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Lin T, Meegaskumbura M. Fish MicroRNA Responses to Thermal Stress: Insights and Implications for Aquaculture and Conservation Amid Global Warming. Animals (Basel) 2025; 15:624. [PMID: 40075907 PMCID: PMC11898199 DOI: 10.3390/ani15050624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/11/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
In the context of global warming, heat tolerance is becoming a crucial physiological trait influencing fish species' distribution and survival. While our understanding of fish heat tolerance and stress has expanded from behavioral studies to transcriptomic analyses, knowledge at the transcriptomic level is still limited. Recently, the highly conserved microRNAs (miRNAs) have provided new insights into the molecular mechanisms of heat stress in fish. This review systematically examines current research across three main reference databases to elucidate the universal responses and mechanisms of fish miRNAs under heat stress. Our initial screening of 569 articles identified 13 target papers for comprehensive analysis. Among these, at least 214 differentially expressed miRNAs (DEMs) were found, with 15 DEMs appearing in at least two studies (12 were upregulated and 13 were downregulated). The 15 recurrent DEMs were analyzed using DIANA mirPath v.3 and the microT-CDS v5.0 database to identify potential target genes. The results suggest that multiple miRNAs target various genes, forming a complex network that regulates glucose and energy metabolism, maintains homeostasis, and modulates inflammation and immune responses. Significantly, miR-1, miR-122, let-7a, and miR-30b were consistently differentially expressed in multiple studies, indicating their potential relevance in heat stress responses. However, these miRNAs should not be considered definitive biomarkers without further validation. Future research should focus on experimentally confirming their regulatory roles through functional assays, conducting transcriptomic comparisons across different species, and performing target validation studies. These miRNAs, conserved across species, could be valuable for monitoring wild fish health, enhancing aquaculture breeding, and guiding conservation strategies. However, the specific regulatory mechanisms of these miRNAs need clarification to confirm their reliability as biomarkers for thermal stress.
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Affiliation(s)
| | - Madhava Meegaskumbura
- Guangxi Key Laboratory of Forest Ecology and Conservation, College of Forestry, Guangxi University, Nanning 530004, China
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2
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Wu CC, Meyer DN, Haimbaugh A, Baker TR. Implications of Lead (Pb)-Induced Transcriptomic and Phenotypic Alterations in the Aged Zebrafish ( Danio rerio). TOXICS 2024; 12:745. [PMID: 39453165 PMCID: PMC11511149 DOI: 10.3390/toxics12100745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/26/2024]
Abstract
Lead (Pb) is a well-known neurotoxin with established adverse effects on the neurological functions of children and younger adults, including motor, learning, and memory abilities. However, its potential impact on older adults has received less attention. Using the zebrafish model, our study aims to characterize the dose-response relationship between environmentally relevant Pb exposure levels and their effects on changes in behavior and transcriptomics during the geriatric periods. We exposed two-year-old zebrafish to waterborne lead acetate (1, 10, 100, 1000, or 10,000 µg/L) or a vehicle (DMSO) for 5 days. While lower concentrations (1-100 µg/L) reflect environmentally relevant Pb levels, higher concentrations (1000-10,000 µg/L) were included to assess acute toxicity under extreme exposure scenarios. We conducted adult behavior assessment to evaluate the locomotor activity following exposure. The same individual fish were subsequently sacrificed for brain dissection after a day of recovery in the aquatic system. RNA extraction and sequencing were then performed to evaluate the Pb-induced transcriptomic changes. Higher (1000-10,000 ug/L) Pb levels induced hyperactive locomotor patterns in aged zebrafish, while lower (10-100 ug/L) Pb levels resulted in the lowest locomotor activity compared to the control group. Exposure to 100 µg/L led to the highest number of differentially expressed genes (DEGs), while 10,000 µg/L induced larger fold changes in both directions. The neurological pathways impacted by Pb exposure include functions related to neurotransmission, such as cytoskeletal regulation and synaptogenesis, and oxidative stress response, such as mitochondrial dysfunction and downregulation of heat shock protein genes. These findings emphasize a U-shape dose-response relationship with Pb concentrations in locomotor activity and transcriptomic changes in the aging brain.
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Affiliation(s)
- Chia-Chen Wu
- Institute of Environmental Engineering, National Yang Ming Chiao Tung University, 1001, Daxue Rd, East District, Hsinchu City 300093, Taiwan;
- Department of Environmental and Global Health, University of Florida, 1225 Center Drive, Gainesville, FL 32610, USA; (D.N.M.)
| | - Danielle N. Meyer
- Department of Environmental and Global Health, University of Florida, 1225 Center Drive, Gainesville, FL 32610, USA; (D.N.M.)
- Department of Pharmacology, School of Medicine, Wayne State University, 540 E. Canfield, Detroit, MI 48201, USA
| | - Alex Haimbaugh
- Department of Environmental and Global Health, University of Florida, 1225 Center Drive, Gainesville, FL 32610, USA; (D.N.M.)
- Department of Pharmacology, School of Medicine, Wayne State University, 540 E. Canfield, Detroit, MI 48201, USA
| | - Tracie R. Baker
- Department of Environmental and Global Health, University of Florida, 1225 Center Drive, Gainesville, FL 32610, USA; (D.N.M.)
- Department of Pharmacology, School of Medicine, Wayne State University, 540 E. Canfield, Detroit, MI 48201, USA
- UF Genetics Institute, University of Florida, 2033 Mowry Road, Gainesville, FL 32610, USA
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Zummo L, Vitale AM, Caruso Bavisotto C, De Curtis M, Garbelli R, Giallonardo AT, Di Bonaventura C, Fanella M, Conway de Macario E, Cappello F, Macario AJL, Marino Gammazza A. Molecular Chaperones and miRNAs in Epilepsy: Pathogenic Implications and Therapeutic Prospects. Int J Mol Sci 2021; 22:ijms22168601. [PMID: 34445306 PMCID: PMC8395327 DOI: 10.3390/ijms22168601] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 11/16/2022] Open
Abstract
Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.
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Affiliation(s)
- Leila Zummo
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Department of Neurology and Stroke Unit, A.R.N.A.S. Ospedale Civico—Di Cristina Benfratelli, 90127 Palermo, Italy
| | - Alessandra Maria Vitale
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;
| | - Celeste Caruso Bavisotto
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;
| | - Marco De Curtis
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (M.D.C.); (R.G.)
| | - Rita Garbelli
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (M.D.C.); (R.G.)
| | - Anna Teresa Giallonardo
- Department of Human Neurosciences “Sapienza”, University of Rome, 00185 Rome, Italy; (A.T.G.); (C.D.B.); (M.F.)
- Policlinico Umberto I, 00161 Rome, Italy
| | - Carlo Di Bonaventura
- Department of Human Neurosciences “Sapienza”, University of Rome, 00185 Rome, Italy; (A.T.G.); (C.D.B.); (M.F.)
- Policlinico Umberto I, 00161 Rome, Italy
| | - Martina Fanella
- Department of Human Neurosciences “Sapienza”, University of Rome, 00185 Rome, Italy; (A.T.G.); (C.D.B.); (M.F.)
- Policlinico Umberto I, 00161 Rome, Italy
| | - Everly Conway de Macario
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA;
| | - Francesco Cappello
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;
| | - Alberto J. L. Macario
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA;
| | - Antonella Marino Gammazza
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; (L.Z.); (A.M.V.); (C.C.B.); (F.C.)
- Correspondence:
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Dutysheva EA, Utepova IA, Trestsova MA, Anisimov AS, Charushin VN, Chupakhin ON, Margulis BA, Guzhova IV, Lazarev VF. Synthesis and approbation of new neuroprotective chemicals of pyrrolyl- and indolylazine classes in a cell model of Alzheimer's disease. Eur J Med Chem 2021; 222:113577. [PMID: 34087544 DOI: 10.1016/j.ejmech.2021.113577] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/18/2021] [Accepted: 05/19/2021] [Indexed: 12/19/2022]
Abstract
One of the major causes of neurodegeneration in the pathogenesis of Alzheimer's disease is the accumulation of cytotoxic amyloid species within the intercellular compartments of the brain. The efficacy of the anti-proteotoxic mechanism based on the molecular chaperones Hsp70 and Hsp90 in numerous types of neurons is often low, while its pharmacological enhancement has been shown to ameliorate the physiological and cognitive functions of the brain. Suggesting that the chemicals able to induce heat shock protein synthesis and therefore rescue neural cells from cytotoxicity associated with amyloid, we have synthesized a group of pyrrolyl- and indolylazines that cause the accumulation of heat shock proteins, using a novel method of photocatalysis that is employed in green chemistry. The selected compounds were tested in a cell model of Alzheimer's disease and demonstrated a pronounced neuroprotective effect. These substances increased the survival of neurons, blocked the activation of β-galactosidase, and prevented apoptosis in neurons cultured in the presence of β-amyloid.
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Affiliation(s)
| | - Irina A Utepova
- Ural Federal University, Ekaterinburg, 620002, Russia; Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620108, Russia
| | - Maria A Trestsova
- Ural Federal University, Ekaterinburg, 620002, Russia; Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620108, Russia
| | - Alexander S Anisimov
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia
| | - Valery N Charushin
- Ural Federal University, Ekaterinburg, 620002, Russia; Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620108, Russia
| | - Oleg N Chupakhin
- Ural Federal University, Ekaterinburg, 620002, Russia; Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620108, Russia
| | - Boris A Margulis
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia
| | - Irina V Guzhova
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia
| | - Vladimir F Lazarev
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
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5
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Zheng YH, Yin LQ, Xu HK, Gong X. Non-invasive physical therapy as salvage measure for ischemic skin flap: A literature review. World J Clin Cases 2021; 9:3227-3237. [PMID: 34002132 PMCID: PMC8107891 DOI: 10.12998/wjcc.v9.i14.3227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/26/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the available evidence regarding the molecular mechanisms and treatment potential of several non-surgical physical therapies for managing flap ischemia to propose a non-invasive, economical, and simple treatment to improve flap survival. A review of the literature was conducted on the topics of various non-invasive methods for the treatment of ischemic necrosis of the distal end of the flap between 1988 and 2019. A total of 52 published studies were reviewed on the applications of hyperbaric oxygen therapy, electrical stimulation therapy, heat stress pretreatment, phototherapy, and vibration therapy to manage skin flap necrosis. The underlying molecular mechanisms of these physical therapies on revitalizing the dying skin flaps were discussed and preliminary clinical uses of these therapies to salvage the necrotic skin flaps were pooled and summarized for clarifying the safety and feasibility of these methods. Various physical therapy regimens have been ushered to manage necrotic development in cutaneous flaps. With the refinement of these new technologies and enhancement of related basic science research on vascular revitalization, the prevention and treatment of flap ischemia will enter a new era.
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Affiliation(s)
- Yin-Hua Zheng
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Quan Yin
- Department of Rehabilitation Medicine, The Third Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Hai-Kun Xu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xu Gong
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Zhang X, Zhang J, Liu Y, Li J, Tan J, Song Z. Bcl-2 Associated Athanogene 2 (BAG2) is Associated With Progression and Prognosis of Hepatocellular Carcinoma: A Bioinformatics-Based Analysis. Pathol Oncol Res 2021; 27:594649. [PMID: 34257542 PMCID: PMC8262200 DOI: 10.3389/pore.2021.594649] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 02/12/2021] [Indexed: 12/28/2022]
Abstract
Background: Bcl-2 associated athanogene2 (BAG2) is reported to act as an oncogene or a tumor-suppressor in tumors in a context-dependent way; however, its function in hepatocellular carcinoma (HCC) remains unclear. Methods: Immunohistochemistry (IHC) staining, cell counting kit-8 (CCK-8) assay, apoptotic assay, cell invasion assay and a set of bioinformatics tools were integrated to analyze the role of BAG2 in hepatocellular carcinoma. Results: BAG2 was significantly up-regulated in HCC. Prognostic analysis indicated that HCC patients with high expression of BAG2 had significantly shorter overall survival, progression free survival and disease specific survival. Besides, silencing BAG2 in HCC cells impaired cell proliferation, facilitated apoptosis and repressed invasion of the cells. Bioinformatics analysis showed that BAG2 might regulate ribosome biogenesis in HCC. Conclusion: This study revealed that the up-regulated BAG2 in HCC was associated with a worse prognosis and might favor the progression of the disease.
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Affiliation(s)
- Xi Zhang
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Junjun Zhang
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yang Liu
- Department of Pathology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jie Li
- Department of Information Science and Engineering, Hunan University of Chinese Medicine, Changsha, China
| | - Juan Tan
- Department of Pathology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zewen Song
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, China
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7
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Disruption of the Complex between GAPDH and Hsp70 Sensitizes C6 Glioblastoma Cells to Hypoxic Stress. Int J Mol Sci 2021; 22:ijms22041520. [PMID: 33546324 PMCID: PMC7913589 DOI: 10.3390/ijms22041520] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/28/2021] [Accepted: 01/30/2021] [Indexed: 12/11/2022] Open
Abstract
Hypoxia, which commonly accompanies tumor growth, depending on its strength may cause the enhancement of tumorigenicity of cancer cells or their death. One of the proteins targeted by hypoxia is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and we demonstrated here that hypoxia mimicked by treating C6 rat glioblastoma cells with cobalt chloride caused an up-regulation of the enzyme expression, while further elevation of hypoxic stress caused the enzyme aggregation concomitantly with cell death. Reduction or elevation of GAPDH performed with the aid of specific shRNAs resulted in the augmentation of the tumorigenicity of C6 cells or their sensitization to hypoxic stress. Another hypoxia-regulated protein, Hsp70 chaperone, was shown to prevent the aggregation of oxidized GAPDH and to reduce hypoxia-mediated cell death. In order to release the enzyme molecules from the chaperone, we employed its inhibitor, derivative of colchicine. The compound was found to substantially increase aggregation of GAPDH and to sensitize C6 cells to hypoxia both in vitro and in animals bearing tumors with distinct levels of the enzyme expression. In conclusion, blocking the chaperonic activity of Hsp70 and its interaction with GAPDH may become a promising strategy to overcome tumor resistance to multiple environmental stresses and enhance existing therapeutic tools.
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8
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Pyrrolylquinoxaline-2-One Derivative as a Potent Therapeutic Factor for Brain Trauma Rehabilitation. Pharmaceutics 2020; 12:pharmaceutics12050414. [PMID: 32366047 PMCID: PMC7285016 DOI: 10.3390/pharmaceutics12050414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/22/2020] [Accepted: 04/29/2020] [Indexed: 01/10/2023] Open
Abstract
Traumatic brain injury (TBI) often causes massive brain cell death accompanied by the accumulation of toxic factors in interstitial and cerebrospinal fluids. The persistence of the damaged brain area is not transient and may occur within days and weeks. Chaperone Hsp70 is known for its cytoprotective and antiapoptotic activity, and thus, a therapeutic approach based on chemically induced Hsp70 expression may become a promising approach to lower post-traumatic complications. To simulate the processes of secondary damage, we used an animal model of TBI and a cell model based on the cultivation of target cells in the presence of cerebrospinal fluid (CSF) from injured rats. Here we present a novel low molecular weight substance, PQ-29, which induces the synthesis of Hsp70 and empowers the resistance of rat C6 glioma cells to the cytotoxic effect of rat cerebrospinal fluid taken from rats subjected to TBI. In an animal model of TBI, PQ-29 elevated the Hsp70 level in brain cells and significantly slowed the process of the apoptosis in acceptor cells in response to cerebrospinal fluid action. The compound was also shown to rescue the motor function of traumatized rats, thus proving its potential application in rehabilitation therapy after TBI.
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9
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Sverchinsky DV, Nikotina AD, Komarova EY, Mikhaylova ER, Aksenov ND, Lazarev VF, Mitkevich VA, Suezov R, Druzhilovskiy DS, Poroikov VV, Margulis BA, Guzhova IV. Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3. Int J Mol Sci 2018; 19:ijms19092519. [PMID: 30149619 PMCID: PMC6163214 DOI: 10.3390/ijms19092519] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 08/14/2018] [Accepted: 08/21/2018] [Indexed: 11/16/2022] Open
Abstract
The Hsp70 chaperone binds and inhibits proteins implicated in apoptotic signaling including Caspase-3. Induction of apoptosis is an important mechanism of anti-cancer drugs, therefore Hsp70 can act as a protective system in tumor cells against therapeutic agents. In this study we present an assessment of candidate compounds that are able to dissociate the complex of Hsp70 with Caspase-3, and thus sensitize cells to drug-induced apoptosis. Using the PASS program for prediction of biological activity we selected a derivative of benzodioxol (BT44) that is known to affect molecular chaperones and caspases. Drug affinity responsive target stability and microscale thermophoresis assays indicated that BT44 bound to Hsp70 and reduced the chaperone activity. When etoposide was administered, heat shock accompanied with an accumulation of Hsp70 led to an inhibition of etoposide-induced apoptosis. The number of apoptotic cells increased following BT44 administration, and forced Caspase-3 processing. Competitive protein–protein interaction and immunoprecipitation assays showed that BT44 caused dissociation of the Hsp70–Caspase-3 complex, thus augmenting the anti-tumor activity of etoposide and highlighting the potential role of molecular separators in cancer therapy.
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Affiliation(s)
- Dmitry V Sverchinsky
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
| | - Alina D Nikotina
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
| | - Elena Y Komarova
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
| | - Elena R Mikhaylova
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
| | - Nikolay D Aksenov
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
| | - Vladimir F Lazarev
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
| | - Vladimir A Mitkevich
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova, Moscow 119991, Russia.
| | - Roman Suezov
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
| | - Dmitry S Druzhilovskiy
- Institute of Biomedical Chemistry, Pogodinskaya str., 10, bldg. 8, Moscow 119121, Russia.
| | - Vladimir V Poroikov
- Institute of Biomedical Chemistry, Pogodinskaya str., 10, bldg. 8, Moscow 119121, Russia.
| | - Boris A Margulis
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
| | - Irina V Guzhova
- Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia.
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10
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Shabbir A, Bianchetti E, Cargonja R, Petrovic A, Mladinic M, Pilipović K, Nistri A. Role of HSP70 in motoneuron survival after excitotoxic stress in a rat spinal cord injury modelin vitro. Eur J Neurosci 2015; 42:3054-65. [DOI: 10.1111/ejn.13108] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 10/15/2015] [Accepted: 10/15/2015] [Indexed: 01/06/2023]
Affiliation(s)
- Ayisha Shabbir
- Neuroscience Department; Scuola Internazionale Superiore di Studi Avanzati (SISSA); Via Bonomea 265 34136 Trieste Italy
| | - Elena Bianchetti
- Neuroscience Department; Scuola Internazionale Superiore di Studi Avanzati (SISSA); Via Bonomea 265 34136 Trieste Italy
| | - Renato Cargonja
- Neuroscience Department; Scuola Internazionale Superiore di Studi Avanzati (SISSA); Via Bonomea 265 34136 Trieste Italy
- Department of Biotechnology; University of Rijeka; Rijeka Croatia
| | - Antonela Petrovic
- Neuroscience Department; Scuola Internazionale Superiore di Studi Avanzati (SISSA); Via Bonomea 265 34136 Trieste Italy
- Department of Biotechnology; University of Rijeka; Rijeka Croatia
| | - Miranda Mladinic
- Neuroscience Department; Scuola Internazionale Superiore di Studi Avanzati (SISSA); Via Bonomea 265 34136 Trieste Italy
- Department of Biotechnology; University of Rijeka; Rijeka Croatia
| | - Kristina Pilipović
- Neuroscience Department; Scuola Internazionale Superiore di Studi Avanzati (SISSA); Via Bonomea 265 34136 Trieste Italy
| | - Andrea Nistri
- Neuroscience Department; Scuola Internazionale Superiore di Studi Avanzati (SISSA); Via Bonomea 265 34136 Trieste Italy
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11
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Wang F, Dai AY, Tao K, Xiao Q, Huang ZL, Gao M, Li H, Wang X, Cao WX, Feng WL. Heat shock protein-70 neutralizes apoptosis inducing factor in Bcr/Abl expressing cells. Cell Signal 2015; 27:1949-55. [DOI: 10.1016/j.cellsig.2015.06.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 06/22/2015] [Accepted: 06/25/2015] [Indexed: 11/30/2022]
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12
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Leak RK. Heat shock proteins in neurodegenerative disorders and aging. J Cell Commun Signal 2014; 8:293-310. [PMID: 25208934 DOI: 10.1007/s12079-014-0243-9] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 09/01/2014] [Indexed: 12/20/2022] Open
Abstract
Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stress-induced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.
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Affiliation(s)
- Rehana K Leak
- Division of Pharmaceutical Sciences, Duquesne University, 600 Forbes Ave, Pittsburgh, PA, 15282, USA,
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13
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Chaitanya GV, Eeka P, Munker R, Alexander JS, Babu PP. Role of cytotoxic protease granzyme-b in neuronal degeneration during human stroke. Brain Pathol 2011; 21:16-30. [PMID: 20825413 DOI: 10.1111/j.1750-3639.2010.00426.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Infiltration of leukocytes into post-ischemic cerebrum is a well-described phenomenon in stroke injury. Because CD-8(+) T-lymphocytes secrete cytotoxic proteases, including granzyme-b (Gra-b) that exacerbates post-ischemic brain damage, we investigated roles of Gra-b in human stroke. To study the role of Gra-b in stroke, ischemic and non-ischemic tissues (from post-mortem stroke patients) were analyzed using immunoblotting, co-immunoprecipitation, terminal deoxy uridine nick end labeling (TUNEL) and Annexin-V immunostaining, and in vitro neuron survival assays. Activated CG-SH cells and supernatants were used to model leukocyte-dependent injury. Non-ischemic brain tissues were used as non-pathological controls. Non-activated CG-SH cells and supernatants were used as controls for in vitro experiments. Human stroke (ischemic) samples contained significantly higher levels of Gra-b and interferon-gamma inducible protein-10 (IP-10/CXCL10) than non-ischemic controls. In stroke, poly (ADP-ribose) polymerase-1 and heat shock protein-70 were cleaved to canonical proteolytic "signature" fragments by Gra-b. Gra-b was also found to bind to Bid and caspase-3. Gra-b also co-localized with Annexin-V(+) /TUNEL(+) in degenerating neurons. Importantly, Gra-b inhibition protected both normal and ischemia-reperfused neurons against in vitro neurotoxicity mediated by activated CG-SH cells and supernatants. These results suggest that increased leukocyte infiltration and elevated Gra-b levels in the post-stroke brain can induce contact-dependent and independent post-ischemic neuronal death to aggravate stroke injury.
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Affiliation(s)
- Ganta Vijay Chaitanya
- Department of Molecular and Cellular Physiology, School of Medicine, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, La, USA
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Gupta S, Deepti A, Deegan S, Lisbona F, Hetz C, Samali A. HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction. PLoS Biol 2010; 8:e1000410. [PMID: 20625543 PMCID: PMC2897763 DOI: 10.1371/journal.pbio.1000410] [Citation(s) in RCA: 194] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2009] [Accepted: 05/20/2010] [Indexed: 12/22/2022] Open
Abstract
Endoplasmic reticulum (ER) stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR). Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1alpha, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1alpha or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.
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Affiliation(s)
- Sanjeev Gupta
- Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland
| | - Ayswaria Deepti
- Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland
| | - Shane Deegan
- Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland
| | - Fernanda Lisbona
- Institute of Biomedical Sciences, FONDAP Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile
| | - Claudio Hetz
- Institute of Biomedical Sciences, FONDAP Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile
| | - Afshin Samali
- Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland
- * E-mail:
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15
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Expression of Heat Shock Protein 70 in the Periodontal Ligament During Orthodontic Tooth Movement. ACTA ACUST UNITED AC 2010. [DOI: 10.5466/ijoms.9.115] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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16
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Cui ZG, Kondo T, Ogawa R, Feril LB, Zhao QL, Wada S, Arai T, Makino K. Enhancement of Radiation-induced Apoptosis by 6-Formylpterin. Free Radic Res 2009; 38:363-73. [PMID: 15190933 DOI: 10.1080/1071576042000191754] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Radiation-induced apoptosis and its possible enhancement in the presence of 6-formylpterin (6-FP), a metabolite of folic acid, were examined in human myelomonocytic lymphoma U937 cells. When cells were treated with 6-FP at a nontoxic concentration of 300 microM, and then exposed to X-rays at a dose of 10 Gy, significant enhancement of radiation-induced apoptosis as determined by nuclear morphological change, phosphatidylserine (PS) externalization and DNA fragmentation were observed. Flow cytometry for the detection of intracellular hydrogen peroxide (H2O2) revealed that 6-FP increased the formation of intracellular H2O2, which further increased when the cells were irradiated. Decrease of mitochondria trans-membrane potential (MMP), release of cytochrome c from mitochondria, and activation of caspase-3 were enhanced after the combined treatment. Remarkable activation of protein kinase C delta (PKC delta) and its translocation from cytosol to mitochondria were detected in combined treatment. Increase of intracellular Ca2+ concentrations ([Ca2+]i) was also observed, however, neither calpain I nor calpain II could inhibit the apoptosis. In addition, c-Jun NH2-terminal kinase (JNK) activation was not enhanced in the combined treatment. A protein involved in a caspase-independent apoptosis pathway, apoptosis inducing factor (AIF), remained unchanged even 3 h after treatment. These results indicate that intracellular H2O2 generated by 6-FP enhances radiation-induced apoptosis via the mitochondria-mediated caspase-dependent pathway, with the active involvement of PKC delta.
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Affiliation(s)
- Zheng-Guo Cui
- Department of Radiological Sciences, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
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17
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Barbouti A, Amorgianiotis C, Kolettas E, Kanavaros P, Galaris D. Hydrogen peroxide inhibits caspase-dependent apoptosis by inactivating procaspase-9 in an iron-dependent manner. Free Radic Biol Med 2007; 43:1377-87. [PMID: 17936184 DOI: 10.1016/j.freeradbiomed.2007.06.020] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2007] [Revised: 06/08/2007] [Accepted: 06/18/2007] [Indexed: 11/28/2022]
Abstract
Apoptosis represents a physiological form of cell death, the perturbation of which may contribute to the development of several diseases connected with accumulation of unwanted cells or excessive cell loss. We have previously shown that the continuous presence of low concentrations of H2O2 (generated by the action of glucose oxidase) was able to inhibit caspase-mediated apoptosis in Jurkat cells. The main purpose of the present study was to elucidate the exact molecular mechanism(s) underlying this inhibitory action of H2O2. The results presented show that events like outer mitochondrial membrane permeabilization, release of cytochrome c from mitochondria, oligomerization of Apaf-1, and recruitment of procaspase-9 to apoptosomes were taking place normally, but further advancement toward activation of the execution caspases was interrupted when H2O2 was present during the apoptotic process. From the results presented in this work, it emerges that the inhibition of procaspase-9 autoactivation was probably due to the reversible oxidation of sensitive cysteine residues in this molecule. Remarkably, caspase-9 activation and the ensuing caspase cascade proceeded normally in the presence of H2O2 under conditions of iron deprivation, indicating that the inhibition of procaspase-9 activation was an iron-dependent process. Collectively, these results highlighted the potential role of available intracellular iron ions in signaling mechanisms related to apoptotic cell death.
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Affiliation(s)
- Alexandra Barbouti
- Laboratory of Biological Chemistry, University of Ioannina Medical School, 45110 Ioannina, Greece
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18
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Lui JCK, Kong SK. Heat shock protein 70 inhibits the nuclear import of apoptosis-inducing factor to avoid DNA fragmentation in TF-1 cells during erythropoiesis. FEBS Lett 2006; 581:109-17. [PMID: 17182042 DOI: 10.1016/j.febslet.2006.11.082] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2006] [Accepted: 11/30/2006] [Indexed: 11/24/2022]
Abstract
Loss of mitochondrial membrane potential (DeltaPsi(m)) and release of AIF (apoptosis-inducing factor) from mitochondria are key steps in apoptosis. In TF-1 model, DeltaPsi(m) was depolarized with AIF release during erythroid development. Yet, no DNA fragmentation was observed. When DeltaPsi(m) depolarization had been blocked, erythropoiesis was suppressed. Interestingly, heat shock protein 70 (Hsp70) was found transiently upregulated during depolarization and it retained AIF in the cytosol to avoid DNA damages. When Hsp inhibitor was added, DNA fragmentation occurred. We show this mechanism for the first time in erythropoiesis how cells with DeltaPsi(m) depolarization and AIF release escape apoptosis.
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Affiliation(s)
- Julian Chun-Kin Lui
- Department of Biochemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, China
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19
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Reyes I, Reyes N, Iatropoulos M, Mittelman A, Geliebter J. Aging-associated changes in gene expression in the ACI rat prostate: Implications for carcinogenesis. Prostate 2005; 63:169-86. [PMID: 15486989 DOI: 10.1002/pros.20164] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Prostate cancer is the most frequently diagnosed neoplasm and the second leading cause of cancer-related mortality in men. Although the incidence of prostate cancer increases with age, the link between aging and prostate cancer is poorly understood. METHODS Affymetrix oligonucleotide microarrays were used to analyze the mRNA expression levels in the dorsolateral prostates from 6- and 18-month-old ACI rats. Real-time RT-PCR and immunohistochemistry was performed to validate microarray data in a select set of genes. RESULTS Microarray analysis revealed changes in gene expression associated with inflammation, oxidative stress, tissue remodeling, and energy metabolism. Most of these changes have been related to increased proliferative status of the prostate, anti-apoptosis, activated stroma, and alteration of the energy metabolism. CONCLUSIONS Age-associated alterations in the gene expression profile may put the aging prostate in risk for the initiation, promotion, and progression of neoplastic transformation in both our animal model and humans.
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Affiliation(s)
- Ismael Reyes
- Department of Microbiology and Immunology, New York Medical College (NYMC), Valhalla, New York, USA
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Harmand PO, Duval R, Delage C, Simon A. Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu melanoma cells. Int J Cancer 2005; 114:1-11. [PMID: 15523687 DOI: 10.1002/ijc.20588] [Citation(s) in RCA: 115] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Over the coming years, skin cancer could become a significant public health problem. Previous results indicate that ursolic acid (UA), a pentacyclic triterpene acid, has pleiotropic biologic activities such as antiinflammatory and antiproliferative activities on cancer cells. As UA represents a promising chemical entity for the protection of human skin, in agreement with tests done by the cosmetic industry, we investigated its effects on the M4Beu human melanoma cell line. In this report, we demonstrated for the first time that UA had a significant antiproliferative effect on M4Beu, associated with the induction of an apoptotic process, characterized by caspase-3 activation, the downstream central effector of apoptosis. We demonstrated that UA-induced apoptosis was dependent on the mitochondrial intrinsic pathway, as shown by transmembrane potential collapse (DeltaPsim) and by alteration of the Bax-Bcl-2 balance, with a concomitant increase in Bax expression and decrease in Bcl-2 expression. We also showed that UA-induced DeltaPsim was associated with apoptosis-inducing factor leakage from mitochondria. Taken together, our results suggest that UA-induced apoptosis on M4Beu cells is accomplished via triggering of mitochondrial pathway. In conclusion, UA could be an encouraging compound in the treatment or prevention of skin cancer and may represent a new promising anticancer agent in the treatment of melanoma.
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Affiliation(s)
- Pierre-Olivier Harmand
- Laboratoire de Chimie-Physique, UPRES EA 1085, Faculté de Pharmacie, Limoges Cedex, France
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Harder Y, Contaldo C, Klenk J, Banic A, Jakob SM, Erni D. Improved skin flap survival after local heat preconditioning in pigs. J Surg Res 2004; 119:100-5. [PMID: 15126089 DOI: 10.1016/j.jss.2003.11.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2003] [Indexed: 10/26/2022]
Abstract
BACKGROUND Preconditioning induces the expression of heat shock proteins (HSPs), which can help a cell survive an acute episode of stress. Similar to the induction of HSP expression, the cell protection is independent of the type of stress. The aim of this study was to test in a large, randomized animal model, if skin flap survival may be improved by local heat preconditioning and induction of HSP 70. MATERIALS AND METHODS Twenty-four hours before surgery, a heating blanket was laid on the buttocks of large white pigs. In the preconditioned group (n = 6), the blanket was warmed up to 43 degrees C for 3 x 30 min, whereas it was kept at room temperature in between the heating episodes as well as in the control animals (n = 6). A random pattern skin flap was raised on both sides of the buttocks. Flap survival was measured clinically. Induction of HSP and apoptosis were assessed quantitatively by immunohistochemistry and TUNEL assay, respectively. RESULTS Preconditioning reduced flap necrosis from 40 +/- 8% of the total flap surface to 7 +/- 14% (P < 0.01). Induction of HSP was significantly higher in the experimental group (79 +/- 12% versus 42 +/- 13%, P < 0.01), whereas apoptosis in healthy flap tissue was reduced from 30 +/- 11 to 11 +/- 6 cells/visual field (P < 0.01). CONCLUSION In the present study, necrosis and apoptosis rate of skin flaps could be reduced significantly due to local heat preconditioning. Our results suggest that ischemia-related wound healing complications could be diminished with local heat application, a most simple and least invasive method of preconditioning.
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Affiliation(s)
- Y Harder
- Division of Plastic, Reconstructive, and Aesthetic Surgery, University Hospital, CH-3010 Berne, Switzerland.
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