Melatonin protects endothelial progenitor cells against AGE-induced apoptosis via autophagy flux stimulation and promotes wound healing in diabetic mice

Jin, Haiming; Zhang, Zengjie; Wang, Chengui; Tang, Qian; Wang, Jianle; Bai, Xueqin; Wang, Qingqing; Nisar, Majid; Tian, Naifeng; Wang, Quan; Mao, Cong; Zhang, Xiaolei; Wang, Xiangyang

doi:10.1038/s12276-018-0177-z

Cited by 72 publications

(53 citation statements)

References 34 publications

(38 reference statements)

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“…AGEs affect normal physiological functions of cells and hinder diabetic wound healing through inducing the production of cytokines and in ammatory factors, inhibiting the generation of collagen, and inducing excessive immune response [35,36]. Therefore, AGEs have been used widely as a stimulant for preparing in vitro models of diabetic wounds [37,38]. Our results con rmed that AGEs signi cantly inhibit the proliferation, migration, and tubular structure formation of HUVECs, whereas KLX signi cantly reverses the inhibitory effect of AGEs.…”

Section: Discussionsupporting

confidence: 57%

Kanglexin promotes diabetic wound healing through activating FGFR/ERK1/2 signaling pathway mediated angiogenesis.

Zhao¹,

Wang²,

Yang³

et al. 2020

Preprint

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Background: Diabetic wounds (DWs), especially leg or foot ulcers, are common diabetic complications, accounting for about 20% of diabetic patients. At present, there is still lack of effective measures to treat DWs in clinical practice. Kanglexin (KLX) is an anthraquinone compound with vasoprotective effect. This study will explore the therapeutic effects of KLX on DWs and the underlying mechanisms.Method: KM mice were injected with streptozocin (180 mg/kg) intraperitoneally to establish animal model of Type 1 Diabetes. The full-thickness skin wounds with the diameter of 5 mm were prepared on the back of diabetic mice with a skin punch. KLX is dissolved in sterile injection oil and applied to the wound once a day for 14 consecutive days. The wounds were photographed every day and the wound size was analyzed by Image Pro Plus software. On the 3rd, 7th, 11th day after KLX administration, skin tissues with a diameter of 1cm around the wound were fixed in paraformaldehyde and subjected to HE, Masson and immunohistochemical staining. Collagen deposition were evaluated by hydroxyproline kit. Angiogenesis of wound skin was evaluated by recording the formation of new blood vessels on its subsurface. In vitro study, human umbilical vein endothelial cells (HUVECs) were treated with advanced glycation end products (AGEs, 100 μg/mL) to establish the cell model of DWs. The proliferation, migration and tubular structure formation of HUVECs were measured by MTT, scratch and tubule formation experiments, respectively. Phosphorylation of ERK1/2 was detected by Western blot analysis.ResultsFirstly, in-vivo study showed that KLX significantly accelerated the closure of diabetic wounds through promoting granulation tissue formation, collagen synthesis and angiogenesis. Secondly, in vitro study results further confirmed that KLX promoted the proliferation, migration and tubular structure formation of HUVECs. Besides, KLX significantly up-regulated phospho-ERK1/2 both in diabetic wounds and AGEs-treated HUVECs. Thirdly, molecular docking simulation results indicated that there were multiple hydrogen bonds between KLX and FGFR amino acid residues, and FGFR inhibitor PD173074 significantly reversed KLX’s promotion of ERK1/2 phosphorylation and angiogenesis. Conclusions:KLX promotes angiogenesis and accelerates the healing of diabetic wounds by activating FGFR and ERK1/2 signaling pathway.

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Section: Discussionsupporting

confidence: 57%

Kanglexin promotes diabetic wound healing through activating FGFR/ERK1/2 signaling pathway mediated angiogenesis.

Zhao¹,

Wang²,

Yang³

et al. 2020

Preprint

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“…Growing evidence has demonstrated that activation of p38 and JNK signals may lead to MMP-13 expression enhancement (23)(24)(25), whereas NF-kB signaling was also reported to act as a crucial regulator in MMP-13 expression in NPCs (26). Meanwhile, our studies have found that autophagy may also be activated by AGEs and regulate MMP-13 in NPCs (27)(28)(29).These studies above suggest that MAPK, NF-kB signaling, and autophagy may regulate MMP-13 in IVDD, which may also be implicated in diabetic IVDD; however, the relationship between them and BRD4 in diabetic IVDD is still unknown.…”

mentioning

confidence: 51%

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Wang

Chen³

et al. 2019

FASEB j.

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Diabetes mellitus may lead to intervertebral disc degeneration (IVDD). Matrix metalloproteinase‐13 (MMP‐13) is one of the major catabolic factors in extracellular matrix (ECM) metabolism of nucleus pulposus cells (NPCs) and contributes to diabetic IVDD. Bromodomain‐containing protein 4 (BRD4) is a member of the bromodomain and extraterminal protein family and is implicated in chronic inflammation. Here, we report that the expression of BRD4 and MMP‐13 was elevated in diabetic nucleus pulposus tissues as well as in advanced glycation end products (AGEs)‐treated NPCs; also, the regulatory effect of BRD4 on MMP‐13 was studied. We found that MMP‐13 was regulated by MAPK and NF‐κB signaling as well as autophagy in AGEs‐treated NPCs. Next, we explored the role of BRD4 in regulation of MAPK, NF‐κB signaling, and autophagy. The results showed that BRD4 is the upstream regulator of all of these 3 factors, and inhibition of BRD4 may suppress MAPK and NF‐κB signaling while activating autophagy in AGEs‐treated NPCs. Finally, we demonstrated that BRD4 inhibition may suppress MMP‐13 expression in diabetic NPCs in vitro as well as in vivo; meanwhile, it may preserve ECM in diabetic rats. Our study demonstrates that inhibition of BRD4 may suppress MAPK and NF‐κB signaling and activate autophagy to suppress MMP‐13 expression in diabetic IVDD, and diabetic IVDD may be compromised by BRD4 inhibitors.—Wang, J., Hu, J., Chen, X., Huang, C., Lin, J., Shao, Z., Gu, M., Wu, Y., Tian, N., Gao, W., Zhou, Y., Wang, X., Zhang, X. BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration. FASEB J. 33, 11555–11566 (2019). http://www.fasebj.org

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“…In a diabetic wound healing model, melatonin improved disrupted wound healing. Therefore, melatonin is suggested to improve disrupted wound healing through inhibiting apoptotic events by stimulation of autophagy pathway [191]. Melatonin also promotes umbilical cord blood (UCB)mesenchymal stem cells (MSCs) motility through enhancing cytoskeletal reorganization which this effect is mediated by melatonin MT2 receptor triggering Gq protein alpha (Gαq)-dependent protein kinase (PK)Cζ phosphorylation regulating Focal adhesion kinase (FAK)/ paxillin-mediated cell division cycle 42 (Cdc42)/actinrelated proteins (Arp2/3) activation [192].…”

Section: Melatonin and Diabetic Wound Healingmentioning

confidence: 99%

Melatonin: new insights on its therapeutic properties in diabetic complications

Pourhanifeh

Hosseinzadeh

Dehdashtian

et al. 2020

Diabetol Metab Syndr

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Diabetes and diabetic complications are considered as leading causes of both morbidity and mortality in the world. Unfortunately, routine medical treatments used for affected patients possess undesirable side effects, including kidney and liver damages as well as gastrointestinal adverse reactions. Therefore, exploring the novel therapeutic strategies for diabetic patients is a crucial issue. It has been recently shown that melatonin, as main product of the pineal gland, despite its various pharmacological features including anticancer, anti-aging, antioxidant and antiinflammatory effects, exerts anti-diabetic properties through regulating various cellular mechanisms. The aim of the present review is to describe potential roles of melatonin in the treatment of diabetes and its complications.

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Melatonin protects endothelial progenitor cells against AGE-induced apoptosis via autophagy flux stimulation and promotes wound healing in diabetic mice

Cited by 72 publications

References 34 publications

Kanglexin promotes diabetic wound healing through activating FGFR/ERK1/2 signaling pathway mediated angiogenesis.

Kanglexin promotes diabetic wound healing through activating FGFR/ERK1/2 signaling pathway mediated angiogenesis.

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Melatonin: new insights on its therapeutic properties in diabetic complications

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