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Ghasemi M, Nouri M, Ansari A, Kouhbanani MT, Nazeri S, Abbasi M, Nori P, Arianejad MM, Dehzangi A, Choudhury PK. Direct Interaction of Long-Term Reactive Oxygen-Based Species Stored in Microencapsulation of Olive Oil on Burn Scars of Wistar Rats. ACS APPLIED BIO MATERIALS 2025; 8:2771-2786. [PMID: 40153251 DOI: 10.1021/acsabm.4c01214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2025]
Abstract
Oxygen anions (superoxide and peroxide anions) are naturally unstable and prone to chemical interactions. These reactive oxygen species (ROS) are formed during long-term storage in olive oil (OO), the structural properties of which extend the ROS lifespan more effectively than those of other vegetable oils. In wound treatment, superoxide anions serve as precursors for hydrogen peroxide and play a crucial role in cell proliferation, migration, and angiogenesis. These anions were encapsulated within the OO medium for crystallization. Piezoelectric actuators were employed to distribute the trapped bubbles evenly throughout the crystallized OO. The ROS-filled OO microcapsules eliminated volatile organic compounds and particulate matter (from the air). Samples stored in crystallized OO were utilized to investigate the antibacterial effects. Both Escherichia coli and Staphylococcus aureus were implicated in skin infections (with S. aureus as the primary pathogen and E. coli as the secondary pathogen) and were selected for antibacterial testing. Microcapsules applied to cultured E. coli and S. aureus resulted in different inhibition zones. Two groups [control (C-) and treatment (T-)] of second-degree burn wounds were created on the dorsal area of 15 Wistar rats. Over a period of 2 weeks, statistical analysis using a t-test demonstrated a significant reduction in the wound size in the T-zones. Histological examination with hematoxylin, eosin, and trichrome staining of tissue samples from the wound areas revealed a notable reduction in inflammation, enhanced epidermal cell proliferation, improved activity in producing hair follicles, and increased collagen deposition in the treated regions on different days of observation.
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Affiliation(s)
- M Ghasemi
- Laser and Plasma Research Institute, Shahid Beheshti University, Daneshju Blvd., Evin, 19839 69411 Tehran, Iran
- Nanotech Anion AB, Kulgranden, 11C, Lgh 11032, 22649 Lund, Sweden
| | - M Nouri
- Nanotech Anion AB, Kulgranden, 11C, Lgh 11032, 22649 Lund, Sweden
| | - A Ansari
- Nanotech Anion AB, Kulgranden, 11C, Lgh 11032, 22649 Lund, Sweden
| | - M T Kouhbanani
- Nanotech Anion AB, Kulgranden, 11C, Lgh 11032, 22649 Lund, Sweden
| | - S Nazeri
- Zhinogene Pazhoohan Research Laboratory, Unit 5, Level 2, Iranzamin Shomali, Yas Street, Poonak, 1476714156 Tehran, Iran
| | - M Abbasi
- Zhinogene Pazhoohan Research Laboratory, Unit 5, Level 2, Iranzamin Shomali, Yas Street, Poonak, 1476714156 Tehran, Iran
| | - P Nori
- Department of Sport Sciences, Faculty of Humanities, Semnan University, 3513119111 Semnan, Iran
| | - Mohammad Mahdi Arianejad
- Department of Electrical and Electronics Engineering, Xiamen University, 43900 Sepang, Selangor, Malaysia
| | - A Dehzangi
- Department of Electrical and Computer Engineering, University of Texas at Dallas, Richardson, Texas 750803021, United States
| | - Pankaj Kumar Choudhury
- College of Optical Science and Engineering, International Research Center for Advanced Photonics, Zhejiang University, Building 1A, 718 East Haizhou Rd., Haining 314400, Zhejiang, China
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Wang X, Meng G, Zhang Z, Zhao J, Wang S, Hua D, JingZhang, Zhang J. Prodigiosin hydrogel to promote healing of trauma-infected multidrug-resistant Staphylococcus aureus mice wounds. Int J Pharm X 2024; 8:100306. [PMID: 39678263 PMCID: PMC11638630 DOI: 10.1016/j.ijpx.2024.100306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 11/15/2024] [Accepted: 11/16/2024] [Indexed: 12/17/2024] Open
Abstract
Wound infections caused by Multidrug-resistant Staphylococcus aureus (MRSA) have been regarded as a challenging problem in clinic for the long time. In this study, based on the excellent antimicrobial effect of prodigiosin(PG) and the ability of hydrogel dressing in terms of tissue repair and regeneration, we prepared the PG hydrogel as a treatment for the wound infection induced by MRSA. Rheological tests indicated that PG hydrogel as a semi-solid gel had good mechanical properties. In ex vitro drug permeation studies and dermatokinetic studies showed that PG hydrogel had high PG permeability and were capable of short-term retention in the skin. In addition, in vivo experiments for mouse skin wounds showed that the serum levels of inflammatory factors including IL-β and other inflammatory factors were reduced, the inflammatory infiltration of tissues was reduced, the transcript levels of genes such as COL1A1 were up-regulated at different stages of wound healing, and the relative abundance of genera such as Desulfovibrio was lowered after treatment with PG hydrogel, which facilitated wound healing in mice. Our study would provide a new solution to the clinical shortage of drugs for the treatment of MRSA infection and provide a research basis for improving the comprehensive values of PG.
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Affiliation(s)
- Xin Wang
- School of Bioengineering, State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Guangfan Meng
- School of Bioengineering, State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Zongyu Zhang
- School of Bioengineering, State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Jiacheng Zhao
- School of Bioengineering, State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Shaoyu Wang
- School of Bioengineering, State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Dongliang Hua
- School of Bioengineering, State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - JingZhang
- School of Bioengineering, State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Jie Zhang
- School of Bioengineering, State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
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Garcia AD, White Chu EF. The Challenge of Chronic Wounds in Older Adults. Clin Geriatr Med 2024; 40:367-373. [PMID: 38960530 DOI: 10.1016/j.cger.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2024]
Abstract
Care for the older patient living with a chronic wound comes with challenges not seen in younger patients. The aging skin, impacted by the environment and intrinsic physiologic changes, makes it susceptible to injury and poor healing. Likewise, older adults' goals with regards to wound healing may vary depending on their functional abilities and quality of life. The clinician must pay attention to these nuances and collaborate with the older patient in developing a treatment plan. Careful systematic description, documentation, and communication with the patient/caregiver aids the clinician in tracking the treatment goals and potentially reducing medical liability risk.
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Affiliation(s)
- Aimee D Garcia
- Department of Medicine, Baylor College of Medicine; Wound Clinic and Consult Service, Michael E. DeBakey VA Medical Center, 2002 Holcombe Boulevard, Houston, TX 77030, USA.
| | - Elizabeth Foy White Chu
- Department of Geriatrics, Oregon Health & Science University, Portland VA Health Care System, 3710 SW, US Veterans Hospital Road, Portland, OR 97239, USA
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Boothe PF, Kumar VP, Kong Y, Wang K, Levinson H, Mu D, Brown ML. Radiation Induced Skin Fibrosis (RISF): Opportunity for Angiotensin II-Dependent Intervention. Int J Mol Sci 2024; 25:8261. [PMID: 39125831 PMCID: PMC11312688 DOI: 10.3390/ijms25158261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Medical procedures, such as radiation therapy, are a vital element in treating many cancers, significantly contributing to improved survival rates. However, a common long-term complication of such exposure is radiation-induced skin fibrosis (RISF), a complex condition that poses substantial physical and psychological challenges. Notably, about 50% of patients undergoing radiation therapy may achieve long-term remission, resulting in a significant number of survivors managing the aftereffects of their treatment. This article delves into the intricate relationship between RISF, reactive oxygen species (ROS), and angiotensin II (Ang II) signaling. It proposes the underlying mechanisms and examines potential treatments for mitigating skin fibrosis. The primary goal is to offer essential insights in order to better care for and improve the quality of life of cancer survivors who face the risk of developing RISF.
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Affiliation(s)
- Patricia F. Boothe
- Department of Internal Medicine, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA
| | - Vidya P. Kumar
- Armed Forces Radiobiology Research Institute, The Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA
| | - Yali Kong
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA; (Y.K.); (D.M.)
| | - Kan Wang
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA; (Y.K.); (D.M.)
| | - Howard Levinson
- The Center for Plastic Surgery at Sentara, 301 Riverview Ave. #400, Norfolk, VA 23510, USA;
| | - David Mu
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA; (Y.K.); (D.M.)
- Leroy T. Canoles Jr. Cancer Research Center, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA
| | - Milton L. Brown
- Department of Internal Medicine, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA
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Elawa S, Fredriksson I, Steinvall I, Zötterman J, Farnebo S, Tesselaar E. Skin perfusion and oxygen saturation after mastectomy and radiation therapy in breast cancer patients. Breast 2024; 75:103704. [PMID: 38460441 PMCID: PMC10943105 DOI: 10.1016/j.breast.2024.103704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/04/2024] [Accepted: 03/05/2024] [Indexed: 03/11/2024] Open
Abstract
The pathophysiological mechanism behind complications associated with postmastectomy radiotherapy (PMRT) and subsequent implant-based breast reconstruction are not completely understood. The aim of this study was to examine if there is a relationship between PMRT and microvascular perfusion and saturation in the skin after mastectomy and assess if there is impaired responsiveness to a topically applied vasodilator (Methyl nicotinate - MN). Skin microvascular perfusion and oxygenation >2 years after PMRT were measured using white light diffuse reflectance spectroscopy (DRS) and laser Doppler flowmetry (LDF) in the irradiated chest wall of 31 women with the contralateral breast as a control. In the non-irradiated breast, the perfusion after application of MN (median 0.84, 25th-75th centile 0.59-1.02 % RBC × mm/s) was higher compared to the irradiated chest wall (median 0.51, 25th-75th centile 0.21-0.68 % RBC × mm/s, p < 0.001). The same phenomenon was noted for saturation (median 91 %, 25th-75th centile 89-94 % compared to 89 % 25th-75th centile 77-93 %, p = 0.001). Eight of the women (26%) had a ≥10 % difference in skin oxygenation between the non-irradiated breast and the irradiated chest wall. These results indicate that late microvascular changes caused by radiotherapy of the chest wall significantly affect skin perfusion and oxygenation.
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Affiliation(s)
- Sherif Elawa
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, Hand Surgery, and Burns, Linköping University, Linköping, Sweden.
| | - Ingemar Fredriksson
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Perimed AB, Järfälla, Stockholm, Sweden
| | - Ingrid Steinvall
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, Hand Surgery, and Burns, Linköping University, Linköping, Sweden
| | - Johan Zötterman
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, Hand Surgery, and Burns, Linköping University, Linköping, Sweden
| | - Simon Farnebo
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, Hand Surgery, and Burns, Linköping University, Linköping, Sweden
| | - Erik Tesselaar
- Department of Medical Radiation Physics, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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Berry CE, Abbas DB, Lintel HA, Churukian AA, Griffin M, Guo JL, Cotterell AC, Parker JBL, Downer MA, Longaker MT, Wan DC. Adipose-Derived Stromal Cell-Based Therapies for Radiation-Induced Fibrosis. Adv Wound Care (New Rochelle) 2024; 13:235-252. [PMID: 36345216 PMCID: PMC11304913 DOI: 10.1089/wound.2022.0103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 10/25/2022] [Indexed: 11/11/2022] Open
Abstract
Significance: Half of all cancer patients receive radiation therapy as a component of their treatment regimen, and the most common resulting complication is radiation-induced fibrosis (RIF) of the skin and soft tissue. This thickening of the dermis paired with decreased vascularity results in functional limitations and esthetic concerns and poses unique challenges when considering surgical exploration or reconstruction. Existing therapeutic options for RIF of the skin are limited both in scope and efficacy. Cell-based therapies have emerged as a promising means of utilizing regenerative cell populations to improve both functional and esthetic outcomes, and even as prophylaxis for RIF. Recent Advances: As one of the leading areas of cell-based therapy research, adipose-derived stromal cells (ADSCs) demonstrate significant therapeutic potential in the treatment of RIF. The introduction of the ADSC-augmented fat graft has shown clinical utility. Recent research dedicated to characterizing specific ADSC subpopulations points toward further granularity in understanding of the mechanisms driving the well-established clinical outcomes seen with fat grafting therapy. Critical Issues: Various animal models of RIF demonstrated improved clinical outcomes following treatment with cell-based therapies, but the cellular and molecular basis underlying these effects remains poorly understood. Future Directions: Recent literature has focused on improving the efficacy of cell-based therapies, most notably through (1) augmentation of fat grafts with platelet-rich plasma and (2) the modification of expressed RNA through epitranscriptomics. For the latter, new and promising gene targets continue to be identified which have the potential to reverse the effects of fibrosis by increasing angiogenesis, decreasing inflammation, and promoting adipogenesis.
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Affiliation(s)
- Charlotte E. Berry
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Darren B. Abbas
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Hendrik A. Lintel
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Andrew A. Churukian
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Michelle Griffin
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Jason L. Guo
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Asha C. Cotterell
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Jennifer B. Laufey Parker
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Mauricio A. Downer
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Michael T. Longaker
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Derrick C. Wan
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
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Heo YM, Lee DG, Mun S, Kim M, Baek C, Lee H, Yun SK, Kang S, Han K. Skin benefits of postbiotics derived from Micrococcus luteus derived from human skin: an untapped potential for dermatological health. Genes Genomics 2024; 46:13-25. [PMID: 37971618 DOI: 10.1007/s13258-023-01471-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 10/15/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND The skin microbiome, a diverse community of microorganisms, plays a crucial role in maintaining skin health. Among these microorganisms, the gram-positive bacterium Micrococcus luteus exhibits potential for promoting skin health. This study focuses on postbiotics derived from M. luteus YM-4, a strain isolated from human skin. OBJECTIVE Our objective is to explore the beneficial effects of YM-4 culture filtrate on dermatological health, including enhancing barrier function, modulating immune response, and aiding recovery from environmental damage. METHODS The effects of the YM-4 culture filtrate were tested on human keratinocytes and fibroblasts under various conditions using real-time PCR for gene expression analysis and fibroblast migration assays. A dehydration-simulated model was employed to prepare RNA-Seq samples from HaCaT cells treated with the YM-4 culture filtrate. Differentially expressed genes were identified and functionally classified through k-means clustering, gene ontology terms enrichment analyses, and protein-protein interactions mapping. RESULTS The YM-4 culture filtrate enhanced the expression of genes involved in skin hydration, hyaluronic acid synthesis, barrier function, and cell proliferation. It also reduced inflammation markers in keratinocytes and fibroblasts under stress conditions. It mitigated UVB-induced collagen degradation while promoted collagen synthesis, suggesting anti-aging properties, and accelerated wound healing processes by promoting cell proliferation and migration. RNA sequencing analysis revealed that the YM-4 culture filtrate could reverse dehydration-induced transcriptional changes towards a state similar to untreated cells. CONCLUSION M. luteus YM-4 culture filtrate exhibits significant therapeutic potential for dermatological applications.
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Affiliation(s)
- Young Mok Heo
- R&I Center, COSMAX BTI, Seongnam, 13486, Republic of Korea
| | - Dong-Geol Lee
- R&I Center, COSMAX BTI, Seongnam, 13486, Republic of Korea
- Department of Microbiology, College of Science & Technology, Dankook University, Cheonan, 31116, Republic of Korea
| | - Seyoung Mun
- Department of Microbiology, College of Science & Technology, Dankook University, Cheonan, 31116, Republic of Korea
| | - Minji Kim
- R&I Center, COSMAX BTI, Seongnam, 13486, Republic of Korea
| | - Chaeyun Baek
- R&I Center, COSMAX BTI, Seongnam, 13486, Republic of Korea
| | - Haeun Lee
- R&I Center, COSMAX BTI, Seongnam, 13486, Republic of Korea
| | - Seok Kyun Yun
- R&I Center, COSMAX BTI, Seongnam, 13486, Republic of Korea
| | - Seunghyun Kang
- R&I Center, COSMAX BTI, Seongnam, 13486, Republic of Korea
| | - Kyudong Han
- Department of Microbiology, College of Science & Technology, Dankook University, Cheonan, 31116, Republic of Korea.
- Center for Bio Medical Engineering Core Facility, Dankook University, Cheonan, 31116, Republic of Korea.
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Deliberador TM, Macalossi JMS, Tenorio C, Dall Agnol GDS, Boia MF, Zielak JC. An oxygen-releasing agent promotes healing of skin wounds in rats. J Wound Care 2023; 32:738-747. [PMID: 37907358 DOI: 10.12968/jowc.2023.32.11.738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
OBJECTIVE To evaluate the local effect of a slow oxygen-release gel on the healing of standardised skin wounds caused in rats. METHOD Skin wounds were created on the backs of male rats (Rattus norvegicus, Wistar) that were randomly allocated into two groups. In the treated (T) and control (C) groups, oxygen gel and distilled water, respectively, were applied to the wounds on alternate days for 28 days. Postoperatively, euthanasia was performed at 5, 10, 14, 21 and 28 days, followed by clinical, histological (Masson's trichrome) and immunohistochemical analysis. Data were subjected to analysis of variance (ANOVA) and Bonferroni's test. RESULTS The cohort comprised 50 rats. On clinical and histological analysis, groups C and T showed similar characteristics 5 days post-operation. Subsequently, group T showed better healing at 14, 21 and 28 days and presented more intense inflammatory infiltrate up to 10 days. At days 14, 21 and 28, group T exhibited a reduction in oedema and increased angiogenesis, granulation tissue formation, and deposition of collagen fibres than group C. Immunohistochemical analysis showed the presence of tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) in both the groups, but the levels were significantly higher in group T (p<0.05). CONCLUSION The local application of slow oxygen-release gel accelerated the healing of standardised skin wounds created surgically in rats, with increased angiogenesis and better collagen fibre formation.
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Naas S, Schiffer M, Schödel J. Hypoxia and renal fibrosis. Am J Physiol Cell Physiol 2023; 325:C999-C1016. [PMID: 37661918 DOI: 10.1152/ajpcell.00201.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/25/2023] [Accepted: 08/25/2023] [Indexed: 09/05/2023]
Abstract
Renal fibrosis is the final stage of most progressive kidney diseases. Chronic kidney disease (CKD) is associated with high comorbidity and mortality. Thus, preventing fibrosis and thereby preserving kidney function increases the quality of life and prolongs the survival of patients with CKD. Many processes such as inflammation or metabolic stress modulate the progression of kidney fibrosis. Hypoxia has also been implicated in the pathogenesis of renal fibrosis, and oxygen sensing in the kidney is of outstanding importance for the body. The dysregulation of oxygen sensing in the diseased kidney is best exemplified by the loss of stimulation of erythropoietin production from interstitial cells in the fibrotic kidney despite anemia. Furthermore, hypoxia is present in acute or chronic kidney diseases and may affect all cell types present in the kidney including tubular and glomerular cells as well as resident immune cells. Pro- and antifibrotic effects of the transcription factors hypoxia-inducible factors 1 and 2 have been described in a plethora of animal models of acute and chronic kidney diseases, but recent advances in sequencing technologies now allow for novel and deeper insights into the role of hypoxia and its cell type-specific effects on the progression of renal fibrosis, especially in humans. Here, we review existing literature on how hypoxia impacts the development and progression of renal fibrosis.
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Affiliation(s)
- Stephanie Naas
- Department of Nephrology and Hypertension, Uniklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Mario Schiffer
- Department of Nephrology and Hypertension, Uniklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Johannes Schödel
- Department of Nephrology and Hypertension, Uniklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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10
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Prescher H, Froimson JR, Hanson SE. Deconstructing Fat to Reverse Radiation Induced Soft Tissue Fibrosis. Bioengineering (Basel) 2023; 10:742. [PMID: 37370673 PMCID: PMC10295516 DOI: 10.3390/bioengineering10060742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Adipose tissue is composed of a collection of cells with valuable structural and regenerative function. Taken as an autologous graft, these cells can be used to address soft tissue defects and irregularities, while also providing a reparative effect on the surrounding tissues. Adipose-derived stem or stromal cells are primarily responsible for this regenerative effect through direct differentiation into native cells and via secretion of numerous growth factors and cytokines that stimulate angiogenesis and disrupt pro-inflammatory pathways. Separating adipose tissue into its component parts, i.e., cells, scaffolds and proteins, has provided new regenerative therapies for skin and soft tissue pathology, including that resulting from radiation. Recent studies in both animal models and clinical trials have demonstrated the ability of autologous fat grafting to reverse radiation induced skin fibrosis. An improved understanding of the complex pathologic mechanism of RIF has allowed researchers to harness the specific function of the ASCs to engineer enriched fat graft constructs to improve the therapeutic effect of AFG.
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Affiliation(s)
| | | | - Summer E. Hanson
- Section of Plastic & Reconstructive Surgery, University of Chicago Medical Center, Chicago, IL 60615, USA
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11
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Collagen-Based Biomimetic Systems to Study the Biophysical Tumour Microenvironment. Cancers (Basel) 2022; 14:cancers14235939. [PMID: 36497421 PMCID: PMC9739814 DOI: 10.3390/cancers14235939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/22/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022] Open
Abstract
The extracellular matrix (ECM) is a pericellular network of proteins and other molecules that provides mechanical support to organs and tissues. ECM biophysical properties such as topography, elasticity and porosity strongly influence cell proliferation, differentiation and migration. The cell's perception of the biophysical microenvironment (mechanosensing) leads to altered gene expression or contractility status (mechanotransduction). Mechanosensing and mechanotransduction have profound implications in both tissue homeostasis and cancer. Many solid tumours are surrounded by a dense and aberrant ECM that disturbs normal cell functions and makes certain areas of the tumour inaccessible to therapeutic drugs. Understanding the cell-ECM interplay may therefore lead to novel and more effective therapies. Controllable and reproducible cell culturing systems mimicking the ECM enable detailed investigation of mechanosensing and mechanotransduction pathways. Here, we discuss ECM biomimetic systems. Mainly focusing on collagen, we compare and contrast structural and molecular complexity as well as biophysical properties of simple 2D substrates, 3D fibrillar collagen gels, cell-derived matrices and complex decellularized organs. Finally, we emphasize how the integration of advanced methodologies and computational methods with collagen-based biomimetics will improve the design of novel therapies aimed at targeting the biophysical and mechanical features of the tumour ECM to increase therapy efficacy.
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12
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Li X, Sun X, Kan C, Chen B, Qu N, Hou N, Liu Y, Han F. COL1A1: A novel oncogenic gene and therapeutic target in malignancies. Pathol Res Pract 2022; 236:154013. [PMID: 35816922 DOI: 10.1016/j.prp.2022.154013] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 06/28/2022] [Accepted: 07/04/2022] [Indexed: 02/07/2023]
Abstract
Collagen type I alpha 1 (COL1A1), a member of the collagen family, is involved in epithelial-mesenchymal transition, which is closely linked to malignant tumorigenesis. COL1A1 is highly expressed in various cancers and regulates various cellular processes, including cell proliferation, metastasis, apoptosis, and cisplatin resistance. COL1A1 is also associated with cancer progression and prognosis; elevated COL1A1 expression is associated with poor prognosis in cancer patients. However, the main role of COL1A as a cancer-promoting factor in specific tumors has not been reported. Additionally, the protein levels and mechanisms of action of this protein differ among tumor types. This review discusses current research progress concerning COL1A1 in different tumor types, and then summarizes its contributions to cancer progression, thus providing a basis for follow-up research and potential targets for cancer treatment.
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Affiliation(s)
- Xue Li
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China; Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China; Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, and Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China; Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, and Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China; Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, and Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Bing Chen
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China; Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China; Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, and Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Na Qu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China; Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China; Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, and Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China; Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, and Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yongping Liu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China; Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, and Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
| | - Fang Han
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China; Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China; Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, and Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
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13
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The Synergistic Cooperation between TGF-β and Hypoxia in Cancer and Fibrosis. Biomolecules 2022; 12:biom12050635. [PMID: 35625561 PMCID: PMC9138354 DOI: 10.3390/biom12050635] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 03/10/2022] [Accepted: 04/14/2022] [Indexed: 12/24/2022] Open
Abstract
Transforming growth factor β (TGF-β) is a multifunctional cytokine regulating homeostasis and immune responses in adult animals and humans. Aberrant and overactive TGF-β signaling promotes cancer initiation and fibrosis through epithelial–mesenchymal transition (EMT), as well as the invasion and metastatic growth of cancer cells. TGF-β is a key factor that is active during hypoxic conditions in cancer and is thereby capable of contributing to angiogenesis in various types of cancer. Another potent role of TGF-β is suppressing immune responses in cancer patients. The strong tumor-promoting effects of TGF-β and its profibrotic effects make it a focus for the development of novel therapeutic strategies against cancer and fibrosis as well as an attractive drug target in combination with immune regulatory checkpoint inhibitors. TGF-β belongs to a family of cytokines that exert their function through signaling via serine/threonine kinase transmembrane receptors to intracellular Smad proteins via the canonical pathway and in combination with co-regulators such as the adaptor protein and E3 ubiquitin ligases TRAF4 and TRAF6 to promote non-canonical pathways. Finally, the outcome of gene transcription initiated by TGF-β is context-dependent and controlled by signals exerted by other growth factors such as EGF and Wnt. Here, we discuss the synergistic cooperation between TGF-β and hypoxia in development, fibrosis and cancer.
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14
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Yoo YI, Ko KW, Cha SG, Park SY, Woo J, Han DK. Highly effective induction of cell-derived extracellular matrix by macromolecular crowding for osteogenic differentiation of mesenchymal stem cells. J IND ENG CHEM 2021. [DOI: 10.1016/j.jiec.2021.12.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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15
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Haller HL, Sander F, Popp D, Rapp M, Hartmann B, Demircan M, Nischwitz SP, Kamolz LP. Oxygen, pH, Lactate, and Metabolism-How Old Knowledge and New Insights Might Be Combined for New Wound Treatment. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57111190. [PMID: 34833408 PMCID: PMC8617754 DOI: 10.3390/medicina57111190] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/23/2021] [Accepted: 10/26/2021] [Indexed: 12/23/2022]
Abstract
Over time, we have come to recognize a very complex network of physiological changes enabling wound healing. An immunological process enables the body to distinguish damaged cells and begin a cleaning mechanism by separating damaged proteins and cells with matrix metalloproteinases, a complement reaction, and free radicals. A wide variety of cell functions help to rebuild new tissue, dependent on energy provision and oxygen supply. Like in an optimized “bio-reactor,” disturbance can lead to prolonged healing. One of the earliest investigated local factors is the pH of wounds, studied in close relation to the local perfusion, oxygen tension, and lactate concentration. Granulation tissue with the wrong pH can hinder fibroblast and keratinocyte division and proliferation, as well as skin graft takes. Methods for influencing the pH have been tested, such as occlusion and acidification by the topical application of acidic media. In most trials, this has not changed the wound’s pH to an acidic one, but it has reduced the strong alkalinity of deeper or chronic wounds. Energy provision is essential for all repair processes. New insights into the metabolism of cells have changed the definition of lactate from a waste product to an indispensable energy provider in normoxic and hypoxic conditions. Neovascularization depends on oxygen provision and lactate, signaling hypoxic conditions even under normoxic conditions. An appropriate pH is necessary for successful skin grafting; hypoxia can change the pH of wounds. This review describes the close interconnections between the local lactate levels, metabolism, healing mechanisms, and pH. Furthermore, it analyzes and evaluates the different possible ways to support metabolism, such as lactate enhancement and pH adjustment. The aim of wound treatment must be the optimization of all these components. Therefore, the role of lactate and its influence on wound healing in acute and chronic wounds will be assessed.
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Affiliation(s)
| | - Frank Sander
- Burn Center, Plastic Surgery of Trauma Hospital Berlin, Warener Strasse 7, 12683 Berlin, Germany; (F.S.); (B.H.)
| | - Daniel Popp
- Department of Surgery, Division of Plastic, Aesthetic and Reconstructive Surgery, Medical University Graz, Auenbruggerplatz 29, 8036 Graz, Austria; (D.P.); (S.P.N.); (L.P.K.)
| | - Matthias Rapp
- Clinic for Orthopedics, Trauma Surgery and Sports Traumatology, Burn Center, Marienhospital Stuttgart, Böheimstraße 37, 70199 Stuttgart, Germany;
| | - Bernd Hartmann
- Burn Center, Plastic Surgery of Trauma Hospital Berlin, Warener Strasse 7, 12683 Berlin, Germany; (F.S.); (B.H.)
| | - Mehmet Demircan
- Pediatric Intensive Burn Care Unit, Department of Pediatric Surgery, Faculty of Medicine, İnönü University, 44315 Malatya, Turkey;
| | - Sebastian Philipp Nischwitz
- Department of Surgery, Division of Plastic, Aesthetic and Reconstructive Surgery, Medical University Graz, Auenbruggerplatz 29, 8036 Graz, Austria; (D.P.); (S.P.N.); (L.P.K.)
- COREMED—Cooperative Centre for Regenerative Medicine, JOANNEUM RESEARCH Forschungsgsellschaft mbH, 8036 Graz, Austria
| | - Lars Peter Kamolz
- Department of Surgery, Division of Plastic, Aesthetic and Reconstructive Surgery, Medical University Graz, Auenbruggerplatz 29, 8036 Graz, Austria; (D.P.); (S.P.N.); (L.P.K.)
- COREMED—Cooperative Centre for Regenerative Medicine, JOANNEUM RESEARCH Forschungsgsellschaft mbH, 8036 Graz, Austria
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16
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Ntentakis DP, Ntentaki AM, Delavogia E, Kalomoiris L, Venieri D, Arkadopoulos N, Kalogerakis N. Dissolved oxygen technologies as a novel strategy for non-healing wounds: A critical review. Wound Repair Regen 2021; 29:1062-1079. [PMID: 34655455 DOI: 10.1111/wrr.12972] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/14/2021] [Accepted: 09/09/2021] [Indexed: 02/07/2023]
Abstract
Non-healing wounds are steadily becoming a global-health issue. Prolonged hypoxia propagates wound chronicity; yet, oxygenating treatments are considered inadequate to date. Dissolved oxygen (DO) in aqueous solutions introduces a novel approach to enhanced wound oxygenation, and is robustly evaluated for clinical applications. A systematic literature search was conducted, whereby experimental and clinical studies of DO technologies were categorized per engineering approach. Technical principles, methodology, endpoints and outcomes were analysed for both oxygenating and healing effects. Forty articles meeting our inclusion criteria were grouped as follows: DO solutions (17), oxygen (O2 ) dressings (9), O2 hydrogels (11) and O2 emulsions (3). All technologies improved wound oxygenation, each to a variable degree. They also achieved at least one statistically significant outcome related to wound healing, mainly in epithelialization, angiogenesis and collagen synthesis. Scarcity in clinical data and methodological variability precluded quantitative comparisons among the biotechnologies studied. DO technologies warrantee further evaluation for wound oxygenation in the clinical setting. Standardised methodologies and targeted research questions are pivotal to facilitate global integration in healthcare.
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Affiliation(s)
- Dimitrios P Ntentakis
- School of Chemical and Environmental Engineering, Technical University of Crete, Chania, Greece
| | | | - Eleni Delavogia
- Department of Paediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Loukas Kalomoiris
- Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Danae Venieri
- School of Chemical and Environmental Engineering, Technical University of Crete, Chania, Greece
| | - Nikolaos Arkadopoulos
- Fourth Department of Surgery, Faculty of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Nicolas Kalogerakis
- School of Chemical and Environmental Engineering, Technical University of Crete, Chania, Greece
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17
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Shen C, Jiang Y, Li Q, Liu C, Hu F, Li M. Bone morphogenetic protein-7 inhibits endothelial-to-mesenchymal transition in primary human umbilical vein endothelial cells and mouse model of systemic sclerosis via Akt/mTOR/p70S6K pathway. J Dermatol Sci 2021; 103:82-92. [PMID: 34266726 DOI: 10.1016/j.jdermsci.2021.06.009] [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: 02/03/2021] [Revised: 06/14/2021] [Accepted: 06/25/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Systemic sclerosis (SSc) is an autoimmune inflammatory and vascular disorder that causes tissue fibrosis of the skin and internal organs. Endothelial-to-mesenchymal transition (EndoMT) has been considered an important mechanism in the pathogenesis of vascular remodeling in SSc. Recent studies suggested that bone morphogenic protein 7 (BMP-7) has anti-fibrotic effects in several fibrotic diseases. OBJECTIVES To investigate the mechanism of BMP-7 in inhibiting TGF-β-induced EndoMT in systemic sclerosis (SSc). METHODS Skin tissues of both healthy controls and SSc patients were detected the distribution of BMP-7. TGF-β was applied to induce the EndoMT model of human umbilical vein endothelial cells (HUVECs), and bleomycin was used to established the SSc mouse model. After treatment of BMP-7, the protein levels of endothelial specific markers, mesenchymal cell products, transcription factors and Akt signal pathway were examined by western blotting, immunofluorescence or immunohistochemistry both in vivo and in vitro. RESULTS The expression of BMP-7 was decreased in the basal layer of epidermis and dermis of SSc patients. EndoMT in TGF-β-treated HUVECs and skins of SSc mouse model were markedly attenuated after treatment with rh-BMP-7. Moreover, Akt/mTOR/p70S6K phosphorylation was involved in EndoMT and BMP-7 suppressed TGF-β- or bleomycin-induced theses phosphorylation in HUVECs or SSc mouse model. CONCLUSION BMP-7 reduced the production of TGF-β-induced EndoMT in HUVECs and SSc mouse model through Akt/mTOR/p70S6K signaling pathway. These findings suggested that BMP-7 could be employed as a promising antifibrotic therapy for SSc.
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Affiliation(s)
- Chen Shen
- Department of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Jiang
- Department of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qiao Li
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chaofan Liu
- Department of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Feifei Hu
- Department of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming Li
- Department of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, China.
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18
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Raghunath M, Zeugolis DI. Transforming eukaryotic cell culture with macromolecular crowding. Trends Biochem Sci 2021; 46:805-811. [PMID: 33994289 DOI: 10.1016/j.tibs.2021.04.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/07/2021] [Accepted: 04/16/2021] [Indexed: 01/10/2023]
Abstract
In multicellular organisms, the intracellular and extracellular spaces are considerably packed with a diverse range of macromolecular species. Yet, standard eukaryotic cell culture is performed in dilute, and deprived of macromolecules culture media, that barely imitate the density and complex macromolecular composition of tissues. Essentially, we drown cells in a sea of media and then expect them to perform physiologically. Herein, we argue the use of macromolecular crowding (MMC) in eukaryotic cell culture for regenerative medicine and drug discovery purposes.
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Affiliation(s)
- Michael Raghunath
- Center for Cell Biology and Tissue Engineering, Institute for Chemistry and Biotechnology, Zurich University of Applied Sciences, Wädenswil, Switzerland
| | - Dimitrios I Zeugolis
- Regenerative, Modular, and Developmental Engineering Laboratory (REMODEL), National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway (NUI Galway), Galway, Ireland; Regenerative, Modular, and Developmental Engineering Laboratory (REMODEL), Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland; Regenerative, Modular, and Developmental Engineering Laboratory (REMODEL), School of Mechanical and Materials Engineering, University College Dublin (UCD), Dublin, Ireland.
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19
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Scaffold-free cell-based tissue engineering therapies: advances, shortfalls and forecast. NPJ Regen Med 2021; 6:18. [PMID: 33782415 PMCID: PMC8007731 DOI: 10.1038/s41536-021-00133-3] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 02/24/2021] [Indexed: 02/01/2023] Open
Abstract
Cell-based scaffold-free therapies seek to develop in vitro organotypic three-dimensional (3D) tissue-like surrogates, capitalising upon the inherent capacity of cells to create tissues with efficiency and sophistication that is still unparalleled by human-made devices. Although automation systems have been realised and (some) success stories have been witnessed over the years in clinical and commercial arenas, in vitro organogenesis is far from becoming a standard way of care. This limited technology transfer is largely attributed to scalability-associated costs, considering that the development of a borderline 3D implantable device requires very high number of functional cells and prolonged ex vivo culture periods. Herein, we critically discuss advancements and shortfalls of scaffold-free cell-based tissue engineering strategies, along with pioneering concepts that have the potential to transform regenerative and reparative medicine.
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20
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Morimoto C, Takedachi M, Kawasaki K, Shimomura J, Murata M, Hirai A, Kawakami K, Sawada K, Iwayama T, Murakami S. Hypoxia stimulates collagen hydroxylation in gingival fibroblasts and periodontal ligament cells. J Periodontol 2021; 92:1635-1645. [PMID: 33660864 DOI: 10.1002/jper.20-0670] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/03/2021] [Accepted: 02/24/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Cellular responses to hypoxia regulate various biological events, including angiogenesis and extracellular matrix metabolism. Collagen is a major component of the extracellular matrix in periodontal tissues and its coordinated production is essential for tissue homeostasis. In this study, we investigated the effects of hypoxia on collagen production in human gingival fibroblasts (HGFs) and human periodontal ligament cells (HPDLs). METHODS HGFs and HPDLs were cultured under either normoxic (20% O2 ) or hypoxic (1% O2 ) conditions. Nuclear expression of hypoxia-inducible factor-1α (HIF-1α) was determined by western blotting. Peri-cellular expression of type I collagen was examined by immunocytochemistry analysis. Synthesis of type I collagen was evaluated by measuring the concentration of procollagen type I C-peptide (PIP) in culture supernatant using enzyme-linked immunosorbent assay. Expression of collagen hydroxylase enzymes prolyl 4-hydroxylase alpha polypeptide 1 (P4HA1) and 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was determined by RT-qPCR and western blotting. The roles of these enzymes were analyzed using siRNA transfection. RESULTS Cultivation under hypoxic conditions stimulated type I collagen production via HIF-1α in both cell types. Interestingly, hypoxic conditions did not affect collagen 1a1 or 1a2 gene expression but upregulated that of P4HA1 and PLOD2. Additionally, suppressing P4HA1 significantly decreased the levels of hypoxia-induced procollagen type I C-peptide, a product of stable triple helical collagen, in the supernatant. In contrast, PLOD2 suppression decreased cross-linked collagen expression in the pericellular region. CONCLUSION Our results suggest that hypoxia activates collagen synthesis in HGFs and HPDLs by upregulating hydroxylases P4HA1 and PLOD2 in an HIF-1α-dependent manner.
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Affiliation(s)
- Chiaki Morimoto
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Masahide Takedachi
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Kohsuke Kawasaki
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Junpei Shimomura
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Mari Murata
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Asae Hirai
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Kazuma Kawakami
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Keigo Sawada
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Tomoaki Iwayama
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Shinya Murakami
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
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21
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Guo W, Yin G, Liu H, Duan H, Huang Z. Analysis of vascular-associated factors and the prognosis of poorly differentiated hypopharyngeal carcinoma. Oncol Lett 2020; 20:271. [PMID: 32989405 PMCID: PMC7517535 DOI: 10.3892/ol.2020.12134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 07/08/2020] [Indexed: 01/18/2023] Open
Abstract
The aim of the present study was to analyze the characteristics of angiogenic factors in patients with hypopharyngeal cancer, and to study the effects of these factors on induction chemotherapy, patient prognosis and survival. Data from 60 eligible patients with hypopharyngeal cancer that were treated between January 2012 and December 2016 were collected retrospectively. The differential expression of angiogenic factors in tumor and peritumoral tissues was analyzed retrospectively to assess the association between five differentially expressed genes, including interleukin (IL)-1β, transforming growth factor (TGF)-β, matrix metalloproteinase-9 (MMP-9), angiopoietin-2 and interferon-inducible T-cell α chemoattractant, and clinicopathological characteristics in different types of chemotherapy-associated blood vessels within samples of poorly differentiated hypopharyngeal cancer. The χ2 test or t-test was used to compare the frequency data, the Kaplan-Meier method was used for survival analysis and the log-rank test was used to compare the Kaplan-Meier curves. P<0.05 was considered to indicate a statistically significant difference. The results of the present study demonstrated that there was a significant difference in the expression levels of vascular-associated factors between hypopharyngeal carcinoma and peritumoral tissues. Additionally, the results revealed a significant difference in the overall survival and prognosis of patients with a decreased vascular classification compared with patients with an unchanged vascular classification, which was assessed using narrowband imaging (NBI) following induction chemotherapy (P<0.05). The results of single factor analysis indicated that IL-1β, TGF-β and MMP-9 were associated with decreased blood vessel classification (P<0.05). In conclusion, IL-1β, TGF-β and MMP-9 may be used as predictors of the effect of induction chemotherapy on poorly differentiated hypopharyngeal cancer. Therefore, when patients with advanced hypopharyngeal cancer undergo chemotherapy, NBI vascular examination and screening for associated vascular factors should be performed before and after chemotherapy. Alterations in vascular classification, assessed using NBI, and abnormal expression of vascular factors may also be used as reference factors for prognosis.
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Affiliation(s)
- Wei Guo
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China
| | - Gaofei Yin
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China
| | - Hongfei Liu
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China
| | - Hanyuan Duan
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China
| | - Zhigang Huang
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China
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22
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Wang Y, Guerrero-Juarez CF, Qiu Y, Du H, Chen W, Figueroa S, Plikus MV, Nie Q. A multiscale hybrid mathematical model of epidermal-dermal interactions during skin wound healing. Exp Dermatol 2020; 28:493-502. [PMID: 30801791 DOI: 10.1111/exd.13909] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 02/13/2019] [Indexed: 12/18/2022]
Abstract
Following injury, skin activates a complex wound healing programme. While cellular and signalling mechanisms of wound repair have been extensively studied, the principles of epidermal-dermal interactions and their effects on wound healing outcomes are only partially understood. To gain new insight into the effects of epidermal-dermal interactions, we developed a multiscale, hybrid mathematical model of skin wound healing. The model takes into consideration interactions between epidermis and dermis across the basement membrane via diffusible signals, defined as activator and inhibitor. Simulations revealed that epidermal-dermal interactions are critical for proper extracellular matrix deposition in the dermis, suggesting these signals may influence how wound scars form. Our model makes several theoretical predictions. First, basal levels of epidermal activator and inhibitor help to maintain dermis in a steady state, whereas their absence results in a raised, scar-like dermal phenotype. Second, wound-triggered increase in activator and inhibitor production by basal epidermal cells, coupled with fast re-epithelialization kinetics, reduces dermal scar size. Third, high-density fibrin clot leads to a raised, hypertrophic scar phenotype, whereas low-density fibrin clot leads to a hypotrophic phenotype. Fourth, shallow wounds, compared to deep wounds, result in overall reduced scarring. Taken together, our model predicts the important role of signalling across dermal-epidermal interface and the effect of fibrin clot density and wound geometry on scar formation. This hybrid modelling approach may be also applicable to other complex tissue systems, enabling the simulation of dynamic processes, otherwise computationally prohibitive with fully discrete models due to a large number of variables.
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Affiliation(s)
- Yangyang Wang
- NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California.,Center for Complex Biological Systems, University of California, Irvine, Irvine, California.,Department of Mathematics, University of California, Irvine, Irvine, California
| | - Christian F Guerrero-Juarez
- NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California.,Center for Complex Biological Systems, University of California, Irvine, Irvine, California.,Department of Mathematics, University of California, Irvine, Irvine, California.,Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, California.,Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California
| | - Yuchi Qiu
- NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California.,Center for Complex Biological Systems, University of California, Irvine, Irvine, California.,Department of Mathematics, University of California, Irvine, Irvine, California
| | - Huijing Du
- Department of Mathematics, University of Nebraska-Lincoln, Lincoln, Nebraska
| | - Weitao Chen
- Department of Mathematics, University of California, Riverside, Riverside, California
| | - Seth Figueroa
- NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California.,Center for Complex Biological Systems, University of California, Irvine, Irvine, California.,Department of Mathematics, University of California, Irvine, Irvine, California
| | - Maksim V Plikus
- NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California.,Center for Complex Biological Systems, University of California, Irvine, Irvine, California.,Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, California.,Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California
| | - Qing Nie
- NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California.,Center for Complex Biological Systems, University of California, Irvine, Irvine, California.,Department of Mathematics, University of California, Irvine, Irvine, California.,Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California
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23
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Shen AH, Borrelli MR, Adem S, Deleon NMD, Patel RA, Mascharak S, Yen SJ, Sun BY, Taylor WL, Januszyk M, Nguyen DH, Momeni A, Gurtner GC, Longaker MT, Wan DC. Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis. Sci Rep 2020; 10:12346. [PMID: 32704071 PMCID: PMC7378074 DOI: 10.1038/s41598-020-69293-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 07/06/2020] [Indexed: 12/22/2022] Open
Abstract
Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.
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Affiliation(s)
- Abra H Shen
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Mimi R Borrelli
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Sandeep Adem
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Nestor M Diaz Deleon
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Ronak A Patel
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Shamik Mascharak
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Sara J Yen
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Blake Y Sun
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Walter L Taylor
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Michael Januszyk
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Dung H Nguyen
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Arash Momeni
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Geoffrey C Gurtner
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
| | - Michael T Longaker
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Derrick C Wan
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA.
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Zhang G, Du Y, Sun N, Sun Y, Zhang L, Li X, Li X. Ulinastatin enhances autophagy against radiation-induced lung injury in mice. Transl Cancer Res 2020; 9:4162-4172. [PMID: 35117785 PMCID: PMC8798660 DOI: 10.21037/tcr-19-3018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 06/12/2020] [Indexed: 01/09/2023]
Abstract
Background To investigate the enhancement of autophagy by ulinastatin for protecting against radiation-induced lung injury (RILI) in mice. Methods Forty C57BL/6 mice were equally divided into (I) control (C), (II) irradiation (R), (III) ulinastatin (U), (IV) 3-methyladenine (3-MA) (M), and (V) ulinastatin plus 3-MA (U+M) groups. Three mice in each group were infected with adeno-associated virus (AAV) carrying green fluorescent protein (GFP)-1A/1B-light chain 3 (GFP-LC3) in the lung for the marker of autophagy. All mice in R, U, M and U+M groups were given chest irradiation (1 Gy/min, 12 min), following injection with normal saline in C and U groups, ulinastatin (500,000 IU/kg·d, i.p., 7 d) in U group, 3-MA (10 mg/kg·d, i.p., 7 d) in M group, and ulinastatin plus 3-MA in U+M group. The effects of ulinastatin on lung injury and autophagy were evaluated by electron microscope (EM), immunohistochemistry, mRNA expression levels of collagen alpha-1 (COL1A1), collagen alpha-2 (COL1A2), α-smooth muscle actin (α-SMA) and transforming growth factor β1 (TGF-β1), and protein levels of LC3, α-SMA, COL1A2, TGF-β1, matrix metalloproteinase-2 (MMP-2) and MMP-9. Results EM observation revealed that the radiation caused the injury of type I and II alveolar epithelial cells, which was improved by ulinastatin treatment associated with increased the numbers of autophagosomes. GFP-LC3 signals was significantly enhanced by ulinastatin detected by immune histochemical tests. At transcriptional and/or translational levels, ulinastatin significantly enhanced the expression levels of TGF-β1 and LC3 but reduced COL1A1, COL1A2, α-SMA, MMP-2 and MMP-9 after radiation-induced RILI. Conclusions Ulinastatin reduces RILI by enhancing autophagy, which might be a potential therapeutic drug in the protection against RILI.
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Affiliation(s)
- Guoxing Zhang
- Department of Intensive Care Unit, Jilin Cancer Hospital, Changchun, China
| | - Yujun Du
- Department of Kidney, The First Hospital of Jilin University, Changchun, China
| | - Ni Sun
- Department of Intensive Care Unit, Jilin Cancer Hospital, Changchun, China
| | - Yu Sun
- Department of Intensive Care Unit, Jilin Cancer Hospital, Changchun, China
| | - Liying Zhang
- Department of Intensive Care Unit, Jilin Cancer Hospital, Changchun, China
| | - Xiaohua Li
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, China
| | - Xiujiang Li
- Department of Intensive Care Unit, Jilin Cancer Hospital, Changchun, China
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Jia R, Wang C. MiR-29b-3p Reverses Cisplatin Resistance by Targeting COL1A1 in Non-Small-Cell Lung Cancer A549/DDP Cells. Cancer Manag Res 2020; 12:2559-2566. [PMID: 32368137 PMCID: PMC7170551 DOI: 10.2147/cmar.s246625] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 03/16/2020] [Indexed: 12/14/2022] Open
Abstract
Objective To investigate the expression of miR-29b-3p in tissues and cells of non-small-cell lung cancer (NSCLC) and its effect on cisplatin resistance in NSCLC cells and its mechanism. Methods The mRNA expression of miR-29b-3p and COL1A1 in NSCLC tissue, cell line A549 and cisplatin-resistant cell line A549/DDP was detected by RT-qPCR. MiR-29b-3p Mimics was transfected into A549/DDP cells, and the cell viability, proliferation, apoptosis and related protein expression were detected by CCK-8, flow cytometry and Western blot. Also, luciferase reporter gene assay was used to verify the targeting relationship between miR-29b-3p and COL1A1. Moreover, COL1A1 overexpression lentivirus and miR-29b-3p mimics (Mimics+COL1A1) were simultaneously transfected into A549/DDP cells, and then the cell viability and related protein expression were measured. Results In NSCLC tissue and its cell line, miR-29b-3p was downregulated and COL1A1 was upregulated (P<0.05). After A549/DDP cell was transfected by mimics, its cell viability and proliferation rate decreased, apoptosis rate and the expression of tumor suppressor gene PTEN and apoptosis-related protein BAX were increased (P<0.05), which could be reversed by Mimics+COL1A1 co-transfection. Luciferase reporter gene assay indicated that COL1A1 was the target gene of miR-29b-3p. Conclusion All in all, miR-29b-3p can reverse the cisplatin resistance of A549/DDP cells by inhibiting the expression of COL1A1 gene and increasing the expression of PTEN and BAX.
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Affiliation(s)
- Rui Jia
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin 300000, People's Republic of China.,Department of Thoracic Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, People's Republic of China
| | - Changli Wang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin 300000, People's Republic of China
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Tuning mPEG-PLA/vitamin E-TPGS-based mixed micelles for combined celecoxib/honokiol therapy for breast cancer. Eur J Pharm Sci 2020; 146:105277. [DOI: 10.1016/j.ejps.2020.105277] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 01/13/2020] [Accepted: 02/21/2020] [Indexed: 12/24/2022]
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Tsiapalis D, De Pieri A, Spanoudes K, Sallent I, Kearns S, Kelly JL, Raghunath M, Zeugolis DI. The synergistic effect of low oxygen tension and macromolecular crowding in the development of extracellular matrix-rich tendon equivalents. Biofabrication 2020; 12:025018. [PMID: 31855856 DOI: 10.1088/1758-5090/ab6412] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cellular therapies play an important role in tendon tissue engineering, with tenocytes being the most prominent and potent cell population available. However, for the development of a rich extracellular matrix tenocyte-assembled tendon equivalent, prolonged in vitro culture is required, which is associated with phenotypic drift. Recapitulation of tendon tissue microenvironment in vitro with cues that enhance and accelerate extracellular matrix synthesis and deposition, whilst maintaining tenocyte phenotype, may lead to functional cell therapies. Herein, we assessed the synergistic effect of low oxygen tension (enhances extracellular matrix synthesis) and macromolecular crowding (enhances extracellular matrix deposition) in human tenocyte culture. Protein analysis demonstrated that human tenocytes at 2% oxygen tension and with 50 μg ml-1 carrageenan (macromolecular crowder used) significantly increased synthesis and deposition of collagen types I, III, V and VI. Gene analysis at day 7 illustrated that human tenocytes at 2% oxygen tension and with 50 μg ml-1 carrageenan significantly increased the expression of prolyl 4-hydroxylase subunit alpha 1, procollagen-lysine 2- oxoglutarate 5-dioxygenase 2, scleraxis, tenomodulin and elastin, whilst chondrogenic (e.g. runt-related transcription factor 2, cartilage oligomeric matrix protein, aggrecan) and osteogenic (e.g. secreted phosphoprotein 1, bone gamma-carboxyglutamate protein) trans-differentiation markers were significantly down-regulated or remained unchanged. Collectively, our data clearly illustrates the beneficial synergistic effect of low oxygen tension and macromolecular crowding in the accelerated development of tissue equivalents.
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Affiliation(s)
- Dimitrios Tsiapalis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland. Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
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Miura Y, Hayakawa A, Kikuchi S, Tsumoto H, Umezawa K, Chiba Y, Soejima Y, Sawabe M, Fukui K, Akimoto Y, Endo T. Fumarate accumulation involved in renal diabetic fibrosis in Goto-Kakizaki rats. Arch Biochem Biophys 2019; 678:108167. [PMID: 31704098 DOI: 10.1016/j.abb.2019.108167] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/31/2019] [Accepted: 11/02/2019] [Indexed: 01/01/2023]
Abstract
The Goto-Kakizaki (GK) rat is a spontaneous animal model of type 2 diabetes and early stage of diabetic nephropathy. However, the pathophysiological mechanisms contributing to the progression of diabetic nephropathy in GK rats remain unclear. Kidneys from 15-week old male diabetic GK/Jcl rats and age-matched Wistar rats, which have the same genetic background as GK rats, were used. Proteomic analyses of GK and Wistar kidneys were performed using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Differentially expressed proteins in GK rats were subjected to pathway analysis, and expression levels of hypoxia inducible factor 1α (HIF-1α) and transforming growth factor-β1 (TGF-β1), and fumarate accumulation in GK kidneys were examined. Azan staining and immunohistochemical staining of α-smooth muscle actin were performed in relation to fibrosis in GK kidneys. Proteomic analysis using 2D-DIGE, analysis of fumarate content, and expression analysis of HIF-1α, TGF-β1, and α-smooth muscle actin of GK rat's kidney, suggested the mechanism of fibrosis characterized as two stages in diabetic nephropathy of GK rats. Abnormalities of glucose metabolism such as elevated levels of 2-oxoglutarate dehydrogenase and reduction of fumarate hydratase caused the accumulation of fumarate followed by the upregulation of HIF-1α and TGF-β1 leading to fibrosis in diabetic nephropathy. Alterations in proteins involved in the tricarboxylic acid cycle are associated with fibrosis through fumarate accumulation in diabetic nephropathy of GK rats.
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Affiliation(s)
- Yuri Miura
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
| | - Atsuko Hayakawa
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan; Department of Bioscience and Engineering, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, 337-8570, Japan
| | - Shohei Kikuchi
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan; Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Hiroki Tsumoto
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Keitaro Umezawa
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Yuko Chiba
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Yurie Soejima
- Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Motoji Sawabe
- Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Koji Fukui
- Department of Bioscience and Engineering, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, 337-8570, Japan
| | - Yoshihiro Akimoto
- Department Anatomy, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
| | - Tamao Endo
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
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Borrelli MR, Shen AH, Lee GK, Momeni A, Longaker MT, Wan DC. Radiation-Induced Skin Fibrosis: Pathogenesis, Current Treatment Options, and Emerging Therapeutics. Ann Plast Surg 2019; 83:S59-S64. [PMID: 31513068 PMCID: PMC6746243 DOI: 10.1097/sap.0000000000002098] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Radiotherapy (RT) has become an indispensable part of oncologic treatment protocols for a range of malignancies. However, a serious adverse effect of RT is radiodermatitis; almost 95% of patients develop moderate to severe skin reactions following radiation treatment. In the acute setting, these can be erythema, desquamation, ulceration, and pain. Chronically, soft tissue atrophy, alopecia, and stiffness can be noted. Radiodermatitis can delay oncologic treatment protocols and significantly impair quality of life. There is currently a paucity of effective treatment options and prevention strategies for radiodermatitis. Importantly, recent preclinical and clinical studies have suggested that fat grafting may be of therapeutic benefit, reversing detrimental changes to soft tissue following RT. This review outlines the damaging effects of RT on the skin and soft tissue as well as discusses available treatment options for radiodermatitis. Emerging strategies to mitigate detrimental, chronic radiation-induced changes are also presented.
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Affiliation(s)
- Mimi R. Borrelli
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, California
| | - Abra H. Shen
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, California
| | - Gordon K. Lee
- Division of Plastic and Reconstructive Surgery, Stanford University Medical Center, Palo Alto, California
| | - Arash Momeni
- Division of Plastic and Reconstructive Surgery, Stanford University Medical Center, Palo Alto, California
| | - Michael T. Longaker
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, California
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California
| | - Derrick C. Wan
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, California
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Alcaraz J, Carrasco JL, Millares L, Luis IC, Fernández-Porras FJ, Martínez-Romero A, Diaz-Valdivia N, De Cos JS, Rami-Porta R, Seijo L, Ramírez J, Pajares MJ, Reguart N, Barreiro E, Monsó E. Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer. Lung Cancer 2019; 135:151-160. [PMID: 31446988 DOI: 10.1016/j.lungcan.2019.07.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 06/18/2019] [Accepted: 07/22/2019] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Tumor associated fibroblasts (TAFs) are essential contributors of the progression of non-small cell lung cancer (NSCLC). Most lung TAFs exhibit an activated phenotype characterized by the expression of α-SMA and fibrillar collagens. However, the prognostic value of these activation markers in NSCLC remains unclear. MATERIAL AND METHODS We conducted a quantitative image analysis of α-SMA immunostaining and picrosirius red staining of fibrillar collagens imaged by bright-field and polarized microscopy, respectively, using tissue microarrays with samples from 220 surgical patients, which elicited a percentage of positive staining area for each marker and patient. RESULTS Kaplan-Meier curves showed that all TAF activation markers were significantly associated with poor survival, and their prognostic value was independent of TNM staging as revealed by multivariate analysis, which elicited an adjusted increased risk of death after 3 years of 129% and 94% for fibrillar collagens imaged with bright-field (p = 0.004) and polarized light (p = 0.003), respectively, and of 89% for α-SMA (p = 0.009). We also found a significant association between all TAF activation markers and tumor necrosis, which is often indicative of hypoxia, supporting a pathologic link between tumor desmoplasia and necrosis/hypoxia. CONCLUSIONS Our findings identify patients with large histologic coverage of fibrillar collagens and α-SMA + TAFs to be at higher risk of recurrence and death, supporting that they could be considered for adjuvant therapy.
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Affiliation(s)
- Jordi Alcaraz
- Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
| | - Josep Lluís Carrasco
- Unit of Biostatistics, Department of Basic Clinical Practice, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Laura Millares
- CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Respiratory Medicine, Hospital Universitari Parc Taulí, Sabadell, Spain
| | - Iuliana-Cristiana Luis
- Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Francisco J Fernández-Porras
- Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Anabel Martínez-Romero
- CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Muscle Wasting and Cachexia in Chronic Respiratory Diseases and Lung Cancer, IMIM-Hospital del Mar, CEXS, UPF, PRBB, Barcelona, Spain
| | - Natalia Diaz-Valdivia
- Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Julio Sánchez De Cos
- CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Hospital San Pedro de Alcántara, Cáceres, Spain
| | - Ramon Rami-Porta
- CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Hospital Universitari Mutua Terrassa, Terrassa, Spain
| | - Luis Seijo
- Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Fundación Jímenez Díaz, Madrid, Spain
| | - Josep Ramírez
- Anatomopathology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - María José Pajares
- Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA) and CIBERONC, Pamplona, Spain
| | - Noemí Reguart
- Medical Oncology Department, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain
| | - Esther Barreiro
- CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Muscle Wasting and Cachexia in Chronic Respiratory Diseases and Lung Cancer, IMIM-Hospital del Mar, CEXS, UPF, PRBB, Barcelona, Spain
| | - Eduard Monsó
- CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Respiratory Medicine, Hospital Universitari Parc Taulí, Sabadell, Spain; Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
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Stechmiller JK, Lyon D, Schultz G, Gibson DJ, Weaver MT, Wilkie D, Ferrell AV, Whitney J, Kim J, Millan SB. Biobehavioral Mechanisms Associated With Nonhealing Wounds and Psychoneurologic Symptoms (Pain, Cognitive Dysfunction, Fatigue, Depression, and Anxiety) in Older Individuals With Chronic Venous Leg Ulcers. Biol Res Nurs 2019; 21:407-419. [PMID: 31142148 DOI: 10.1177/1099800419853881] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The prevalence and incidence of chronic venous leg ulcers (CVLUs) are increasing worldwide, as are the associated financial costs. Although it has long been known that their underlying etiology is venous insufficiency, the molecular aspects of healing versus nonhealing, as well as the psychoneurologic symptoms (PNS; pain, cognitive dysfunction, fatigue, depression, and anxiety) associated with CVLUs remain understudied. In this biobehaviorally focused review, we aim to elucidate the complex mechanisms that link the biological and molecular aspects of CLVUs with their PNS. Innovations in "omics" research have increased our understanding of important wound microenvironmental factors (e.g., inflammation, microbial pathogenic biofilm, epigenetic processes) that may adversely alter the wound bed's molecular milieu so that microbes evade immune detection. Although these molecular factors are not singularly responsible for wound healing, they are major components of wound development, nonhealing, and PNS that, until now, have not been amenable to systematic study, especially over time. Further, this review explores our current understanding of the molecular mechanisms by which the immune activation that contributes to the development and persistence of CVLUs also leads to the development, persistence, and severity of wound-related PNS. We also make recommendations for future research that will expand the field of biobehavioral wound science. Biobehavioral research that focuses on the interrelated mechanisms of PNS will lead to symptom-management interventions that improve quality of life for the population burdened by CVLUs.
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Affiliation(s)
- Joyce K Stechmiller
- 1 Department of Biobehavioral Nursing Science, College of Nursing, University of Florida, Gainesville, FL, USA
| | - Debra Lyon
- 2 College of Nursing, University of Florida, Gainesville, FL, USA
| | - Gregory Schultz
- 3 Department of Obstetrics and Gynecology, Institute for Wound Research, University of Florida, Gainesville, FL, USA
| | - Daniel J Gibson
- 3 Department of Obstetrics and Gynecology, Institute for Wound Research, University of Florida, Gainesville, FL, USA
| | - Michael T Weaver
- 2 College of Nursing, University of Florida, Gainesville, FL, USA
| | - Diana Wilkie
- 4 Center for Palliative Care Research and Education, University of Florida, Gainesville, FL, USA
| | | | - Joanne Whitney
- 5 School of Nursing, Harborview Medical Center, University of Washington, Seattle, WA, USA
| | - Junglyun Kim
- 2 College of Nursing, University of Florida, Gainesville, FL, USA
| | - Susan B Millan
- 6 UF Health Wound Care and Hyperbaric Center, Gainesville, FL, USA
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Cobalt-mediated multi-functional dressings promote bacteria-infected wound healing. Acta Biomater 2019; 86:465-479. [PMID: 30599244 DOI: 10.1016/j.actbio.2018.12.048] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/21/2018] [Accepted: 12/28/2018] [Indexed: 01/13/2023]
Abstract
Wound dressings with multiple functions are required to meet the complexity of the wound healing process. The multifunctionality often leads to an increase in the complexity and difficulty in dressing preparation. To surmount this problem, we used a facile preparation and fabrication process to fabricate a multi-functional dressing by integrating four widely accessible materials: plain gauze, sodium alginate (SA), Ca2+ and Co2+. Firstly, mixed Ca2+/Co2+ ion solutions with different concentration were applied to gauzes. After drying, SA solution was added to ionized gauze and Co2+-Ca2+/Gauze/SA (Ion-GSA) composite dressings were formed easily. In vitro results showed that all Ion-GSA dressings exhibited strong mechanical properties, uniform dispersion and sustained release of Ca2+ and Co2+, and the ability to retain moisture and absorb wound exudate. Besides the above advantages, dressings prepared with 0.25 g/L Co2+ and 4 g/L Ca2+ (Co2+0.25-Ca2+4 GSA composite dressings) exhibited the best overall effect for inducing a hypoxia-like response, and favorable cytocompatibility, hemostatic property and antibacterial activity. In vivo wound healing assays revealed that Co2+0.25-Ca2+4 GSA composite dressings inhibited bacterial growth, increased local Hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1) protein expression, and accelerated full-thickness skin wound healing in mouse bacterial-infected wound model. The quick healing wounds had improved angiogenesis, macrophages regulation, re-epithelialization and dense collagen deposition. Collectively, our results indicated that Co2+0.25-Ca2+4 GSA composite dressings promote wound healing. STATEMENT OF SIGNIFICANCE: Wound dressings with integrated functionalities are required to meet complex clinical requirements. However, there is often a trade-off between reducing preparation complexity and increasing the multifunctionality of the dressing's properties. In this study, we prepared multifunctional composite dressings by a facile preparation process using widely accessible materials. The composite dressings possessed the mechanical strength of gauze, had the effective wound exudate absorption, moisture maintenance and hemostatic property capacity of calcium alginate hydrogels, and had the hypoxia-like induction and the antimicrobial effects of Co2+. These functions all together promote bacteria-infected wound healing. Thus, we believed that the composite dressings can be widely applied in skin wound repair duo to their facile preparation method and good therapeutic effect.
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Fat Chance: The Rejuvenation of Irradiated Skin. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2019; 7:e2092. [PMID: 30881833 PMCID: PMC6416118 DOI: 10.1097/gox.0000000000002092] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 10/10/2018] [Indexed: 12/25/2022]
Abstract
Radiotherapy (RT) helps cure and palliate thousands of patients with a range of malignant diseases. A major drawback, however, is the collateral damage done to tissues surrounding the tumor in the radiation field. The skin and subcutaneous tissue are among the most severely affected regions. Immediately following RT, the skin may be inflamed, hyperemic, and can form ulcers. With time, the dermis becomes progressively indurated. These acute and chronic changes cause substantial patient morbidity, yet there are few effective treatment modalities able to reduce radiodermatitis. Fat grafting is increasingly recognized as a tool able to reverse the fibrotic skin changes and rejuvenate the irradiated skin. This review outlines the current progress toward describing and understanding the cellular and molecular effects of fat grafting in irradiated skin. Identification of the key factors involved in the pathophysiology of fibrosis following RT will inform therapeutic interventions to enhance its beneficial effects.
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Abstract
It is a tenet of modern biology that species adapt through natural selection to cope with the ever-changing environment. By comparing genetic variants between the island and mainland populations of a passerine, we inferred the related age of genetic variants across its entire genome and suggest that preexisting standing variants played the predominant role in local adaptation. Our findings not only resolve a long-standing fundamental problem in biology regarding the genetic sources of adaptation, but imply that the evolutionary potential of a population is highly associated with its preexisting genetic variation. What kind of genetic variation contributes the most to adaptation is a fundamental question in evolutionary biology. By resequencing genomes of 80 individuals, we inferred the origin of genomic variants associated with a complex adaptive syndrome involving multiple quantitative traits, namely, adaptation between high and low altitudes, in the vinous-throated parrotbill (Sinosuthora webbiana) in Taiwan. By comparing these variants with those in the Asian mainland population, we revealed standing variation in 24 noncoding genomic regions to be the predominant genetic source of adaptation. Parrotbills at both high and low altitudes exhibited signatures of recent selection, suggesting that not only the front but also the trailing edges of postglacial expanding populations could be subjected to environmental stresses. This study verifies and quantifies the importance of standing variation in adaptation in a cohort of genes, illustrating that the evolutionary potential of a population depends significantly on its preexisting genetic diversity. These findings provide important context for understanding adaptation and conservation of species in the Anthropocene.
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Sorushanova A, Delgado LM, Wu Z, Shologu N, Kshirsagar A, Raghunath R, Mullen AM, Bayon Y, Pandit A, Raghunath M, Zeugolis DI. The Collagen Suprafamily: From Biosynthesis to Advanced Biomaterial Development. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1801651. [PMID: 30126066 DOI: 10.1002/adma.201801651] [Citation(s) in RCA: 602] [Impact Index Per Article: 100.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 06/03/2018] [Indexed: 05/20/2023]
Abstract
Collagen is the oldest and most abundant extracellular matrix protein that has found many applications in food, cosmetic, pharmaceutical, and biomedical industries. First, an overview of the family of collagens and their respective structures, conformation, and biosynthesis is provided. The advances and shortfalls of various collagen preparations (e.g., mammalian/marine extracted collagen, cell-produced collagens, recombinant collagens, and collagen-like peptides) and crosslinking technologies (e.g., chemical, physical, and biological) are then critically discussed. Subsequently, an array of structural, thermal, mechanical, biochemical, and biological assays is examined, which are developed to analyze and characterize collagenous structures. Lastly, a comprehensive review is provided on how advances in engineering, chemistry, and biology have enabled the development of bioactive, 3D structures (e.g., tissue grafts, biomaterials, cell-assembled tissue equivalents) that closely imitate native supramolecular assemblies and have the capacity to deliver in a localized and sustained manner viable cell populations and/or bioactive/therapeutic molecules. Clearly, collagens have a long history in both evolution and biotechnology and continue to offer both challenges and exciting opportunities in regenerative medicine as nature's biomaterial of choice.
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Affiliation(s)
- Anna Sorushanova
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Luis M Delgado
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Zhuning Wu
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Naledi Shologu
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Aniket Kshirsagar
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Rufus Raghunath
- Centre for Cell Biology and Tissue Engineering, Competence Centre Tissue Engineering for Drug Development (TEDD), Department Life Sciences and Facility Management, Institute for Chemistry and Biotechnology (ICBT), Zürich University of Applied Sciences, Wädenswil, Switzerland
| | | | - Yves Bayon
- Sofradim Production-A Medtronic Company, Trevoux, France
| | - Abhay Pandit
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Michael Raghunath
- Centre for Cell Biology and Tissue Engineering, Competence Centre Tissue Engineering for Drug Development (TEDD), Department Life Sciences and Facility Management, Institute for Chemistry and Biotechnology (ICBT), Zürich University of Applied Sciences, Wädenswil, Switzerland
| | - Dimitrios I Zeugolis
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
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Modulation of Oxidative Status by Normoxia and Hypoxia on Cultures of Human Dermal Fibroblasts: How Does It Affect Cell Aging? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:5469159. [PMID: 30405877 PMCID: PMC6199889 DOI: 10.1155/2018/5469159] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/10/2018] [Accepted: 07/25/2018] [Indexed: 01/10/2023]
Abstract
Reactive oxygen species (ROS) production in the skin is among the highest compared to other organs, and a clear correlation exists between ROS production and skin aging. Many attempts are underway to reduce oxidative stress in the skin by topical treatment or supplementation with antioxidants/cosmeceuticals, and cultures of human dermal fibroblasts (HDF) are widely used for these studies. Here, we examined the influence of oxygen tension on cell aging in HDF and how this impacted ROS production, the enzymatic and nonenzymatic antioxidant response system, and the efficacy of this defense system in limiting DNA damage and in modulating gene expression of proteins involved in the extracellular matrix, linked to skin aging. We investigated a selection of parameters that represent and reflect the behavior of cellular responses to aging and oxygen tension. Serial passaging of HDF under normoxia (21%) and hypoxia (5%) leads to cell aging as confirmed by β-galactosidase activity, p16 expression, and proliferation rate. However, in HDF under 21% O2, markers of aging were significantly increased compared to those under 5% O2 at matched cell passages despite having lower levels of intracellular ROS and higher levels of CoQ10, total GSH, SOD1, SOD3, and mitochondrial superoxide anion. miRNA-181a, which is known to be upregulated in HDF senescence, was also analyzed, and indeed, its expression was significantly increased in old cells at 21% O2 compared to those at 5% O2. Upregulation of MMP1 and downregulation of COL1A1 along with increased DNA damage were also observed under 21% O2 vs 5% O2. The data highlight that chronic exposure to atmospheric 21% O2 is able to trigger hormetic adaptive responses in HDF that however fail, in the long term, to prevent cellular aging. This information could be useful in further investigating molecular mechanisms involved in adaptation of skin fibroblasts to oxidative stress and may provide useful hints in addressing antiaging strategies.
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Tartar DM, Chung L, Fiorentino DF. Clinical significance of autoantibodies in dermatomyositis and systemic sclerosis. Clin Dermatol 2018; 36:508-524. [DOI: 10.1016/j.clindermatol.2018.04.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Abstract
Activation of TGF-β1 initiates a program of temporary collagen accumulation important to wound repair in many organs. However, the outcome of temporary extracellular matrix strengthening all too frequently morphs into progressive fibrosis, contributing to morbidity and mortality worldwide. To avoid this maladaptive outcome, TGF-β1 signaling is regulated at numerous levels and intimately connected to feedback signals that limit accumulation. Here, we examine the current understanding of the core functions of TGF-β1 in promoting collagen accumulation, parallel pathways that promote physiological repair, and pathological triggers that tip the balance toward progressive fibrosis. Implicit in better understanding of these processes is the identification of therapeutic opportunities that will need to be further advanced to limit or reverse organ fibrosis.
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Affiliation(s)
- Kevin K Kim
- Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109
| | - Dean Sheppard
- Department of Medicine, Cardiovascular Research Institute, and Lung Biology Center, University of California, San Francisco, San Francisco, California 94143
| | - Harold A Chapman
- Department of Medicine, Cardiovascular Research Institute, and Lung Biology Center, University of California, San Francisco, San Francisco, California 94143
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Ohmaru-Nakanishi T, Asanoma K, Fujikawa M, Fujita Y, Yagi H, Onoyama I, Hidaka N, Sonoda K, Kato K. Fibrosis in Preeclamptic Placentas Is Associated with Stromal Fibroblasts Activated by the Transforming Growth Factor-β1 Signaling Pathway. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:683-695. [DOI: 10.1016/j.ajpath.2017.11.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 10/12/2017] [Accepted: 11/02/2017] [Indexed: 01/11/2023]
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40
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Liang Y, Idrees E, Andrews SHJ, Labib K, Szojka A, Kunze M, Burbank AD, Mulet-Sierra A, Jomha NM, Adesida AB. Plasticity of Human Meniscus Fibrochondrocytes: A Study on Effects of Mitotic Divisions and Oxygen Tension. Sci Rep 2017; 7:12148. [PMID: 28939894 PMCID: PMC5610182 DOI: 10.1038/s41598-017-12096-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 09/04/2017] [Indexed: 02/07/2023] Open
Abstract
Meniscus fibrochondrocytes (MFCs) may be the optimal cell source to repair non-healing meniscus injuries using tissue engineering strategies. In this study, we investigated the effects of mitotic divisions and oxygen tension on the plasticity of adult human MFCs. Our assessment techniques included gene expression, biochemical, histological, and immunofluorescence assays. MFCs were expanded in monolayer culture with combined growth factors TGFβ1 and FGF-2 (T1F2) under normoxia (21% O2). Trilineage (adipogenesis, chondrogenesis and osteogenesis) differentiation was performed under both normoxic (21% O2) and hypoxic (3% O2) conditions. The data demonstrated that MFCs with a mean total population doubling of 10 can undergo adipogenesis and chondrogenesis. This capability was enhanced under hypoxic conditions. The MFCs did not undergo osteogenesis. In conclusion, our findings suggest that extensively expanded human MFCs have the capacity to generate tissues with the functional matrix characteristics of avascular meniscus. To this end, expanded MFCs may be an ideal cell source for engineering functional constructs for the replacement or repair of avascular meniscus.
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Affiliation(s)
- Yan Liang
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
- Division of Burn and Reconstructive Surgery, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, People's Republic of China
| | - Enaam Idrees
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
| | - Stephen H J Andrews
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
| | - Kirollos Labib
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
| | - Alexander Szojka
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
| | - Melanie Kunze
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
| | - Andrea D Burbank
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
| | - Aillette Mulet-Sierra
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
| | - Nadr M Jomha
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada
| | - Adetola B Adesida
- University of Alberta, Department of Surgery, Divisions of Orthopaedic Surgery and Surgical Research, Edmonton, T6G 2E1, Canada.
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Kumar P, Satyam A, Cigognini D, Pandit A, Zeugolis DI. Low oxygen tension and macromolecular crowding accelerate extracellular matrix deposition in human corneal fibroblast culture. J Tissue Eng Regen Med 2017; 12:6-18. [PMID: 27592127 DOI: 10.1002/term.2283] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 07/30/2016] [Accepted: 08/26/2016] [Indexed: 12/13/2022]
Abstract
Development of implantable devices based on the principles of in vitro organogenesis has been hindered due to the prolonged time required to develop an implantable device. Herein we assessed the influence of serum concentration (0.5% and 10%), oxygen tension (0.5%, 2% and 20%) and macromolecular crowding (75 μg/ml carrageenan) in extracellular matrix deposition in human corneal fibroblast culture (3, 7 and 14 days). The highest extracellular matrix deposition was observed after 14 days in culture at 0.5% serum, 2% oxygen tension and 75 μg/ml carrageenan. These data indicate that low oxygen tension coupled with macromolecular crowding significantly accelerate the development of scaffold-free tissue-like modules. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Pramod Kumar
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland.,Centre for Research in Medical Devices (CÚRAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Abhigyan Satyam
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland.,Centre for Research in Medical Devices (CÚRAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Daniela Cigognini
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland.,Centre for Research in Medical Devices (CÚRAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Abhay Pandit
- Centre for Research in Medical Devices (CÚRAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Dimitrios I Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland.,Centre for Research in Medical Devices (CÚRAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
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42
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Quercetin Inhibits Pulmonary Arterial Endothelial Cell Transdifferentiation Possibly by Akt and Erk1/2 Pathways. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6147294. [PMID: 28428963 PMCID: PMC5385898 DOI: 10.1155/2017/6147294] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 02/18/2017] [Accepted: 02/23/2017] [Indexed: 12/20/2022]
Abstract
This study aimed to investigate the effects and mechanisms of quercetin on pulmonary arterial endothelial cell (PAEC) transdifferentiation into smooth muscle-like cells. TGF-β1-induced PAEC transdifferentiation models were applied to evaluate the pharmacological actions of quercetin. PAEC proliferation was detected with CCK8 method and BurdU immunocytochemistry. Meanwhile, the identification and transdifferentiation of PAECs were determined by FVIII immunofluorescence staining and α-SMA protein expression. The related mechanism was elucidated based on the levels of Akt and Erk1/2 signal pathways. As a result, quercetin effectively inhibited the TGF-β1-induced proliferation and transdifferentiation of the PAECs and activation of Akt/Erk1/2 cascade in the cells. In conclusion, quercetin is demonstrated to be effective for pulmonary arterial hypertension (PAH) probably by inhibiting endothelial transdifferentiation possibly via modulating Akt and Erk1/2 expressions.
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COL1A1, PRPF40A, and UCP2 correlate with hypoxia markers in non-small cell lung cancer. J Cancer Res Clin Oncol 2017; 143:1133-1141. [PMID: 28258342 PMCID: PMC5486546 DOI: 10.1007/s00432-017-2381-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/20/2017] [Indexed: 12/21/2022]
Abstract
Purpose Collagen 1A1 (COL1A1), RNA-binding and pre-mRNA Processing Factor (PRPF40A), and Uncoupling Protein 2 (UCP2) were identified as downstream effectors of cytoglobin (CYGB), which was shown implicated in tumour biology. Although these three genes have been previously associated with cancer, little is known about their status in lung malignancies. Methods Hereby, we investigated the expression and promoter methylation of COL1A1, PRPF40A, and UCP2 in 156 non-small cell lung cancer (NSCLC) and adjacent normal tissues. Results We demonstrate that COL1A1 and PRPF40A mRNAs are significantly overexpressed in NSCLC (p < 1 × 10−4), while UCP2 exhibits a trend of upregulation (p = 0.066). Only COL1A1 promoter revealed hypermethylation in NSCLCs (36%), which was particularly evident in squamous cell carcinomas (p = 0.024) and in the tumours with moderate-to-good differentiation (p = 0.01). Transcript level of COL1A1, as well as PRPF40A and UCP2, exhibited striking association (p ≤ 0.001) with the expression of hypoxia markers. In addition, we demonstrate in lung cancer cell lines exposed to hypoxia or oxidative stress that COL1A1 transcription significantly responds to oxygen depletion, while other genes showed the modest upregulation in stress conditions. Conclusion In conclusion, our data revealed that COL1A1, UCP2, and PRPF40A are novel players implicated in the complex network of hypoxia response in NSCLC.
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Satyam A, Kumar P, Cigognini D, Pandit A, Zeugolis DI. Low, but not too low, oxygen tension and macromolecular crowding accelerate extracellular matrix deposition in human dermal fibroblast culture. Acta Biomater 2016; 44:221-31. [PMID: 27506127 DOI: 10.1016/j.actbio.2016.08.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 07/31/2016] [Accepted: 08/05/2016] [Indexed: 12/17/2022]
Abstract
UNLABELLED A key challenge of in vitro organogenesis is the development in timely manner tissue equivalents. Herein, we assessed the simultaneous effect of oxygen tension (0.5%, 2% and 20%), foetal bovine serum concentration (0.5% and 10%) and macromolecular crowding (75μg/ml carrageenan) in human dermal fibroblast culture. Our data demonstrate that cells cultured at 2% oxygen tension, in the presence of carrageenan and at 0.5% serum concentration deposited within 3days in culture more extracellular matrix than cells grown for 14days, at 20% oxygen tension, 10% serum concentration and in the absence of carrageenan. These data suggest that optimal oxygen tension coupled with macromolecular crowding are important in vitro microenvironment modulators for accelerated development of tissue-like modules in vitro. STATEMENT OF SIGNIFICANCE To enable clinical translation and commercialisation of in vitro organogenesis therapies, we cultured human dermal fibroblast at 2% oxygen tension, under macromolecular crowding conditions (75μg/ml carrageenan) and at low foetal bovine serum concentration (0.5%). Within 3days in culture, more extracellular matrix was deposited under these conditions than cells grown for 14days, at 20% oxygen tension, 10% FBS concentration and in the absence of crowding agents. These data bring us closer to the development of more clinically relevant tissue-like modules.
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Affiliation(s)
- Abhigyan Satyam
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Pramod Kumar
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Daniela Cigognini
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Abhay Pandit
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Dimitrios I Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland.
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Duval E, Bouyoucef M, Leclercq S, Baugé C, Boumédiene K. Hypoxia inducible factor 1 alpha down-regulates type i collagen through Sp3 transcription factor in human chondrocytes. IUBMB Life 2016; 68:756-63. [PMID: 27521280 DOI: 10.1002/iub.1539] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 07/14/2016] [Indexed: 11/05/2022]
Abstract
Cartilage engineering is one challenging issue in regenerative medicine. Low oxygen tension or hypoxia inducible factor-1 (HIF-1α) gene therapy are promising strategies in the field of cartilage repair. Previously, we showed that hypoxia and its mediator HIF-1 regulate matrix genes expression (collagens and aggrecan). Here, we investigated the molecular mechanism involved in the regulation of type I collagen (COL1A1) by HIF-1 in human articular chondrocytes. We show that HIF-1α reduces COL1A1 transcription, through a distal promoter (-2300 to -1816 bp upstream transcription initiation site), containing two GC boxes that bind Sp transcription factors (Sp1/Sp3). Sp1 acts as a positive regulator but is not induced by HIF-1. COL1A1 inhibition caused by HIF-1 implies only Sp3, which accumulates and competes Sp1 binding on COL1A1 promoter. Additionally, Sp3 ectopic expression inhibits COL1A1, while Sp3 knockdown counteracts the downregulation of COL1A1 induced by HIF-1. In conclusion, we established a new regulatory model of COL1A1 regulation by HIF-1, and bring out its relationship with Sp3 transcription factor. In a fundamental level, these findings give insights in the mechanisms controlling COL1A1 gene expression. This may be helpful to improve strategies to impair type I collagen expression during chondrocyte differentiation for cartilage engineering. © 2016 IUBMB Life, 68(9):756-763, 2016.
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Affiliation(s)
- Elise Duval
- EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.,Normandie University, UFR de médecine, Caen, France
| | - Mouloud Bouyoucef
- EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.,Normandie University, UFR de médecine, Caen, France
| | - Sylvain Leclercq
- EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.,Normandie University, UFR de médecine, Caen, France.,Département De Chirurgie Orthopédique, Clinique Saint-Martin, Caen, 14000, France
| | - Catherine Baugé
- EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.,Normandie University, UFR de médecine, Caen, France.,Fédération Hospitalo Universitaire SURFACE, Amiens, Rouen, Caen, France
| | - Karim Boumédiene
- EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.,Normandie University, UFR de médecine, Caen, France.,Fédération Hospitalo Universitaire SURFACE, Amiens, Rouen, Caen, France
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Cheng Y, Lin CH, Chen JY, Li CH, Liu YT, Chen BC. Induction of Connective Tissue Growth Factor Expression by Hypoxia in Human Lung Fibroblasts via the MEKK1/MEK1/ERK1/GLI-1/GLI-2 and AP-1 Pathways. PLoS One 2016; 11:e0160593. [PMID: 27486656 PMCID: PMC4972311 DOI: 10.1371/journal.pone.0160593] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 07/21/2016] [Indexed: 01/25/2023] Open
Abstract
Several reports have indicated that hypoxia, GLI, and connective tissue growth factor (CTGF) contribute to pulmonary fibrosis in idiopathic pulmonary fibrosis. We investigated the participation of mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1)/MEK1/ERK1/GLI-1/2 and activator protein-1 (AP-1) signaling in hypoxia-induced CTGF expression in human lung fibroblasts. Hypoxia time-dependently increased CTGF expression, which was attenuated by the small interfering RNA (siRNA) of GLI-1 (GLI-1 siRNA) and GLI-2 (GLI-2 siRNA) in both human lung fibroblast cell line (WI-38) and primary human lung fibroblasts (NHLFs). Moreover, GLI-1 siRNA and GLI-2 siRNA attenuated hypoxia-induced CTGF-luciferase activity, and the treatment of cells with hypoxia induced GLI-1 and GLI-2 translocation. Furthermore, hypoxia-induced CTGF expression was reduced by an MEK inhibitor (PD98059), MEK1 siRNA, ERK inhibitor (U0126), ERK1 siRNA, and MEKK1 siRNA. Both PD98059 and U0126 significantly attenuated hypoxia-induced CTGF-luciferase activity. Hypoxia time-dependently increased MEKK1, ERK, and p38 MAPK phosphorylation. Moreover, SB203580 (a p38 MAPK inhibitor) also apparently inhibited hypoxia-induced CTGF expression. The treatment of cells with hypoxia induced ERK, GLI-1, or GLI-2 complex formation. Hypoxia-induced GLI-1 and GLI-2 translocation into the nucleus was significantly attenuated by U0126. In addition, hypoxia-induced ERK Tyr204 phosphorylation was impeded by MEKK1 siRNA. Moreover, hypoxia-induced CTGF-luciferase activity was attenuated by cells transfected with AP-1 site mutation in a CTGF construct. Exposure to hypoxia caused a time-dependent phosphorylation of c-Jun, but not of c-Fos. Chromatin immunoprecipitation (ChIP) revealed that hypoxia induced the recruitment of c-Jun, GLI-1, and GLI-2 to the AP-1 promoter region of CTGF. Hypoxia-treated cells exhibited an increase in α-smooth muscle actin (α-SMA) and collagen production, which was blocked by GLI-1 siRNA and GLI-2 siRNA. Overall, these data implied that the MEKK1/MEK1/ERK1/GLI-1/GLI-2, and AP-1 pathways mediated hypoxia-induced CTGF expression in human lung fibroblasts. Furthermore, GLI-1 and GLI-2 found to be involved in hypoxia-induced α-SMA and collagen expression.
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Affiliation(s)
- Yi Cheng
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chien-huang Lin
- Gradual Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jing-Yun Chen
- Gradual Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chien-Hua Li
- Gradual Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yu-Tin Liu
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Bing-Chang Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- * E-mail:
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47
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Yu W, Li Y, Wang Z, Liu L, Liu J, Ding F, Zhang X, Cheng Z, Chen P, Dou J. Transcriptomic changes in human renal proximal tubular cells revealed under hypoxic conditions by RNA sequencing. Int J Mol Med 2016; 38:894-902. [PMID: 27432315 DOI: 10.3892/ijmm.2016.2677] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 07/07/2016] [Indexed: 11/05/2022] Open
Abstract
Chronic hypoxia often occurs among patients with chronic kidney disease (CKD). Renal proximal tubular cells may be the primary target of a hypoxic insult. However, the underlying transcriptional mechanisms remain undefined. In this study, we revealed the global changes in gene expression in HK‑2 human renal proximal tubular cells under hypoxic and normoxic conditions. We analyzed the transcriptome of HK‑2 cells exposed to hypoxia for 24 h using RNA sequencing. A total of 279 differentially expressed genes was examined, as these genes could potentially explain the differences in HK‑2 cells between hypoxic and normoxic conditions. Moreover, 17 genes were validated by qPCR, and the results were highly concordant with the RNA seqencing results. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to better understand the functions of these differentially expressed genes. The upregulated genes appeared to be significantly enriched in the pathyway of extracellular matrix (ECM)-receptor interaction, and in paticular, the pathway of renal cell carcinoma was upregulated under hypoxic conditions. The downregulated genes were enriched in the signaling pathway related to antigen processing and presentation; however, the pathway of glutathione metabolism was downregulated. Our analysis revealed numerous novel transcripts and alternative splicing events. Simultaneously, we also identified a large number of single nucleotide polymorphisms, which will be a rich resource for future marker development. On the whole, our data indicate that transcriptome analysis provides valuable information for a more in depth understanding of the molecular mechanisms in CKD and renal cell carcinoma.
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Affiliation(s)
- Wenmin Yu
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Yiping Li
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhi Wang
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Lei Liu
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Jing Liu
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Fengan Ding
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Xiaoyi Zhang
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhengyuan Cheng
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Pingsheng Chen
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Jun Dou
- Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
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Rajangam T, Park MH, Kim SH. 3D Human Adipose-Derived Stem Cell Clusters as a Model for In Vitro Fibrosis. Tissue Eng Part C Methods 2016; 22:679-90. [DOI: 10.1089/ten.tec.2016.0037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Thanavel Rajangam
- Center for Biomaterials, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Min Hee Park
- Center for Biomaterials, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Sang-Heon Kim
- Center for Biomaterials, Korea Institute of Science and Technology, Seoul, Republic of Korea
- Depatment of Biomedical Engineering, University of Science and Technology, Daejon, Republic of Korea
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49
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Ventricular fibrogenesis activity assessed by serum levels of procollagen type III N-terminal amino peptide during the staged Fontan procedure. J Thorac Cardiovasc Surg 2016; 151:1518-26. [DOI: 10.1016/j.jtcvs.2016.01.020] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 12/23/2015] [Accepted: 01/11/2016] [Indexed: 01/06/2023]
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50
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Ashrafi M, Alonso-Rasgado T, Baguneid M, Bayat A. The efficacy of electrical stimulation in experimentally induced cutaneous wounds in animals. Vet Dermatol 2016; 27:235-e57. [DOI: 10.1111/vde.12328] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2016] [Indexed: 12/01/2022]
Affiliation(s)
- Mohammed Ashrafi
- Plastic and Reconstructive Surgery Research; Centre for Dermatological Research; Institute of Inflammation and Repair; University of Manchester; Oxford Road Manchester M13 9PT UK
| | - Teresa Alonso-Rasgado
- Bioengineering Group; School of Materials; University of Manchester; Oxford Road Manchester M13 9PT UK
| | - Mohamed Baguneid
- Wythenshawe Hospital; University Hospital South Manchester NHS Foundation Trust; Southmoor Road Manchester M23 9LT UK
| | - Ardeshir Bayat
- Plastic and Reconstructive Surgery Research; Centre for Dermatological Research; Institute of Inflammation and Repair; University of Manchester; Oxford Road Manchester M13 9PT UK
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