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Targeting TRPV1-mediated autophagy attenuates nitrogen mustard-induced dermal toxicity

Signal Transduction and Targeted Therapy 2021年第2期6卷 542-554页

作者： Mingliang Chen Xunhu Dong Haoyue Deng Feng Ye Yuanpeng Zhao Jin Cheng Guorong Dan Jiqing Zhao Yan Sai Xiuwu Bian Zhongmin Zou Department of Chemical Defense Medicine School of Military Preventive MedicineThird Military Medical University(Army Medical University)30 Gaotanyan StreetShapingba DistricChongqing 400038China Institute of Pathology and Southwest Cancer Centre Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Institute of Toxicology School of Miliary Preventive MedicineThird Miltay Medical University(Army Medical University)30 Gaotanyan StreetShapingba DistritChongqing 400038China State Key Laboratory of Trauma Burns and Combined InjurySecond Department of Research Institute of SurgeryDaping HospitalThird Military Medical University(Army Medical UniversityChongqing 400042China

Nitrogen mustard(NM)causes severe vesicating skin injury,which lacks effective targeted therapies.The major limitation is that the specific mechanism of NM-induced skin injury is not well understood.Recently,autophagy has been found to play important roles in physical and chemical exposure-caused cutaneous injuries.However,whether autophagy contributes to NM-induced dermal toxicity is unclear.Herein,we initially confrmed that NM dose-dependently caused cell death and induced autophagy in keratinocytes.Suppression of autophagy by 3-methyladenine,chloroquine,and baflomycin A1 or ATG5 siRNA attenuated NM-induced keratinocyte cell death.Furthermore,NM increased transient receptor potential vanilloid 1(TRPV1)expression,intracellular Ca2+content,and the activities of Car+/calmodulin-dependent kinase kinaseβ(CaMKKB),AMP-activated protein kinase(AMPK),unc-51-like kinase 1(ULK1),and mammalian target of rapamycin(mTOR).NM-induced autophagy in keratinocytes was abolished by treatment with inhibitors of TRPV1(capsazepine),CaMKKβ(STO-609),AMPK(compound C),and ULK1(SBI-0206965)as well as TRPV1,CaMKKB,and AMPK siRNA transfection.In addition,an mTOR inhibitor(rapamycin)had no signifcant effect on NM-stimulated autophagy or cell death of keratinocytes.Finally,the results of the in vivo experiment in NM-treated skin tissues were consistent with the findings of the in vitro experiment.In conclusion,NM-caused dermal toxicity by overactivating autophagy partially through the activation of TRPV1-Ca2+-CaMKKB-AMPK-ULK1 signaling pathway.These results suggest that blocking TRPV1-dependent autophagy could be a potential treatment strategy for NM-caused cutaneous injury.

关键词： TRPV1 injuries autophagy

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Neuroprotection mediated by natural products and their chemical derivatives

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Neural Regeneration Research 2020年第11期15卷 2008-2015页

作者： Fei Fei Ning Su Xia Li Zhou Fei Department of Ophthalmology Xijing Hospitalthe Fourth Military Medical UniversityXi’anShaanxi ProvinceChina Department of Radiation Oncology Xijing Hospitalthe Fourth Military Medical UniversityXi’anShaanxi ProvinceChina Department of Neurosurgery Xijing Hospitalthe Fourth Military Medical UniversityXi’anShaanxi ProvinceChina

Neuronal injuries can lead to various diseases such as neurodegenerative diseases,stroke,trauma,ischemia and,more specifically,glaucoma and optic neuritis.The cellular mechanisms that regulate neuronal death include calcium influx and calcium overload,excitatory amino acid release,oxidative stress,inflammation and microglial activation.Much attention has been paid to the effective prevention and treatment of neuroprotective drugs by natural products.This review summarizes the neuroprotective aspects of natural products,extracted from Panax ginseng,Camellia sinensis,soy and some other plants,and some of their chemical derivatives.Their antioxidative and anti-inflammatory action and their inhibition of apoptosis and microglial activation are assessed.This will provide new directions for the development of novel drugs and strategies to treat neurodegenerative diseases.

关键词： antioxidant effect brain injuries Camellia sinensis chemical derivatives curcumin genistein natural products neurodegenerative diseases neuroprotection Panax

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Peripheral nerve injuries

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Plastic and Aesthetic Research 2015年第1期2卷 309-310页

作者： Katerina Anesti Paul Caine Department of Plastic Surgery Royal Devon and Exeter NHS Foundation TrustExeterEX25DWUK Department of Plastic Surgery St Andrew’s CentreMid Essex NHS TrustChelmsfordCM17ETUK

Nerve injuries caused by medical interventions(iatrogenic lesions)can complicate procedures and affect any part of the peripheral nervous system.Available data are fragmentary and little information is accessible on the overall incidence of iatrogenic nerve lesions that ranges from 1.5%to 15%.[1,2]Major drawbacks are the limited number of patients studied and the incomplete and subjective assessment of nerve function.The potential for iatrogenic injuries in the course of any surgical procedure should be thoroughly appreciated by all surgeons and they should be familiar with early diagnostic steps for detecting these lesions.The importance of prompt diagnosis and adequate treatment of iatrogenic nerve injuries for optimal functional recovery should be stressed.Excellent results can be obtained if certain diagnostic and surgical principles are followed.

关键词： injuries prompt incomplete

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Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification

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Bone Research 2019年第4期7卷 371-387页

作者： Charles Hwang Simone Marini Amanda KHuber David MStepien Michael Sorkin Shawn Loder Chase APagani John Li Noelle DVisser Kaetlin Vasquez Mohamed AGarada Shuli Li Jiajia Xu Ching-Yun Hsu Paul BYu Aaron WJames Yuji Mishina Shailesh Agarwal Jun Li Benjamin Levi Department of Surgery University of MichiganAnn ArborMI 48109USA Department of Computational Medicine and Bioinformatics University of MichiganAnn ArborMI 48109USA Department of Pathology Johns Hopkins UniversityBaltimoreMD 21218USA Division of Cardiovascular Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolBostonMA 02115USA Department of Biologic and Materials Sciences&Prosthodontics School of DentistryUniversity of MichiganAnn ArborMI 48109USA

Heterotopic ossification(HO)is a debilitating condition characterized by the pathologic formation of ectopic bone.HO occurs commonly following orthopedic surgeries,burns,and neurologic injuries.While surgical excision may provide palliation,the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone.Based on these clinical observations,we set out to examine the role of vascular signaling in HO.Vascular endothelial growth factor A(VEGFA)has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis.Our findings,using a validated mouse model of HO,demonstrate that HO lesions are highly vascular,and that VEGFA is critical to ectopic bone formation,despite lacking a contribution of endothelial cells within the developing anlagen.

关键词： VEGFA injuries ossification

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An experimental study on shock wave mitigation capability of polyurea and shear thickening fluid based suspension pads

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Defence Technology（防务技术） 2018年第1期14卷 12-18页

作者： Andi Haris Heow Pueh Lee Vincent Beng Chye Tan Department of Mechanical Engineering National University of Singapore

The present experimental study investigates shock wave mitigation capability of potentially new personal protective equipment(PPE) suspension pads made from polyurea and shear thickening fluid(STF).The shock tube test results show that when placed behind Twaron fabric systems with thickness ranging from 2 mm to 18 mm, the replacement of conventional flexible foam pad with STF and STF-infused foam pads with the same thickness of 20 mm greatly reduces the normalized peak pressure(by about 72% for each pad). However, this benefit is partially offset by a large increase in the normalized impulse(by about78% for the STF pad and 131% for the STF-infused foam pad) which may cause the shock wave mitigation performance of these two pads to become less effective. Interestingly, the use of 4 mm thick polyurea pad can greatly reduce the normalized peak pressure and impulse as well(by about 74% and 49%, respectively). These results reveal that among the potentially new suspension pads tested, the polyurea pad displays the best shock wave mitigation performance. Therefore, polyurea has potential for use as a suspension pad in personal protective equipment requiring shock wave mitigation capability such as fabric ballistic vests, bomb suits and combat helmets.

关键词： Shock wave mitigation Polyurea Shear thickening fluid Suspension pad Ballistic fabric Primary blast injuries

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Application of stem cells in tissue engineering for defense medicine

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Military Medical Research 2018年第2期5卷 140-158页

作者： Chinedu Cletus Ude Azizi Miskon Ruszymah Bt Hj Idrus Muhamad Bin Abu Bakar Bio-artifical Organ and Regenerative Medicine Unit National Defence University of MalaysiaSungai Besi Camp57000 Kuala LumpurMalaysia Department of Physiology Pre-clinical BlockNational University of Malaysia Medical CentreJalan Yaacob LatifBandar Tun Razak56000 Kuala LumpurMalaysia

The dynamic nature of modern warfare,including threats and injuries faced by soldiers,necessitates the development of countermeasures that address a wide variety of injuries.Tissue engineering has emerged as a field with the potential to provide contemporary solutions.In this review,discussions focus on the applications of stem cells in tissue engineering to address health risks frequently faced by combatants at war.Human development depends intimately on stem cells,the mysterious precursor to every kind of cell in the body that,with proper instruction,can grow and differentiate into any new tissue or organ.Recent reports have suggested the greater therapeutic effects of the anti-inflammatory,trophic,paracrine and immune-modulatory functions associated with these cells,which induce them to restore normal healing and tissue regeneration by modulating immune reactions,regulating inflammation,and suppressing fibrosis.Therefore,the use of stem cells holds significant promise for the treatment of many battlefield injuries and their complications.These applications include the treatment of injuries to the skin,sensory organs,nervous system tissues,the musculoskeletal system,circulatory/pulmonary tissues and genitals/testicles and of acute radiation syndrome and the development of novel biosensors.The new research developments in these areas suggest that solutions are being developed to reduce critical consequences of wounds and exposures suffered in warfare.Current military applications of stem cell-based therapies are already saving the lives of soldiers who would have died in previous conflicts.injuries that would have resulted in deaths previously now result in wounds today;similarly,today’s permanent wounds may be reduced to tomorrow’s bad memories with further advances in stem cell-based therapies.

关键词： Tissue engineering Defense medicine Stem cells War injuries

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Acellular micronized extracellular matrix and occlusive dressings for open fingertip injuries

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Plastic and Aesthetic Research 2015年第1期2卷 282-283页

作者： Stephanie E.Dreifuss Ronit Wollstein Stephen F.Badylak Peter J.Rubin Department of Plastic and Reconstructive Surgery University of PittsburghPittsburghPA 15261USA Department of Orthopedic Surgery Technion Medical SchoolHaifa 3200003Israel

Sir,Fingertip amputation injuries compromise the sensation,function,and appearance of the hand.They are often exquisitely painful and take a substantial amount of time to heal,causing significant functional disability.Conservative management of these injuries may result in decreased range of motion,hypo-or hyperesthesia,loss of pulp contour,scarring,and other long-term sequelae.[1,2]In addition,they may prolong patient discomfort with dressing changes,hindering adherence with wound therapy regimens,especially in the presence of multiple finger injuries.

关键词： injuries sensation wound

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Differential gene and protein expression between rat tibial nerve and common peroneal nerve during wallerian degeneration

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Neural Regeneration Research 2019年第12期14卷 2183-2191页

作者： Yao-Fa Lin Zheng Xie Jun Zhou Gang Yin Hao-Dong Lin Department of Orthopedic Surgery Changzheng Hospital the Second Military Medical University Shanghai China Department of Orthopedic Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

Wallerian degeneration and nerve regeneration after injury are complex processes involving many genes, proteins and cytokines. After different peripheral nerve injuries the regeneration rate can differ. Whether this is caused by differential expression of genes and proteins during Wallerian degeneration remains unclear. The right tibial nerve and the common peroneal nerve of the same rat were exposed and completely cut through and then sutured in the same horizontal plane. On days 1, 7, 14, and 21 after surgery, 1–2 cm of nerve tissue distal to the suture site was dissected out from the tibial and common peroneal nerves. The differences in gene and protein expression during Wallerian degeneration of the injured nerves were then studied by RNA sequencing and proteomic techniques. In the tibial and common peroneal nerves, there were 1718, 1374, 1187, and 2195 differentially expressed genes, and 477, 447, 619, and 495 differentially expressed proteins on days 1, 7, 14, and 21 after surgery, respectively. Forty-seven pathways were activated during Wallerian degeneration. Three genes showing significant differential expression by RNA sequencing (Hoxd4, Lpcat4 and Tbx1) were assayed by real-time quantitative polymerase chain reaction. RNA sequencing and real-time quantitative polymerase chain reaction results were consistent. Our findings showed that expression of genes and proteins in injured tibial and the common peroneal nerves were significantly different during Wallerian degeneration at different time points. This suggests that the biological processes during Wallerian degeneration are different in different peripheral nerves after injury. The procedure was approved by the Animal Experimental Ethics Committee of the Second Military Medical University, China (approval No. CZ20160218) on February 18, 2016.

关键词： nerve regeneration peripheral nerves peripheral nerve injuries Wallerian degeneration tibial nerve common peroneal nerve RNA sequencing proteomic real-time quantitative polymerase chain reaction neural regeneration

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Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity

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Signal Transduction and Targeted Therapy 2021年第3期6卷 975-987页

作者： Ke-Wu Zeng Jing-Kang Wang Li-Chao Wang Qiang Guo Ting-Ting Liu Fu-Jiang Wang Na Feng Xiao-Wen Zhang Li-Xi Liao Mei-Mei Zhao Dan Liu Yong Jiang Pengfei Tu State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Proteomics Laboratory Medical and Healthy Analytical CenterPeking University Health Science CenterBeijing 100191China

Mitochondrial fusion/hission dynamics plays a fundamental role in neuroprotection;however,there is till a severe lack oftherapeutic targets for this biological process.Here,we found that the naturally derived small molecule echinacoside(ECH)signifhcantly promotes mitochondrial fusion progression.ECH selectively binds to the previously uncharacterized casein kinase 2(CK2)α'subunit(CK2a)as a direct cellular target,and genetic knockdown of CK2α'abolishes ECH-mediated mitochondrial fusion.Mechanistically,ECH allosterically regulates CK2α'conformation to recruit basic transcription factor 3(BTF 3)to form a binary proteincomplex.Then,the CK2α'/BTF3 complex facilitatesβ-catenin nuclear translocation to activate TCF/AEF transcription factors andstimulate transcription of the mitochondrial fusion gene Mfn2.trikingly,in a mouse middle cerebral artery occlusion(MCAO)model,ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2expression in wild-type but not CK2α'^(+/-)mice.Taken together,our findings reveal,for the first time,that CK2 is essential forpromoting mitochondrial fusion in a Wnt/B-catenin-dependent manner and suggest that pharmacologically targeting CK2 is apromising therapeutic strategy for ischemic stroke.

关键词： injuries cerebral Small

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Scientific evidence is just the starting point: A generalizable process for developing sports injury prevention interventions

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Journal of Sport and Health Science 2016年第3期5卷 334-341页

作者： Alex Donaldson David G.Lloyd Belinda J.Gabbe Jill Cook Warren Young Peta White Caroline F.Finch Australian Centre for Research into Injury in Sport and its Prevention (ACRISP) Federation University Australia Centre for Musculoskeletal Research Griffith Health Institute Griffith University Department of Epidemiology and Preventive Medicine Monash University La Trobe Sport and Exercise Medicine Research Centre La Trobe University School of Health Sciences Federation University Australia

Background: The 2 most cited sports injury prevention research frameworks incorporate intervention development, yet little guidance is available in the sports science literature on how to undertake this complex process. This paper presents a generalizable process for developing implementable sports injury prevention interventions, including a case study applying the process to develop a lower limb injury prevention exercise training program(Footy First) for community Australian football.Methods: The intervention development process is underpinned by 2 complementary premises:(1) that evidence-based practice integrates the best available scientific evidence with practitioner expertise and end user values and(2) that research evidence alone is insufficient to develop implementable interventions.Results: The generalizable 6-step intervention development process involves(1) compiling research evidence, clinical experience, and knowledge of the implementation context;(2) consulting with experts;(3) engaging with end users;(4) testing the intervention;(5) using theory; and(6)obtaining feedback from early implementers. Following each step, intervention content and presentation should be revised to ensure that the final intervention includes evidence-informed content that is likely to be adopted, properly implemented, and sustained over time by the targeted intervention deliverers. For Footy First, this process involved establishing a multidisciplinary intervention development group, conducting 2targeted literature reviews, undertaking an online expert consensus process, conducting focus groups with program end users, testing the program multiple times in different contexts, and obtaining feedback from early implementers of the program.Conclusion: This systematic yet pragmatic and iterative intervention development process is potentially applicable to any injury prevention topic across all sports settings and levels. It will guide researchers wishing to undertake intervention development.

关键词： Australian football Implementation Intervention development Lower limb injuries Research-to-practice Sports injury prevention Translation

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