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Skin 11β-hydroxysteroid dehydrogenase type 1 enzyme expression regulates burn wound healing and can be targeted to modify scar characteristics

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Burns & Trauma 2023年第1期11卷 32-45页

作者： Kevin H.-Y.Tsai Huaikai Shi roxanne j.parungao Sina Naficy Xiaotong Ding Xiaofeng Ding jonathan j.Hew Xiaosuo Wang Wojciech Chrzanowski Gareth G.Lavery Zhe Li Andrea C.Issler-Fisher jun Chen Qian Tan Peter K.Maitz Mark S.Cooper Yiwei Wang Adrenal Steroid Group ANZAC Research InstituteConcord HospitalThe University of SydneySydneyNSW 2137Australia Burns and Reconstructive Surgery Research Group ANZAC Research InstituteConcord HospitalThe Uni-versity of SydneySydneyNSW 2137Australia School of Chemical and Biomolecular Engineering The University of SydneySydneyNSW 2006Australia jiangsu Provincial Engineering Research Centre of TCM External Medication Development and Application Nanjing University of Chinese MedicineNanjingJiangsu210023China Department of Burns and Plastic Surgery Nanjing Drum Tower Hospital Clinical CollegeNanjing University of Chinese MedicineNanjingJiangsu210008China Heart Research Institute The University of SydneySydneyNSW 2006Australia Sydney Nano Institute Sydney Pharmacy SchoolFaculty of Medicine and HealthThe University of SydneySydneyNSW2006Australia Department of Biosciences Centre for Healthy Ageing and Understanding DiseaseNottingham Trent UniversityNG14BUUK Burns and Reconstructive Surgery Unit Concord Repatriation General HospitalSydneyNSW 2137Australia

Background:Excessive scarring and fibrosis are the most severe and common complications of burn *** exposure to high levels of glucocorticoids detrimentally impacts on skin,leading to skin thinning and impaired wound *** can generate active glucocorticoids locally through expression and activity of the 11β-hydroxysteroid dehydrogenase type 1 enzyme(11β-HSD1).We hypothesised that burn injury would induce 11β-HSD1 expression and local glucocorticoid metabolism,which would have important impacts on wound healing,fibrosis and *** additionally proposed that pharmacological manipulation of this system could improve aspects of post-burn ***:Skin 11β-HSD1 expression in burns patients and mice was *** impacts of 11β-HSD1 mediating glucocorticoid metabolism on burn wound healing,scar formation and scar elas-ticity and quality were additionally examined using a murine 11β-HSD1 genetic knockout ***-release scaffolds containing therapeutic agents,including active and inactive glucocorticoids,were developed and pre-clinically tested in mice with burn ***:We demonstrate that 11β-HSD1 expression levels increased substantially in both human and mouse skin after burn injury.11β-HSD1 knockout mice experienced faster wound healing than wild type mice but the healed wounds manifested significantly more collagen deposition,tensile strength and stiffness,features characteristic of excessive *** of slow-release prednisone,an inactive glucocorticoid,slowed the initial rate of wound closure but significantly reduced post-burn scarring via reductions in inflammation,myofibroblast generation,collagen production and scar ***:Skin 11β-HSD1 expression is a key regulator of wound healing and scarring after burn *** of an inactive glucocorticoid capable of activation by local 11β-HSD1 in skin slows the initial rate of wound closure but significantlyimproves scar characteristics po

关键词： Wound healing Burn injury Scarring Skin 11β-HSD1 11β-HSD1 knockout Glucocorticoid metabolism Polycaprolactone scaffold Drug delivery

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The contradictory role of androgens in cutaneous and major burn wound healing

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Burns & Trauma 2021年第1期9卷 545-557页

作者： Huaikai Shi Kenny Cheer Ulla Simanainen Brian Lesmana Duncan Ma jonathan j.Hew roxanne j.parungao Zhe Li Mark S.Cooper David j.Handelsman Peter K.Maitz Yiwei Wang Burns Research Group ANZAC Research InstituteUniversity of SydneyConcord HospitalGate3 Hospital roadConcordNSW 2139Australia Andrology ANZAC Research InstituteUniversity of SydneyConcord HospitalGate3 Hospital roadConcordNSW 2139Australia Adrenal Steroid Laboratory ANZAC Research InstituteUniversity of SydneyConcord HospitalGate3 Hospital roadConcordNSW 2139Australia Burns and Reconstructive Surgery Unit Concord HospitalGate3 Hospital roadConcordNSW 2139Australia

Wound healing is a complex process involving four overlapping phases:haemostasis,inflammation,cell recruitment and matrix *** mouse models,surgical,pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-αproduction and reduce wound re-epithelization and matrix deposition,retarding cutaneous wound ***,clinical studies have shown that cutaneous wound healing is slower in men compared to ***,in major burn injury,which triggers not only local wound-healing processes but also systemic hypermetabolism,the role of androgens is poorly *** studies have claimed that a synthetic androgen,oxandrolone,increases protein synthesis,improves lean body mass and shortens length of hospital ***,the possible mechanisms by which oxandrolone regulates major burn injury have not been *** this review,we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing,as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.

关键词： Wound healing Androgen Mouse model Oxandrolone Cutaneous injury Major burn injury

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Low-protein diet accelerates wound healing in mice post-acute injury

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Burns & Trauma 2021年第1期9卷 339-350页

作者： jonathan j.Hew roxanne j.parungao Craig P.Mooney julian K.Smyth Sarah Kim Kevin H.-Y.Tsai Huaikai Shi Cassandra Chong Renee C.F.Chan Beba Attia Caroline Nicholls Zhe Li Samantha M.Solon-Biet David G.Le Couteur Stephen j.Simpson Marc G.jeschke Peter K.Maitz Yiwei Wang Burns Research and Reconstructive Surgery ANZAC Research InstituteConcord HospitalUniversity of SydneySydneyAustralia 2139 Bone Biology Group ANZAC Research InstituteConcord HospitalUniversity of SydneySydneyAustralia 2139 Adrenal Steroids Laboratory ANZAC Research InstituteConcord HospitalUniversity of SydneySydneyAustralia 2139 Electron Microscopy Unit Anatomical PathologyConcord HospitalSydneyAustralia 2139 Burns Unit Concord Repatriation General HospitalConcordAustralia 2139 Ageing and Alzheimer Institute and ANZAC Research Institute Concord HospitalUniversity of SydneySydneyAustralia 2139 Charles Perkins Centre and School of Life and Environmental Sciences University of SydneyAustralia 2006 Sunnybrook Research Institute TorontoOntarioCanadaM4N 3M5 School of Pharmacy Nanjing University of Chinese MedicineNanjingPR China 210023

Background:Wound healing processes are influenced by macronutrient intake(protein,carbohydrate and fat).The most favourable diet for cutaneous wound healing is not known,although highprotein diets are currently favoured *** experimental study investigates the optimal macronutrient balance for cutaneous wound healing using a mouse model and the Geometric Framework,a nutrient modelling method,capable of analyzing the individual and interactive effects of a wide spectrum of macronutrient ***:Two adjacent and identical full-thickness skin excisions(1 cm^(2))were surgically created on the dorsal area of male C57BL/6 *** were then allocated to one of 12 high-energy diets that varied in protein,carbohydrate and fat *** select diets,wound healing processes,cytokine expression,energy expenditure,body composition,muscle and fat reserves were ***:Using the Geometric Framework,we show that a low-protein intake,coupled with a balanced intake of carbohydrate and fat is optimal for wound *** fed a low-protein diet progressed quickly through wound healing stages with favourable wound inflammatory cytokine expression and significantly accelerated collagen *** local processes were associated with an increased early systemic inflammatory response and a higher overall energy expenditure,related to metabolic changes occurring in key macronutrient reserves in lean body mass and fat ***:The results suggest that a low-protein diet may have a greater potential to accelerate wound healing than the current clinically used high-protein diets.

关键词： Wound healing Macronutrients Cutaneous Geometric Framework Mouse model Low-protein diet Nutrition

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逆行脑灌注压力对猪脑保护作用的实验研究

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中华胸心血管外科杂志 2003年第5期19卷 293-296页

作者：郦志军叶箭 Michael j roxanne D 310016 浙江大学医学院附属邵逸夫医院胸心外科加拿大国家研究院生物医学诊断所

目的　探讨逆行脑灌注压力 34～ 4 0mmHg(1mmHg =0 133kPa)是否有益于延长期停循环时的脑保护。方法　 16头猪被降温到食管温度 15℃ ,在 12 0min停循环期间随机分为二组 ,组I(8头 )采用逆灌压力 2 3～ 2 9mmHg ;组II(8头 )采用 34～ 4 ... 详细信息

目的　探讨逆行脑灌注压力 34～ 4 0mmHg(1mmHg =0 133kPa)是否有益于延长期停循环时的脑保护。方法　 16头猪被降温到食管温度 15℃ ,在 12 0min停循环期间随机分为二组 ,组I(8头 )采用逆灌压力 2 3～ 2 9mmHg ;组II(8头 )采用 34～ 4 0mmHg。然后 ,复温至 37℃、体外循环 6 0min。结果　在逆灌期间 ,组II的脑皮层血流量是基础值的 114 %～ 16 8% ,明显高于组I的 4 3%～ 4 8% ,差异有非常显著性 (P <0 0 1)。逆灌 15min脑组织氧摄取率 ,组I是 (6 2 5± 34) % ,组II是 (6 6 4± 30 ) %。提示组II提供了较多的脑组织氧供。 37℃再灌注期间 ,组II的脑组织氧饱和度和还原血红蛋白恢复到 37℃对照值 ;组I的氧饱和度增高 ,还原血红蛋白明显低于对照值 (P <0 0 1) ,表明组II较好地保存了脑组织对氧的利用能力。脑组织水含量和正常对照组比较无差异。结论　在猪的急性实验模型 ,增加逆灌压力从 2 3～2 9mmHg到 34～ 4 0mmHg可提供较多的脑皮层血流 ,较好地保存了脑组织对再灌注早期氧的利用能力 ,没有明显增加脑水肿。提示逆灌压力 34～ 4 0mmHg有益于深低温延长期停循环时的脑保护。

关键词：逆行脑灌注压力脑保护作用实验研究再灌注损伤体外循环

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Synthetic Anticancer Saponins

Synthetic Anticancer Saponins

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多学科交叉，产学研联合，实现西部药用植物资源的可持续利用——第十届全国药用植物及植物药学术研讨会

作者： Matthew j.Kaskiw Stacey Tokar Mary Lynn Tassotto Mac Mok roxanne Pycho johnTh'ng Department of Chemistry Lakehead University Medical Sciences Division Northern Ontario School of Medicine

Diosgenyl saponins are steroidal glycosides found as major components in many traditional oriental medicines.A number of naturally occurring diosgenyl saponins have been shown to exert cytotoxic activity against several strains of human cancer *** example,Dioscin(Fig.1)is one of the most common steroidal saponins and exhibits potent anticancer activity through apoptosis-inducing *** of such saponins for cancer treatment is hampered due to the lack

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A Systematic Review of Proton Pump Inhibitors for the Prevention and Treatment of Preeclampsia and Gestational Hypertension

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Open journal of Obstetrics and Gynecology 2019年第1期9卷 21-28页

作者： Manarangi De Silva Fiona Brownfoot Natalie j. Hannan Susan P. Walker Catherine A. Cluver Anthea Lindquist Stephen Tong roxanne Hastie Translational Obstetrics Group Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Australia Mercy Perinatal Mercy Hospital for Women and Department of Obstetrics and Gynecology University of Melbourne Mercy Hospital Heidelberg Australia Department of Obstetrics and Gynecology Stellenbosch University Cape Town South Africa

Background: Preeclampsia is a hypertensive disorder of pregnancy with a high rate of neonatal and maternal morbidity and mortality. The only definitive treatment is delivery. Through pre-clinical studies, proton pump inhibitors (PPIs), which are commonly and safely used in pregnancy, have been identified as potential therapeutic agents. Objective: To undertake a systematic review evaluating PPIs in the prevention and/or treatment of preeclampsia and gestational hypertension. Search strategy: Electronic databases were searched from inception to 2018. Search terms included preeclampsia, proton-pump inhibitors, pregnancy-induced hypertension, lansoprazole, rabeprazole, esomeprazole and omeprazole. Selection criteria: Studies were included if they were randomized control trials, case-control or cohort studies on human subjects. Case reports, review articles, opinion pieces and conference abstracts were excluded as well as studies with no or inappropriate control arms. Data collection and analysis: Only one eligible study was identified, so no analyses were able to be performed. Main results: There was only one clinical trial eligible for inclusion. This was a randomized clinical trial investigating the role of PPIs in the treatment of preterm preeclampsia in a high-risk, inpatient setting. This was a negative finding, with no change in the primary outcome of prolongation of gestation between the PPI group and placebo control. Conclusion: There is a scarcity of clinical trials published investigating the therapeutic potential of PPIs for preeclampsia and gestational hypertension. Of the one available study, PPIs were not found to prolong gestation among preterm preeclamptic patients compared to placebo control. In order to further elucidate the clinical potential of PPIs to prevent or treat preeclampsia, further trials are required.

关键词： Preeclampsia Proton-Pump-Inhibitors

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TREM2依赖性小胶质细胞功能对于髓鞘再生及其神经保护至关重要

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神经损伤与功能重建 2023年第7期18卷 F0003-F0003页

作者： YuanyuanWang roxanne V Kyauk Yun-An A Shen Luke Xie Mike Reichelt Han Lin Zhiyu jiang Hai Ngu Kimberle Shen jacob j Greene Morgan Sheng Tracy j Yuen 杜一星(编译) Department of Neuroscience Genentech Inc.South San FranciscoCaliforniaUSA Department of Biomedical Imaging Genentech Inc.South San FranciscoCaliforniaUSA Department of Pathology Genentech Inc.South San FranciscoCaliforniaUSA Stanley Center for Psychiatric Research Broad Institute of MIT and HarvardCambridgeMassachusettsUSA. 不详

多发性硬化症(MS)的残疾在一定程度上是由髓鞘再生失败和进行性神经变性引起的。小胶质细胞和髓系细胞触发受体2(TREM2)(一种在小胶质细胞中高度表达的因子)已被证明在髓鞘再生中发挥重要作用。本研究使用大脑局灶性脱髓鞘模型,证明脱... 详细信息

多发性硬化症(MS)的残疾在一定程度上是由髓鞘再生失败和进行性神经变性引起的。小胶质细胞和髓系细胞触发受体2(TREM2)(一种在小胶质细胞中高度表达的因子)已被证明在髓鞘再生中发挥重要作用。本研究使用大脑局灶性脱髓鞘模型,证明脱髓鞘在TREM2敲除小鼠中持续存在;脱髓鞘在注射溶血卵磷脂后持续超过6周,并导致严重的神经变性。我们还发现TREM2敲除小鼠在脱髓鞘后表现出神经胶质反应的改变。TREM2敲除小胶质细胞表现出迁移和吞噬髓磷脂碎片的缺陷。此外,来自携带人类疾病中普遍存在的TREM2突变的受试者的人类单核细胞衍生的巨噬细胞也显示出髓磷脂碎片吞噬作用的缺陷。综上所述,我们强调了TREM2信号在髓鞘再生和神经保护中的核心作用。这些发现揭示了慢性脱髓鞘如何导致轴突损伤,并有助于确定多发性硬化症的新型神经保护治疗靶点。

关键词：髓系细胞触发受体2 轴突变性脱髓鞘小胶质细胞多发性硬化症少突胶质细胞髓鞘再生

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