Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus

Tu, Jian‐Feng; Yang, Yihong; Zhang, Jingzhu; Lu, Guotao; Ke, Lu; Tong, Zhihui; Kasimu, Maimaitijiang; Hu, De Jin; Xu, Qiuran

doi:10.3892/mmr.2020.10915

Cited by 9 publications

(10 citation statements)

References 30 publications

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“…Finally, we examined the effects of chemerin-9 on the expression of chemerin and CMKLR1. Results showed that the circulating chemerin and the AAA-tissue chemerin/CMKLR1 expression were downregulated following the chemerin-9 treatment, contradicting previous studies [ 24 , 52 ]. These conflicts may be attributed to the different dosages or modes of chemerin-9 administration, or the disparate microenvironment of experimental models.…”

Section: Discussioncontrasting

confidence: 79%

“…Chemerin-9, an analog of chemerin, has a higher affinity for CMKLR1 and functions as an anti-inflammatory regulator to inhibit the development of atherosclerosis, Alzheimer's disease, and pancreatogenic diabetes [22][23][24]. However, the role of chemerin-9 in the biological behavior of AAA has so far been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Chemerin-9 (149-157), comprising nine amino acids from the C-terminus of chemerin, retains most agonist activity [22]. In vivo, chemerin-9 exerts an anti-inflammatory effect by targeting CMKLR1, thus restraining the development of several diseases, including atherosclerosis, Alzheimer's disease, and pancreatogenic diabetes [22][23][24]. However, the role of chemerin-9 in AAA behavior has not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

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Chemerin-9 Attenuates Experimental Abdominal Aortic Aneurysm Formation in ApoE−/− Mice

Chen

Han

Bian

et al. 2021

Journal of Oncology

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Chronic inflammation plays an essential role in the pathogenesis of abdominal aortic aneurysm (AAA), a progressive segmental abdominal aortic dilation. Chemerin, a multifunctional adipocytokine, is mainly generated in the liver and adipose tissue. The combination of chemerin and chemokine-like receptor 1 (CMKLR1) has been demonstrated to promote the progression of atherosclerosis, arthritis diseases, and Crohn’s disease. However, chemerin-9 acts as an analog of chemerin to exert an anti-inflammatory effect by binding to CMKLR1. Here, we first demonstrated that AAA exhibited higher levels of chemerin and CMKLR1 expression compared with the normal aortic tissues. Hence, we hypothesized that the chemerin/CMKLR1 axis might be involved in AAA progression. Moreover, we found that chemerin-9 treatment markedly suppressed inflammatory cell infiltration, neovascularization, and matrix metalloproteinase (MMP) expression, while increasing the elastic fibers and smooth muscle cells (SMCs) in Ang II-induced AAA in ApoE−/− mice. This demonstrated that chemerin-9 could inhibit AAA formation. Collectively, our findings indicate a potential mechanism underlying AAA progression and suggest that chemerin-9 can be used therapeutically.

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Section: Discussioncontrasting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemerin-9 Attenuates Experimental Abdominal Aortic Aneurysm Formation in ApoE−/− Mice

Chen

Han

Bian

et al. 2021

Journal of Oncology

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“…Several studies suggest that chemerin and its agonistic derivatives hold considerable potential for treating, e.g., pancreatic diabetes mellitus, 33 cancer, 34 or impaired wound healing. 35 Therefore, the cyclic peptide presented here could directly be a valuable therapeutic tool.…”

Section: ■ Discussionmentioning

confidence: 99%

Cyclic Analogues of the Chemerin C-Terminus Mimic a Loop Conformation Essential for Activating the Chemokine-like Receptor 1

et al. 2021

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The chemokine-like receptor 1 (CMKLR1) is a promising target for treating autoinflammatory diseases, cancer, and reproductive disorders. However, the interaction between CMKLR1 and its protein–ligand chemerin remains uncharacterized, and no drugs targeting this interaction have passed clinical trials. Here, we identify the binding mode of chemerin-9, the C-terminus of chemerin, at the receptor by combining complementary mutagenesis with structure-based modeling. Incorporating our experimental data, we present a detailed model of this binding site, including experimentally confirmed pairwise interactions for the most critical ligand residues: Chemerin-9 residue F8 binds to a hydrophobic pocket in CMKLR1 formed by the extracellular loop (ECL) 2, while F6 interacts with Y2.68, suggesting a turn-like structure. On the basis of this model, we created the first cyclic peptide with nanomolar activity, confirming the overall binding conformation. This constrained agonist mimics the loop conformation adopted by the natural ligand and can serve as a lead compound for future drug design.

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“…Moreover, chemerin was identified as a novel adipokine to regulate adipocyte metabolism [ 11 ]. In addition, chemerin has been implicated to play an important role in the pathogenesis of obesity as well as diabetes [ 12 – 17 ]. As a chemoattractant, adipocyte-secreted chemerin was associated with insulin resistance [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Chemerin/CMKLR1 Axis Promotes the Progression of Proliferative Diabetic Retinopathy

Wang

Zhang²,

Guo

et al. 2021

International Journal of Endocrinology

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Background. Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes, and the levels of chemerin were associated with the severity of DR. However, there is no research on chemerin in the development of proliferative diabetic retinopathy (PDR). Therefore, our study aimed to explore the relationship between chemerin and PDR. Methods. The levels of chemerin/chemokine-like receptor (CMKLR1), proinflammatory cytokines, and vascular endothelial growth factor (VEGF) in 90 cases of PDR and nonproliferative diabetic retinopathy (NPDR) patients and in high glucose (HG) stimulated human retinal pigment epithelium cells (ARPE-19) were evaluated by ELISA. Moreover, chemerin was added into HG-induced ARPE-19 cells to assess its effect on proinflammatory cytokines and VEGF. Results. The levels of chemerin/CMKLR1 were higher in PDR patients than NPDR ones, and chemerin was positively correlated with CMKLR1 in PDR patients. Compared to NPDR, the secretions of proinflammatory cytokines and VEGF were increased in PDR patients and positively correlated with chemerin/CMKLR1. Additionally, chemerin activated CMKLR1 and aggravated HG-induced cell injury, inflammatory responses, and VEGF expressions in ARPE-19 cells. Conclusion. Our study demonstrated that chemerin/CMKLR1 axis aggravated the progression of PDR, which suggested that inhibition of chemerin might serve as a new therapeutic approach to treat PDR.

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Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus

Cited by 9 publications

References 30 publications

Chemerin-9 Attenuates Experimental Abdominal Aortic Aneurysm Formation in ApoE−/− Mice

Chemerin-9 Attenuates Experimental Abdominal Aortic Aneurysm Formation in ApoE−/− Mice

Cyclic Analogues of the Chemerin C-Terminus Mimic a Loop Conformation Essential for Activating the Chemokine-like Receptor 1

Chemerin/CMKLR1 Axis Promotes the Progression of Proliferative Diabetic Retinopathy

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