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Therapeutic effect of Cnidium officinale Makino extract on ovariectomized hind-limb ischemic mice.

ABSTRACT: Background:Cnidium officinale Makino (COM) has been used traditionally to treat female sexual disorders, such as amenorrhea, hypomenorrhea and oligomenorrhea, by improving blood circulation. Methods:The present study aimed to investigate the alleviating effect of COM extracts on surgical injury-induced ischemia in the hind-limb of mice. In this study, female C57BL/6 mice were ovariectomized, and the vessels of the hind-limb were excised after ligation by surgical silk (6-0). The mice were orally administered with COM (150 or 300 mg/kg/day) for 3 weeks, and the blood flow rate of hind-limbs was evaluated by using a laser Doppler system after hind-limb ischemic surgery in an in vivo study. Additionally, the migration and tube formation of human umbilical vein endothelial cells (HUVECs) were evaluated in an in vitro study. Results:The blood flow rate was synchronized to the nonischemic lesion of the hind-limb, and its elevation compared to the vehicle was observed at 14 and 21 days after hind-limb ischemic surgery in COM-treated groups. The number of capillaries increase in a dose-dependent manner in the COM-treated groups (150 and 300 mg/kg). In HUVECs, the activities of cell migration were significantly increased by 50 and 75 ?g/mL for the COM-treated groups. In addition, the number of tubule branches and junctions was also increased by doses of COM (50 and/or 75 ?g/mL). Conclusion:The results of our study suggested that the COM extract may have therapeutic application for the treatment of hind-limb ischemic damage, which is due to the improvement of the peripheral angiogenetic system.

SUBMITTER: Yang H

PROVIDER: S-EPMC6529788 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Therapeutic effect of <i>Cnidium officinale</i> Makino extract on ovariectomized hind-limb ischemic mice.

Yang Hyun H Jung Dong Ho DH Lee Hye Won HW

Integrative medicine research 20190504 2

<h4>Background</h4><i>Cnidium officinale</i> Makino (COM) has been used traditionally to treat female sexual disorders, such as amenorrhea, hypomenorrhea and oligomenorrhea, by improving blood circulation.<h4>Methods</h4>The present study aimed to investigate the alleviating effect of COM extracts on surgical injury-induced ischemia in the hind-limb of mice. In this study, female C57BL/6 mice were ovariectomized, and the vessels of the hind-limb were excised after ligation by surgical silk (6-0) ...[more]

PMID: 31193479

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Project description:Despite intensive investigation, how DNA methylation influences endothelial function remains poorly understood. We used methyl-CpG-binding domain protein 2 (MBD2), an interpreter for DNA methylome-encoded information, to dissect the impact of DNA methylation on endothelial function in both physiological and pathophysiological states.Human umbilical vein endothelial cells under normal conditions express moderate levels of MBD2, but knockdown of MBD2 by siRNA significantly enhanced angiogenesis and provided protection against H(2)O(2)-induced apoptosis. Remarkably, Mbd2(-/-) mice were protected against hind-limb ischemia evidenced by the significant improvement in perfusion recovery, along with increased capillary and arteriole formation. Loss of MBD2 activated endothelial survival and proangiogenic signals downstream of vascular endothelial growth factor signaling characterized by an increase in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor receptor 2 expression, along with enhanced extracellular signal-regulated kinase 1/2 activation and BCL-2 expression. Mechanistic studies confirmed the methylation of CpG elements in the eNOS and vascular endothelial growth factor receptor 2 promoter. MBD2 binds to these methylated CpG elements and suppresses eNOS promoter activity. On ischemic insult, key endothelial genes such as eNOS and vascular endothelial growth factor receptor 2 undergo a DNA methylation turnover, and MBD2 interprets the changes of DNA methylation to suppress their expressions. Moreover, MBD2 modulation of eNOS expression is likely confined to endothelial cells because nonendothelial cells such as splenocytes fail to express eNOS after loss of MBD2.We provided direct evidence supporting that DNA methylation regulates endothelial function, which forms the molecular basis for understanding how environmental insults (epigenetic factor) affect the genome to modify disease susceptibility. Because MBD2 itself does not affect the methylation of DNA and is dispensable for normal physiology in mice, it could be a viable epigenetic target for modulating endothelial function in disease states.

Project description:OBJECTIVE:Peripheral arterial disease can cause not only ischemia but also skeletal muscle damage. It has been known that macrophages (MPs) play an important role in coordinating muscle repair; however, phenotype transition of monocyte-MP in ischemic muscle has not been well defined. Hence, the purpose of this study was to examine the temporal recruitment of MPs and to explore their therapeutic effect on ischemic muscle regeneration. METHODS:Unilateral femoral artery excision was performed on C57BL/6 mice. Myeloid cells were isolated from the ischemic muscles, characterized using flow cytometry. Bone marrow-derived MPs were injected (2 × 106 cells) into the ischemic gastrocnemius muscle 24 hours after injury. Blood flow recovery was measured using laser speckle imaging. Functional outcome was evaluated by assessing the contractile force of ischemic muscles. Histologic analysis included quantification of myofiber size, collagen deposition, number of inflammatory and MyoD-expressing cells, and capillary density. RESULTS:Neutrophils and inflammatory monocytes-MPs were present at day 1 after injury. The mature MPs then remained elevated as the dominant population from day 5 to day 21 with the observation of regenerating fibers. Functional measurements revealed that the force production was significantly enhanced after treatment with proinflammatory M1 MPs (94.9% vs 77.9%; P < .05), and this was consistent with increased myofiber size, capillary- fiber ratio, and perfusion (78.6% vs 39.9%; P < .05). Moreover, the percentage of MyoD-expressing nuclei was significantly higher at day 4, indicating that M1 MPs may hasten muscle repair. Whereas early delivery of anti-inflammatory M2 MPs improved myofiber size, this was accompanied by persistent fibrosis suggesting ongoing tissue remodeling, and lower force production was observed. CONCLUSIONS:We demonstrated the dynamics of myeloid cells in skeletal muscle after ischemic insult, and the administration of exogenous M1 MPs in a temporally coordinated manner successfully improved angiogenesis and skeletal muscle regeneration. Our results suggested that cell therapy using MPs may be a promising adjunctive therapeutic approach for peripheral arterial disease.

Dataset Information

Therapeutic effect of Cnidium officinale Makino extract on ovariectomized hind-limb ischemic mice.

Publications

Therapeutic effect of <i>Cnidium officinale</i> Makino extract on ovariectomized hind-limb ischemic mice.

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