and MMP-9, resulting in the improvement of COL accumulation and diabetic wound healing (39). Moreover, MMP-9 in diabetic wound healing is also mediated by receptor for AGE (RAGE), MAPK as well as NF-kB signaling pathways.…”

Section: Inflammation-associated Signals Pathways and Mmpsmentioning

confidence: 99%

Targeting matrix metalloproteases in diabetic wound healing

et al. 2023

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Chronic inflammation participates in the progression of multiple chronic diseases, including obesity, diabetes mellitus (DM), and DM related complications. Diabetic ulcer, characterized by chronic wounds that are recalcitrant to healing, is a serious complication of DM tremendously affecting the quality of life of patients and imposing a costly medical burden on society. Matrix metalloproteases (MMPs) are a family of zinc endopeptidases with the capacity of degrading all the components of the extracellular matrix, which play a pivotal part in healing process under various conditions including DM. During diabetic wound healing, the dynamic changes of MMPs in the serum, skin tissues, and wound fluid of patients are in connection with the degree of wound recovery, suggesting that MMPs can function as essential biomarkers for the diagnosis of diabetic ulcer. MMPs participate in various biological processes relevant to diabetic ulcer, such as ECM secretion, granulation tissue configuration, angiogenesis, collagen growth, re-epithelization, inflammatory response, as well as oxidative stress, thus, seeking and developing agents targeting MMPs has emerged as a potential way to treat diabetic ulcer. Natural products especially flavonoids, polysaccharides, alkaloids, polypeptides, and estrogens extracted from herbs, vegetables, as well as animals that have been extensively illustrated to treat diabetic ulcer through targeting MMPs-mediated signaling pathways, are discussed in this review and may contribute to the development of functional foods or drug candidates for diabetic ulcer therapy. This review highlights the regulation of MMPs in diabetic wound healing, and the potential therapeutic ability of natural products for diabetic wound healing by targeting MMPs.

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Section: Inflammation-associated Signals Pathways and Mmpsmentioning

confidence: 99%

Targeting matrix metalloproteases in diabetic wound healing

et al. 2023

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“…Mouse keratinocytes were isolated from the skin of newborn ICR CD1 mice and cultured as described previously [ 63 ], according to protocols approved by the Institutional Care and Use Committees of Augusta University (Protocol #2017-0915) and the Charlie Norwood VA Medical Center (Protocol #22-04-135). Keratinocytes were treated with 0, 2.0 µg/mL LPS (Sigma-Aldrich, St. Louis, MO, USA), or 2.5 µg/mL Pam 3 CSK 4 (EMD Millipore Corporation, Burlington, MA, USA) in the presence or absence of 1 µM SAHA (Sigma-Aldrich, St. Louis, MO, USA) at 37 °C with 5% CO 2 for 24 h; or with 0, 50, or 100 µg/mL AGE-BSA (Sigma-Aldrich or BioVision Incorporated, Milpitas, CA, USA), in the presence or absence of 1 or 2 µM SAHA (based on our previous studies [ 40 ]) at 37 °C with 5% CO 2 for 24, 48, and 72 h. Doses of AGEs were selected based on previous literature [ 54 , 64 , 65 , 66 ]. Cells were then harvested for RT-qPCR or Western analysis.…”

Section: Methodsmentioning

confidence: 99%

Advanced Glycation End Products and Activation of Toll-like Receptor-2 and -4 Induced Changes in Aquaporin-3 Expression in Mouse Keratinocytes

Luo

Uaratanawong

Choudhary

et al. 2023

IJMS

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Prolonged inflammation and impaired re-epithelization are major contributing factors to chronic non-healing diabetic wounds; diabetes is also characterized by xerosis. Advanced glycation end products (AGEs), and the activation of toll-like receptors (TLRs), can trigger inflammatory responses. Aquaporin-3 (AQP3) plays essential roles in keratinocyte function and skin wound re-epithelialization/re-generation and hydration. Suberanilohydroxamic acid (SAHA), a histone deacetylase inhibitor, mimics the increased acetylation observed in diabetes. We investigated the effects of TLR2/TLR4 activators and AGEs on keratinocyte AQP3 expression in the presence and absence of SAHA. Primary mouse keratinocytes were treated with or without TLR2 agonist Pam3Cys-Ser-(Lys)4 (PAM), TLR4 agonist lipopolysaccharide (LPS), or AGEs, with or without SAHA. We found that (1) PAM and LPS significantly upregulated AQP3 protein basally (without SAHA) and PAM downregulated AQP3 protein with SAHA; and (2) AGEs (100 µg/mL) increased AQP3 protein expression basally and decreased AQP3 levels with SAHA. PAM and AGEs produced similar changes in AQP3 expression, suggesting a common pathway or potential crosstalk between TLR2 and AGEs signaling. Our findings suggest that TLR2 activation and AGEs may be beneficial for wound healing and skin hydration under normal conditions via AQP3 upregulation, but that these pathways are likely deleterious in diabetes chronically through decreased AQP3 expression.

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“…The Notch1/ NF-κB/MMP-9 axis plays a significant role in the healing of DWs. Zhu et al (2022) demonstrated that the upregulation of notch intracellular domain (NICD), Delta-like 4 (Dll4), and Hes-1 is associated with increased activation of matrix metalloproteinase-9 (MMP-9) in the skin of diabetic rats and primary human keratinocytes treated with advanced glycation end products-bovine serum albumin (AGEs-BSA). Interestingly, the regulatory action of Notch1 on MMP-9 requires the activation of NF-κB and knocking down Notch1 significantly reduces the nuclear translocation of NF-kB caused by AGEs-BSA in keratinocytes.…”

Section: Inflammation-associated Signals Pathways and Mmp In Diabetic...mentioning

confidence: 99%

“…Interestingly, the regulatory action of Notch1 on MMP-9 requires the activation of NF-κB and knocking down Notch1 significantly reduces the nuclear translocation of NF-kB caused by AGEs-BSA in keratinocytes. Strikingly, repressing Notch1-signaling NICD and MMP-9 using dual antiplatelet therapy (DAPT) enhances collagen accumulation and improves diabetic wound healing [18]. Apart from receptor for advanced glycation end products (RAGE), Mitogen-activated protein kinase (MAPK), and NF-κB signaling pathways, MMP-9 is also implicated in the healing of diabetic wounds.…”

Section: Inflammation-associated Signals Pathways and Mmp In Diabetic...mentioning

confidence: 99%

Based on Clinical Research Matrix Metalloprotease (MMP) Inhibitors to Promote Diabetic Wound Healing

Yadav

2023

Horm Metab Res

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Chronic inflammation is a common factor in obesity, diabetes mellitus, and the complications of diabetes, including diabetic wounds. These ulcers are characterized by persistent lesions that are challenging to heal, significantly decreasing patients’ quality of life and imposing a substantial financial burden on society. MMP are zinc endopeptidases that play a role in wound healing in response to various stimuli, including diabetes mellitus. MMP levels fluctuate throughout the wound healing process in diabetic patients' serum, skin tissues, and wound fluid, indicating their potential as biomarkers for diabetic foot ulcers. Targeting MMP has emerged as a promising strategy for treating diabetic wounds, as these enzymes are involved in critical biological processes related to wound healing, including extracellular matrix secretion, angiogenesis, granulation tissue formation, collagen growth, re-epithelization, inflammatory response, and oxidative stress.

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AGEs-induced MMP-9 activation mediated by Notch1 signaling is involved in impaired wound healing in diabetic rats

Cited by 21 publications

References 40 publications

Targeting matrix metalloproteases in diabetic wound healing

Targeting matrix metalloproteases in diabetic wound healing

Advanced Glycation End Products and Activation of Toll-like Receptor-2 and -4 Induced Changes in Aquaporin-3 Expression in Mouse Keratinocytes

Based on Clinical Research Matrix Metalloprotease (MMP) Inhibitors to Promote Diabetic Wound Healing

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