α-Melanocyte-Stimulating Hormone Attenuates Neovascularization by Inducing Nitric Oxide Deficiency via MC-Rs/PKA/NF-κB Signaling

Weng, Wen-Tsan; Wu, Chieh‐Shan; Wang, Feng‐Sheng; Wu, Chang‐Yi; Ma, Yi-Ling; Chan, Hoi‐Hung; Wu, Den-Chiung; Wu, Jian-Ching; Chu, Tian‐Huei; Huang, Shih-Chung; Tai, Ming‐Hong

doi:10.3390/ijms19123823

Cited by 8 publications

(10 citation statements)

References 42 publications

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“…Consistently, our previous studies have demonstrated that the gene delivery of proopiomelanocortin (POMC), the precursor of alpha-melanocyte stimulating hormone (α-MSH), effectively suppresses the progression and metastasis of melanoma though the inhibition of COX-2/PGE2 signaling [24]. Among the POMC-derived peptides, α-MSH has been delineated to participate in the anti-neoplastic mechanism of POMC gene therapy via inflammation inhibition [24], neovascularization blockade [25,26], and sensitizing cancer cells to hypoxia-induced apoptosis [27].…”

Section: Introductionmentioning

confidence: 68%

Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

Tsai

Hsiao

et al. 2020

IJMS

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Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MTII using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MTII potently inhibited the migration, invasion, and colony-forming capability of melanoma cells. Moreover, topical MTII application significantly attenuated the tumor progression in mice bearing established melanoma. Histological analysis revealed that MTII therapy induced apoptosis while inhibiting the proliferation and neovaluarization in melanoma tissues. By immunoblot and immunohistochemical analysis, it was found that MTII dose-dependently increased the phosphatase and tensin homolog (PTEN) protein level while reducing PTEN phosphorylation, which resulted in the inhibition of AKT/nuclear factor kappa B (NFκB) signaling. Consistently, MTII treatment inhibited cyclooxygenase II (COX-2) expression and prostaglandin E2 (PGE2) production in melanoma cells. Finally, studies of antibody neutralization suggest that the melanocortin 1 receptor (MC1R) plays a critical role in MTII-induced PTEN upregulation and melanoma suppression. Together, these results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling. Hence, topical MTII therapy may facilitate a novel therapeutic strategy against melanoma.

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Section: Introductionmentioning

confidence: 68%

Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

Tsai

Hsiao

et al. 2020

IJMS

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“…The angiogenesis of human vessel endothelial cells incubated in ONFH serum was performed using BD BioCoat™ angiogenesis kits (BD Biosciences, San Jose, CA, USA), as previously described [49]. In brief, human umbilical vessel endothelial cells (5 × 10 4 cells/well, 48 well-plates; American Type Culture Collection) were incubated in ONFH serum, with or without 1 μg/mL S100A9 antibody, IgG (Abcam, Cambridge, UK), 250 ng/mL S100A9 (R&D Systems, Minneapolis, MN, USA) and incubated in a humidified incubator at 37 °C for 6 h. In a subset of experiments, the cells were incubated in 250 ng/mL VEGF as positive controls.…”

Section: Methodsmentioning

confidence: 99%

“…2012122901). The protocols for vessel outgrowth of aortic rings were performed, as previously described [49]. In brief, 6 male Sprague-Dawley rats (3 months old) were euthanatized.…”

Section: Methodsmentioning

confidence: 99%

S100 Calcium Binding Protein A9 Represses Angiogenic Activity and Aggravates Osteonecrosis of the Femoral Head

Lian

Kuo

et al. 2019

IJMS

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Ischemic damage aggravation of femoral head collapse is a prominent pathologic feature of osteonecrosis of the femoral head (ONFH). In this regard, S100 calcium binding protein A9 (S100A9) is known to deteriorate joint integrity, however, little is understood about which role S100A9 may play in ONFH. In this study, a proteomics analysis has revealed a decrease in the serum S100A9 level in patients with ONFH upon hyperbaric oxygen therapy. Serum S100A9 levels, along with serum vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), and tartrate-resistant acid phosphatase 5b levels were increased in patients with ONFH, whereas serum osteocalcin levels were decreased as compared to healthy controls. Serum S100A9 levels were increased with the Ficat and Arlet stages of ONFH and correlated with the patients with a history of being on glucocorticoid medication and alcohol consumption. Osteonecrotic tissue showed hypovasculature histopathology together with weak immunostaining for vessel marker CD31 and von Willrbrand factor (vWF) as compared to femoral head fracture specimens. Thrombosed vessels, fibrotic tissue, osteocytes, and inflammatory cells displayed strong S100A9 immunoreactivity in osteonecrotic lesion. In vitro, ONFH serum and S100A9 inhibited the tube formation of vessel endothelial cells and vessel outgrowth of rat aortic rings, whereas the antibody blockade of S100A9 improved angiogenic activities. Taken together, increased S100A9 levels are relevant to the development of ONFH. S100A9 appears to provoke avascular damage, ultimately accelerating femoral head deterioration through reducing angiogenesis. This study provides insight into the molecular mechanism underlying the development of ONFH. Here, analysis also highlights that serum S100A9 is a sensitive biochemical indicator of ONFH.

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“…Many successful studies addressing the molecular mechanisms of blood vessel development, such as angioblast specification and migration, vascular endothelium proliferation and migration, and vessel formation and patterning, have been conducted using zebrafish as a model organism [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Furthermore, the effects of chemicals and drugs on the development of vasculature have been successfully addressed in the zebrafish model [ 12 , 13 , 14 , 15 , 16 ]. For example, we reported that the marine compound WA-25 inhibits angiogenesis [ 13 ], GB9 impairs vascular development [ 14 ], and heteronemin (SP1) suppresses lymphangiogenesis [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Nitrobenzoate-Derived Compound X8 Impairs Vascular Development in Zebrafish

Chiu

Chin

Chung

et al. 2022

IJMS

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Proper growth and patterning of blood vessels are critical for embryogenesis. Chemicals or environmental hormones may interfere with vascular growth and cause developmental defects. Nitrobenzoate-based compounds have been demonstrated to have a wide range of biological and pharmacological functions, leading to the development of numerous 4-nitrobenzoate derivatives for clinical application. In this study, we tested a novel nitrobenzoate-derived compound, X8, and investigated its effects on vascular development using zebrafish as a model organism. We first determined the survival rate of embryos after the addition of exogenous X8 (0.5, 1, 3, 5, and 10 μM) to the fish medium and determined a sublethal dose of 3 μM for use in further assays. We used transgenic fish to examine the effects of X8 treatment on vascular development. At 25–32 h postfertilization (hpf), X8 treatment impaired the growth of intersegmental vessels (ISVs) and caudal vein plexuses (CVPs). Moreover, X8-treated embryos exhibited pericardial edema and circulatory defects at 60–72 hpf, suggesting the effects of X8 in vasculature. Apoptosis tests showed that the vascular defects were likely caused by the inhibition of proliferation and migration. To investigate the molecular impacts underlying the defects in the vasculature of X8-treated fish, the expression levels of vascular markers, including ephrinb2, mrc1, and stabilin, were assessed, and the decreased expression of those genes was detected, indicating that X8 inhibited the expression of vascular genes. Finally, we showed that X8 treatment disrupted exogenous GS4012-induced angiogenesis in Tg(flk:egfp) zebrafish embryos. In addition, vascular defects were enhanced during cotreatment with X8 and the VEGFR2 inhibitor SU5416, suggesting that X8 treatment causes vascular defects mediated by disruption of VEGF/VEGFR2 signaling. Collectively, our findings indicate that X8 could be developed as a novel antiangiogenic agent.

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α-Melanocyte-Stimulating Hormone Attenuates Neovascularization by Inducing Nitric Oxide Deficiency via MC-Rs/PKA/NF-κB Signaling

Cited by 8 publications

References 42 publications

Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

S100 Calcium Binding Protein A9 Represses Angiogenic Activity and Aggravates Osteonecrosis of the Femoral Head

Nitrobenzoate-Derived Compound X8 Impairs Vascular Development in Zebrafish

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