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      Tetramethylpyrazine improved the survival of multiterritory perforator flaps by inducing angiogenesis and suppressing apoptosis via the Akt/Nrf2 pathway

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          Background: Multiterritory perforator flaps were commonly designed to cover the large soft-tissue defects in reconstructive surgery. But the high risk of partial necrosis in the distal portion of the flaps hindered their clinical application. The purpose of this study was to evaluate the effects of tetramethylpyrazine (TMP) on the survival of the multiterritory perforator flaps and to explore the underlying mechanism.

          Materials and methods: Seventy-two Sprague–Dawley rats underwent multiterritory perforator flap procedure and were divided into three groups with 24 each. Flap survival and water content were measured, and the area of angiogenesis and apoptosis in the ischemia skin flaps were assessed on the postoperative day 7. The expressions of angiogenesis-related protein VEGF and apoptosis-related protein Bax, Bcl-2 in each group were detected by Western blotting, which also had been used to assess the expressions levels of Akt, p-Akt, and Nrf2.

          Results: Following TMP treatment, the survival area and number of microvessels presented in the skin flaps increased and tissue edema reduced on postoperative day 7. The expressions of angiogenesis-related protein VEGF increased in the TMP treatment group than in the control group. In addition, compared with the control group, TMP inhibited apoptosis, and increased the expression levels of p-Akt, Nrf2 in the areas of ischemia. These effects were reversed by an Akt protein inhibitor LY294002. Similarly, treatment with LY294002 inhibited TMP induced by interfering the Akt/Nrf2 signaling pathway.

          Conclusion: These results illustrated that TMP could promote the survival of multiterritory perforator flaps by enhancing angiogenesis and attenuating apoptosis. These were involved in Akt/Nrf2 signaling pathway.

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          Most cited references 32

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          A 10-year retrospective review of 758 DIEP flaps for breast reconstruction.

          This study examined 758 deep inferior epigastric perforator flaps for breast reconstruction, with respect to risk factors and associated complications. Risk factors that demonstrated significant association with any breast or abdominal complication included smoking (p = 0.0000), postreconstruction radiotherapy (p = 0.0000), and hypertension (p = 0.0370). Ninety-eight flaps (12.9 percent) developed fat necrosis. Associated risk factors were smoking (p = 0.0226) and postreconstruction radiotherapy (p = 0.0000). Interestingly, as the number of perforators increased, so did the incidence of fat necrosis. There were only 19 cases (2.5 percent) of partial flap loss and four cases (0.5 percent) of total flap loss. Patients with 45 flaps (5.9 percent) were returned to the operating room before the second-stage procedure. Patients with 29 flaps (3.8 percent) were returned to the operating room because of venous congestion. Venous congestion and any complication were observed to be statistically unrelated to the number of venous anastomoses. Overall, postoperative abdominal hernia or bulge occurred after only five reconstructions (0.7 percent). Complication rates in this large series were comparable to those in retrospective reviews of pedicle and free transverse rectus abdominis musculocutaneous flaps. Previous studies of the free transverse rectus abdominis musculocutaneous flap described breast complication rates ranging from 8 to 13 percent and abdominal complication rates ranging from 0 to 82 percent. It was noted that, with experience in microsurgical techniques and perforator selection, the deep inferior epigastric perforator flap offers distinct advantages to patients, in terms of decreased donor-site morbidity and shorter recovery periods. Mastery of this flap provides reconstructive surgeons with more extensive options for the treatment of postmastectomy patients.
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            Neuroprotection and enhanced neurogenesis by tetramethylpyrazine in adult rat brain after focal ischemia.

            To investigate the effects of tetramethylpyrazine (TMP) on neural cell proliferation and differentiation in brain of rat after focal cerebral ischemia. The focal cerebral ischemia of rat was induced by middle cerebral artery occlusion (MCAO). Infarction volume was evaluated by TTC staining method. Immunohistochemistry was used to identify proliferating and differentiating cells. TMP protected brain from damage by reducing volume of infarction, neuronal loss and water content. TMP not only increased the number of BrdU positive cell in SVZ, but also stimulated the cell differentiation after ischemia. The nNOS expression in cortex and dentate gyrus was reduced by treatment of TMP. These results indicate that TMP could protect ischemic brain damage, and promote cell proliferation and differentiation stimulated by ischemia, which might be related to the reduction of nNOS expression after treatment with TMP in rat cerebral ischemia model.
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              Epigallocatechin-3-gallate promotes angiogenesis via up-regulation of Nfr2 signaling pathway in a mouse model of ischemic stroke.

              Epigallocatechin-3-gallate (EGCG) is the major effective component of green tea and has been known as a potential anticancer drug because of its antioxidant and anti-angiogenic properties. EGCG has also been reported to have preventive effects against ischemic stroke via nuclear factor erythroid 2-related factor 2 (Nfr2) signaling pathway, but how EGCG affect angiogenesis after stroke remains unclear. In this study, we investigated whether EGCG treatment in the acute phase of ischemic stroke can promote angiogenesis in a mouse model of transient middle cerebral artery occlusion (MCAO). We assessed neurological function with modified neurologic severity score (mNSS) test, infarct volume by Nessl staining, angiogenesis and oxidative stress by immunofluorescence analysis, intravital lectin perfusion analysis, western blot analysis and enzyme-linked immunosorbent assay (ELISA). In order to explore the role of Nrf2 in the angiogenesis of MCAO+EGCG-treated mice, we used MAPK/ERK inhibitor PD98059 to block the activation of Nrf2. We found MCAO+EGCG-treated mice had better neurologic outcome, less infarct volume, more number of Ki67/CD31-positive vessels, higher vascular density, unregulated VEGF-VEGFR2 signaling pathway, increased Nrf2 expression and decreased oxidative stress than did MCAO+vehicle-treated mice. Blocking Nrf2 with PD98059 significantly reduced the expression of Nrf2, increased oxidative stress and abolished the angiogenic and neuroprotective effects of EGCG on MCAO mice. We conclude that EGCG treatment in the early stage of ischemic stroke can promote angiogenesis in MCAO mice, possibly via upregulation of Nrf2 signaling pathway.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                01 May 2019
                : 13
                : 1437-1447
                [1 ]Department of Orthopedics, Xiangya Hospital, Central South University , Changsha, Hunan, People’s Republic of China
                [2 ]Department of Neurosurgery, Maryland University of Medicine School- Baltimore , Baltimore, MD, USA
                Author notes
                Correspondence: JuYu TangDepartment of Orthopaedics, Xiangya Hospital, Central South University , 87 Xiangya Road, Changsha, Hunan410008, People’s Republic of ChinaEmail tangjuyu7749@ 123456csu.edu.cn

                These authors contributed equally to this work

                © 2019 Qing et al.

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                Page count
                Figures: 5, References: 35, Pages: 11
                Original Research


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