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Yarahmadi A, Dorri Giv M, Hosseininejad R, Rezaie A, Mohammadi N, Afkhami H, Farokhi A. Mesenchymal stem cells and their extracellular vesicle therapy for neurological disorders: traumatic brain injury and beyond. Front Neurol 2025; 16:1472679. [PMID: 39974358 PMCID: PMC11835705 DOI: 10.3389/fneur.2025.1472679] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 01/08/2025] [Indexed: 02/21/2025] Open
Abstract
Traumatic brain injury (TBI) is a complex condition involving mechanisms that lead to brain dysfunction and nerve damage, resulting in significant morbidity and mortality globally. Affecting ~50 million people annually, TBI's impact includes a high death rate, exceeding that of heart disease and cancer. Complications arising from TBI encompass concussion, cerebral hemorrhage, tumors, encephalitis, delayed apoptosis, and necrosis. Current treatment methods, such as pharmacotherapy with dihydropyridines, high-pressure oxygen therapy, behavioral therapy, and non-invasive brain stimulation, have shown limited efficacy. A comprehensive understanding of vascular components is essential for developing new treatments to improve blood vessel-related brain damage. Recently, mesenchymal stem cells (MSCs) have shown promising results in repairing and mitigating brain damage. Studies indicate that MSCs can promote neurogenesis and angiogenesis through various mechanisms, including releasing bioactive molecules and extracellular vesicles (EVs), which help reduce neuroinflammation. In research, the distinctive characteristics of MSCs have positioned them as highly desirable cell sources. Extensive investigations have been conducted on the regulatory properties of MSCs and their manipulation, tagging, and transportation techniques for brain-related applications. This review explores the progress and prospects of MSC therapy in TBI, focusing on mechanisms of action, therapeutic benefits, and the challenges and potential limitations of using MSCs in treating neurological disorders.
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Affiliation(s)
- Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Masoumeh Dorri Giv
- Nuclear Medicine Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Hosseininejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Azin Rezaie
- Department of Microbiology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Narges Mohammadi
- Department of Molecular Cell Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Arastoo Farokhi
- Department of Anesthesiology, Kermanshah University of Medical Sciences, Imam Reza Hospital, Kermanshah, Iran
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2
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Pierro M, Thébaud B. Cell-based strategies for the treatment of injury to the developing lung. THE LUNG 2025:403-426. [DOI: 10.1016/b978-0-323-91824-4.00020-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Soltani S, Zahedi A, Vergara AJS, Noli M, Soltysik FM, Pociot F, Yarani R. Preclinical Therapeutic Efficacy of Extracellular Vesicles Derived from Adipose-Derived Mesenchymal Stromal/Stem Cells in Diabetic Wounds: a Systematic Review and Meta-Analysis. Stem Cell Rev Rep 2024; 20:2016-2031. [PMID: 38970763 DOI: 10.1007/s12015-024-10753-z] [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] [Accepted: 06/20/2024] [Indexed: 07/08/2024]
Abstract
Extracellular vesicles isolated from adipose tissue-derived mesenchymal stromal/stem cells (ADSC-EVs) have demonstrated promising potential in wound healing treatment. To determine the therapeutic efficacy of ADSC-EVs for diabetic wounds in preclinical models, we performed a meta-analysis of available studies. PubMed and Embase were searched (to April 23, 2023). All full-text articles describing the therapeutic application of ADSC-EVs in diabetic wounds were included. Study outcomes were pooled using a random effects meta-analysis, including wound closure, angiogenesis, and collagen deposition. Other outcomes were only discussed descriptively. Seventy unique records were identified from our search; 20 full-text articles were included for qualitative analysis. Twelve studies were eligible for quantitative meta-analysis. The results showed that ADSC-EVs accelerated diabetic wound healing compared to controls with a large effect (standardized mean difference (SMD) 4.22, 95% confidence interval (CI) 3.07 to 5.36). The administration of ADSC-EVs also improved neovascularization (SMD 9.27, 95% CI 4.70 to 13.83) and collagen deposition (SMD 2.19, 95% CI 0.94 to 3.44), with a large effect. The risk of bias was unclear in all included studies. Conclusively, ADSC-EV is an effective treatment for diabetic wounds in preclinical trials, and it appears justified for transfer into the clinical field.
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Affiliation(s)
- Setareh Soltani
- Clinical Research Development Center, Taleghani and Imam Ali Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ahora Zahedi
- Department of Artificial Intelligence in Medical Sciences, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - April Joy S Vergara
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Marta Noli
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Fumie Mitani Soltysik
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark.
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Li P, Alenazi KKK, Dally J, Woods EL, Waddington RJ, Moseley R. Role of oxidative stress in impaired type II diabetic bone repair: scope for antioxidant therapy intervention? FRONTIERS IN DENTAL MEDICINE 2024; 5:1464009. [PMID: 39917650 PMCID: PMC11797775 DOI: 10.3389/fdmed.2024.1464009] [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: 07/12/2024] [Accepted: 10/02/2024] [Indexed: 02/09/2025] Open
Abstract
Impaired bone healing is a significant complication observed in individuals with type 2 diabetes mellitus (T2DM), leading to prolonged recovery, increased risk of complications, impaired quality of life, and increased risk of patient morbidity. Oxidative stress, resulting from an imbalance between the generation of reactive oxygen species (ROS) and cellular/tissue antioxidant defence mechanisms, has been identified as a critical contributor to the pathogenesis of impaired bone healing in T2DM. Antioxidants have shown promise in mitigating oxidative stress and promoting bone repair, particularly non-enzymic antioxidant entities. This comprehensive narrative review aims to explore the underlying mechanisms and intricate relationship between oxidative stress, impaired bone healing and T2DM, with a specific focus on the current preclinical and clinical evidence advocating the potential of antioxidant therapeutic interventions in improving bone healing outcomes in individuals with T2DM. From the ever-emerging evidence available, it is apparent that exogenously supplemented antioxidants, especially non-enzymic antioxidants, can ameliorate the detrimental effects of oxidative stress, inflammation, and impaired cellular function on bone healing processes during uncontrolled hyperglycaemia; and therefore, hold considerable promise as novel efficacious therapeutic entities. However, despite such conclusions, several important gaps in our knowledge remain to be addressed, including studies involving more sophisticated enzymic antioxidant-based delivery systems, further mechanistic studies into how these antioxidants exert their desirable reparative effects; and more extensive clinical trial studies into the optimisation of antioxidant therapy dosing, frequency, duration and their subsequent biodistribution and bioavailability. By enhancing our understanding of such crucial issues, we can fully exploit the oxidative stress-neutralising properties of these antioxidants to develop effective antioxidant interventions to mitigate impaired bone healing and reduce the associated complications in such T2DM patient populations.
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Affiliation(s)
- Pui Li
- Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
| | - Kuraym Khalid Kuraym Alenazi
- Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
| | - Jordanna Dally
- Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
| | - Emma Louise Woods
- Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
| | - Rachel Jane Waddington
- Biomaterials Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
| | - Ryan Moseley
- Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
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Ozcan M, Abdellatif M, Javaheri A, Sedej S. Risks and Benefits of Intermittent Fasting for the Aging Cardiovascular System. Can J Cardiol 2024; 40:1445-1457. [PMID: 38354947 DOI: 10.1016/j.cjca.2024.02.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 02/16/2024] Open
Abstract
Population aging and the associated increase in cardiovascular disease rates pose serious threats to global public health. Different forms of fasting have become an increasingly attractive strategy to directly address aging and potentially limit or delay the onset of cardiovascular diseases. A growing number of experimental studies and clinical trials indicate that the amount and timing of food intake as well as the daily time window during which food is consumed, are crucial determinants of cardiovascular health. Indeed, intermittent fasting counteracts the molecular hallmarks of cardiovascular aging and promotes different aspects of cardiometabolic health, including blood pressure and glycemic control, as well as body weight reduction. In this report, we summarize current evidence from randomized clinical trials of intermittent fasting on body weight and composition as well as cardiovascular and metabolic risk factors. Moreover, we critically discuss the preventive and therapeutic potential of intermittent fasting, but also possible detrimental effects in the context of cardiovascular aging and related disease. We delve into the physiological mechanisms through which intermittent fasting might improve cardiovascular health, and raise important factors to consider in the design of clinical trials on the efficacy of intermittent fasting to reduce major adverse cardiovascular events among aged individuals at high risk of cardiovascular disease. We conclude that despite growing evidence and interest among the lay and scientific communities in the cardiovascular health-improving effects of intermittent fasting, further research efforts and appropriate caution are warranted before broadly implementing intermittent fasting regimens, especially in elderly persons.
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Affiliation(s)
- Mualla Ozcan
- Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Mahmoud Abdellatif
- Department of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria
| | - Ali Javaheri
- Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA; John J. Cochran Veterans Affairs Medical Center, St. Louis, Missouri, USA
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.
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6
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Nasrollahpour H, Mirzaie A, Sharifi M, Rezabakhsh A, Khalilzadeh B, Rahbarghazi R, Yousefi H, Klionsky DJ. Biosensors; a novel concept in real-time detection of autophagy. Biosens Bioelectron 2024; 254:116204. [PMID: 38507929 PMCID: PMC11907300 DOI: 10.1016/j.bios.2024.116204] [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: 05/27/2023] [Revised: 02/23/2024] [Accepted: 03/09/2024] [Indexed: 03/22/2024]
Abstract
Autophagy is an early-stage response with self-degradation properties against several insulting conditions. To date, the critical role of autophagy has been well-documented in physiological and pathological conditions. This process involves various signaling and functional biomolecules, which are involved in different steps of the autophagic response. During recent decades, a range of biochemical analyses, chemical assays, and varied imaging techniques have been used for monitoring this pathway. Due to the complexity and dynamic aspects of autophagy, the application of the conventional methodology for following autophagic progression is frequently associated with a mistake in discrimination between a complete and incomplete autophagic response. Biosensors provide a de novo platform for precise and accurate analysis of target molecules in different biological settings. It has been suggested that these devices are applicable for real-time monitoring and highly sensitive detection of autophagy effectors. In this review article, we focus on cutting-edge biosensing technologies associated with autophagy detection.
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Affiliation(s)
| | - Arezoo Mirzaie
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Sharifi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Balal Khalilzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Applied Cellular Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hadi Yousefi
- Department of Applied Cellular Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Daniel J Klionsky
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
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Hu M, Ladowski JM, Xu H. The Role of Autophagy in Vascular Endothelial Cell Health and Physiology. Cells 2024; 13:825. [PMID: 38786047 PMCID: PMC11120581 DOI: 10.3390/cells13100825] [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: 03/27/2024] [Revised: 04/30/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells (ECs) has been increasingly recognized, and numerous studies have linked the dysregulation of autophagy to the development of endothelial dysfunction and vascular disease. Here, we provide an overview of the molecular mechanisms underlying autophagy in ECs and our current understanding of the roles of autophagy in vascular biology and review the implications of dysregulated autophagy for vascular disease. Finally, we summarize the current state of the research on compounds to modulate autophagy in ECs and identify challenges for their translation into clinical use.
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Affiliation(s)
| | - Joseph M. Ladowski
- Transplant and Immunobiology Research, Department of Surgery, Duke University, Durham, NC 27710, USA;
| | - He Xu
- Transplant and Immunobiology Research, Department of Surgery, Duke University, Durham, NC 27710, USA;
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Mateen MA, Alaagib N, Haider KH. High glucose microenvironment and human mesenchymal stem cell behavior. World J Stem Cells 2024; 16:237-244. [PMID: 38577235 PMCID: PMC10989287 DOI: 10.4252/wjsc.v16.i3.237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/11/2024] [Accepted: 01/29/2024] [Indexed: 03/25/2024] Open
Abstract
High glucose (HG) culture conditions in vitro and persistent exposure to hyperglycemia in diabetes patients are detrimental to stem cells, analogous to any other cell type in our body. It interferes with diverse signaling pathways, i.e. mammalian target of rapamycin (mTOR)-phosphoinositide 3-kinase (PI3K)-Akt signaling, to impact physiological cellular functions, leading to low cell survival and higher cell apoptosis rates. While elucidating the underlying mechanism responsible for the apoptosis of adipose tissue-derived mesenchymal stem cells (MSCs), a recent study has shown that HG culture conditions dysregulate mTOR-PI3K-Akt signaling in addition to mitochondrial malfunctioning due to defective mitochondrial membrane potential (MtMP) that lowers ATP production. This organelle-level dysfunction energy-starves the cells and increases oxidative stress and ultrastructural abnormalities. Disruption of the mitochondrial electron transport chain produces an altered mitochondrial NAD+/NADH redox state as evidenced by a low NAD+/NADH ratio that primarily contributes to the reduced cell survival in HG. Some previous studies have also reported altered mitochondrial membrane polarity (causing hyperpolarization) and reduced mitochondrial cell mass, leading to perturbed mitochondrial homeostasis. The hostile microenvironment created by HG exposure creates structural and functional changes in the mitochondria, altering their bioenergetics and reducing their capacity to produce ATP. These are significant data, as MSCs are extensively studied for tissue regeneration and restoring their normal functioning in cell-based therapy. Therefore, MSCs from hyperglycemic donors should be cautiously used in clinical settings for cell-based therapy due to concerns of their poor survival rates and increased rates of post engraftment proliferation. As hyperglycemia alters the bioenergetics of donor MSCs, rectifying the loss of MtMP may be an excellent target for future research to restore the normal functioning of MSCs in hyperglycemic patients.
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Affiliation(s)
| | | | - Khawaja Husnain Haider
- Cellular and Molecular Pharmacology, Sulaiman AlRajhi Medical School, Al Bukairiyah 51941, Saudi Arabia.
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Kang N, Jung JS, Hwang J, Park SE, Kwon M, Yoon H, Yong J, Woo HM, Park KM. Beneficial Effect of Sirolimus-Pretreated Mesenchymal Stem Cell Implantation on Diabetic Retinopathy in Rats. Biomedicines 2024; 12:383. [PMID: 38397985 PMCID: PMC10886997 DOI: 10.3390/biomedicines12020383] [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: 01/16/2024] [Revised: 02/02/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a vision-threatening complication that affects virtually all diabetic patients. Various treatments have been attempted, but they have many side effects and limitations. Alternatively, stem cell therapy is being actively researched, but it faces challenges due to a low cell survival rate. In this study, stem cells were pretreated with sirolimus, which is known to promote cell differentiation and enhance the survival rate. Additionally, the subconjunctival route was employed to reduce complications following intravitreal injections. METHODS Diabetes mellitus was induced by intraperitoneal injection of 55 mg/kg of streptozotocin (STZ), and DR was confirmed at 10 weeks after DM induction through electroretinogram (ERG). The rats were divided into four groups: intact control group (INT), diabetic retinopathy group (DR), DR group with subconjunctival MSC injection (DR-MSC), and DR group with subconjunctival sirolimus-pretreated MSC injection (DR-MSC-S). The effects of transplantation were evaluated using ERG and histological examinations. RESULTS The ERG results showed that the DR-MSC-S group did not significantly differ from the INT in b-wave amplitude and exhibited significantly higher values than the DR-MSC and DR groups (p < 0.01). The flicker amplitude results showed that the DR-MSC and DR-MSC-S groups had significantly higher values than the DR group (p < 0.01). Histological examination revealed that the retinal layers were thinner in the DR-induced groups compared to the INT group, with the DR-MSC-S group showing the thickest retinal layers among them. CONCLUSIONS Subconjunctival injection of sirolimus-pretreated MSCs can enhance retinal function and mitigate histological changes in the STZ-induced DR rat model.
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Affiliation(s)
- Nanyoung Kang
- Laboratory of Veterinary Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (N.K.); (J.S.J.); (J.H.); (S.-E.P.); (M.K.); (H.Y.); (J.Y.)
| | - Ji Seung Jung
- Laboratory of Veterinary Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (N.K.); (J.S.J.); (J.H.); (S.-E.P.); (M.K.); (H.Y.); (J.Y.)
| | - Jiyi Hwang
- Laboratory of Veterinary Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (N.K.); (J.S.J.); (J.H.); (S.-E.P.); (M.K.); (H.Y.); (J.Y.)
| | - Sang-Eun Park
- Laboratory of Veterinary Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (N.K.); (J.S.J.); (J.H.); (S.-E.P.); (M.K.); (H.Y.); (J.Y.)
| | - Myeongjee Kwon
- Laboratory of Veterinary Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (N.K.); (J.S.J.); (J.H.); (S.-E.P.); (M.K.); (H.Y.); (J.Y.)
| | - Haerin Yoon
- Laboratory of Veterinary Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (N.K.); (J.S.J.); (J.H.); (S.-E.P.); (M.K.); (H.Y.); (J.Y.)
| | - Jungyeon Yong
- Laboratory of Veterinary Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (N.K.); (J.S.J.); (J.H.); (S.-E.P.); (M.K.); (H.Y.); (J.Y.)
| | - Heung-Myong Woo
- Laboratory of Veterinary Surgery, College of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea;
| | - Kyung-Mee Park
- Laboratory of Veterinary Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (N.K.); (J.S.J.); (J.H.); (S.-E.P.); (M.K.); (H.Y.); (J.Y.)
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Milani SZ, Rezabakhsh A, Karimipour M, Salimi L, Mardi N, Narmi MT, Sadeghsoltani F, Valioglu F, Rahbarghazi R. Role of autophagy in angiogenic potential of vascular pericytes. Front Cell Dev Biol 2024; 12:1347857. [PMID: 38380339 PMCID: PMC10877016 DOI: 10.3389/fcell.2024.1347857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 01/24/2024] [Indexed: 02/22/2024] Open
Abstract
The vasculature system is composed of a multiplicity of juxtaposed cells to generate a functional biological barrier between the blood and tissues. On the luminal surface of blood vessels, endothelial cells (ECs) are in close contact with circulating cells while supporting basal lamina and pericytes wrap the abluminal surface. Thus, the reciprocal interaction of pericytes with ECs is a vital element in the physiological activity of the vascular system. Several reports have indicated that the occurrence of pericyte dysfunction under ischemic and degenerative conditions results in varied micro and macro-vascular complications. Emerging evidence points to the fact that autophagy, a conserved self-digestive cell machinery, can regulate the activity of several cells like pericytes in response to various stresses and pathological conditions. Here, we aim to highlight the role of autophagic response in pericyte activity and angiogenesis potential following different pathological conditions.
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Affiliation(s)
- Soheil Zamen Milani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Salimi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Mardi
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Ferzane Valioglu
- Technology Development Zones Management CO., Sakarya University, Sakarya, Türkiye
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Applied Cellular Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Panda D, Nayak S. Stem Cell-Based Tissue Engineering Approaches for Diabetic Foot Ulcer: a Review from Mechanism to Clinical Trial. Stem Cell Rev Rep 2024; 20:88-123. [PMID: 37867186 DOI: 10.1007/s12015-023-10640-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2023] [Indexed: 10/24/2023]
Abstract
Diabetic foot ulcer (DFU) is a complication from incomplete or prolonged wound healing, at times requires amputation, putting substantial health and socioeconomic burden. Wound healing is a dynamic overlapping process that can be regulated by arrays of molecular factors showing redundancy in function. However, dysregulation in the mechanism of angiogenesis, extra cellular matrix (ECM) formation and immune modulation are the major causes for impair wound healing in hyperglycaemic patients. Despite development of wound care research, there is a lack of well-accepted targeted therapy with multidisciplinary approach for DFU treatment. Stem cell therapy holds a promising outcome both in preclinical and clinical trials because of its ability to promote healing via regeneration and specialized tissue differentiation. Among different types of stem cells, regenerative potential of mesenchymal stem cell (MSC) is well demonstrated in both experimental and clinical trial. Still there is a huge knowledge gap among medical practitioners for deciding the best stem cell source, administration route, and safety. This review strengthens the fact that why stem cell therapy is a promising candidate to treat DFU and cited multiple tissue engineering and biomaterial-based approaches for delivering stem cells and their aftermath paracrine events. Based on the pre-clinical and clinical studies, the review tried to come up with optimum stem cell source and delivery route for the treatment of DFU. At last, the review glances on possible direction to enhance therapeutics strategy for the same, including different approaches like: phytocompounds, exosomes, scaffold geometry, cell preconditioning and licensing etc.
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Affiliation(s)
- Debarchan Panda
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sunita Nayak
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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12
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Jo HH, Goh YS, Kim HJ, Kim DH, Kim H, Hwang J, Jung JS, Kang N, Park SE, Park KM, Lee HJ. Tacrolimus Improves Therapeutic Efficacy of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Diabetic Retinopathy by Suppressing DRP1-Mediated Mitochondrial Fission. Antioxidants (Basel) 2023; 12:1727. [PMID: 37760030 PMCID: PMC10525315 DOI: 10.3390/antiox12091727] [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: 07/28/2023] [Revised: 08/16/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Diabetic retinopathy (DR) is a leading cause of blindness in diabetic patients. Umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are emerging as a promising new drug for degenerative disease associated with diabetes. Recent studies have shown that high glucose-increased excessive calcium levels are a major risk factor for mitochondrial reactive oxygen species (mtROS) accumulation and apoptosis. This study aimed to investigate the role of high glucose-induced NFATC1 signaling in mitochondrial oxidative stress-stimulated apoptosis and the effect of tacrolimus on the therapeutic efficacy of subconjunctival transplantation of UCB-MSCs in a DR rat model. High glucose increased mtROS and cleaved caspase-9 expression in UCB-MSCs. High glucose conditions increased O-GlcNAcylated protein expression and nuclear translocation of NFATC1. Tacrolimus pretreatment recovered high glucose-induced mtROS levels and apoptosis. In the DR rat model, subconjunctival transplantation of tacrolimus-pretreated MSCs improved retinal vessel formation, retinal function, and uveitis. In high glucose conditions, tacrolimus pretreatment reduced protein and mRNA expression levels of DRP1 and inhibited mitochondrial fission. In conclusion, we demonstrated that high glucose-induced O-GlcNAcylation activates NFATC1 signaling, which is important for DRP1-mediated mitochondrial fission and mitochondrial apoptosis. Finally, we proposed NFATC1 suppression by tacrolimus as a promising therapeutic strategy to improve the therapeutic efficacy of UCB-MSC transplantation for DR treatment.
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Affiliation(s)
- Hang Hyo Jo
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of Korea; (H.H.J.)
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Yeong Seok Goh
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Hye Jih Kim
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of Korea; (H.H.J.)
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Dae Hyun Kim
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of Korea; (H.H.J.)
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Hyemin Kim
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Jiyi Hwang
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Ji Seung Jung
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Nanyoung Kang
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Sang Eun Park
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Kyung Mee Park
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Hyun Jik Lee
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of Korea; (H.H.J.)
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju 28644, Republic of Korea
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13
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Shabkhizan R, Haiaty S, Moslehian MS, Bazmani A, Sadeghsoltani F, Saghaei Bagheri H, Rahbarghazi R, Sakhinia E. The Beneficial and Adverse Effects of Autophagic Response to Caloric Restriction and Fasting. Adv Nutr 2023; 14:1211-1225. [PMID: 37527766 PMCID: PMC10509423 DOI: 10.1016/j.advnut.2023.07.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 07/04/2023] [Accepted: 07/24/2023] [Indexed: 08/03/2023] Open
Abstract
Each cell is equipped with a conserved housekeeping mechanism, known as autophagy, to recycle exhausted materials and dispose of injured organelles via lysosomal degradation. Autophagy is an early-stage cellular response to stress stimuli in both physiological and pathological situations. It is thought that the promotion of autophagy flux prevents host cells from subsequent injuries by removing damaged organelles and misfolded proteins. As a correlate, the modulation of autophagy is suggested as a therapeutic approach in diverse pathological conditions. Accumulated evidence suggests that intermittent fasting or calorie restriction can lead to the induction of adaptive autophagy and increase longevity of eukaryotic cells. However, prolonged calorie restriction with excessive autophagy response is harmful and can stimulate a type II autophagic cell death. Despite the existence of a close relationship between calorie deprivation and autophagic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible effects of prolonged and short-term calorie restriction on autophagic response and cell homeostasis.
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Affiliation(s)
- Roya Shabkhizan
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanya Haiaty
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marziyeh Sadat Moslehian
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Bazmani
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Sadeghsoltani
- Student Committee Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Applied Cell Sciences, Advanced Faculty of Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ebrahim Sakhinia
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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14
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Salimi L, Seyedaghamiri F, Karimipour M, Mobarak H, Mardi N, Taghavi M, Rahbarghazi R. Physiological and pathological consequences of exosomes at the blood-brain-barrier interface. Cell Commun Signal 2023; 21:118. [PMID: 37208741 DOI: 10.1186/s12964-023-01142-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/22/2023] [Indexed: 05/21/2023] Open
Abstract
Blood-brain barrier (BBB) interface with multicellular structure controls strictly the entry of varied circulating macromolecules from the blood-facing surface into the brain parenchyma. Under several pathological conditions within the central nervous system, the integrity of the BBB interface is disrupted due to the abnormal crosstalk between the cellular constituents and the recruitment of inflammatory cells. Exosomes (Exos) are nano-sized extracellular vesicles with diverse therapeutic outcomes. These particles transfer a plethora of signaling molecules with the potential to modulate target cell behavior in a paracrine manner. Here, in the current review article, the therapeutic properties of Exos and their potential in the alleviation of compromised BBB structure were discussed. Video Abstract.
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Affiliation(s)
- Leila Salimi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemehsadat Seyedaghamiri
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimipour
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Halimeh Mobarak
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Mardi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Taghavi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Bayazidi MG, Rahbarghazi R, Rezabakhsh A, Rezaie J, Hassanpour M, Ahmadi M. Type 2 diabetes mellitus induced autophagic response within pulmonary tissue in the rat model. BIOIMPACTS : BI 2023; 13:43-50. [PMID: 36817001 PMCID: PMC9923816 DOI: 10.34172/bi.2022.22183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 01/23/2021] [Accepted: 01/24/2021] [Indexed: 11/06/2022]
Abstract
Introduction: The current experiment aimed to address the impact of type 2 diabetes mellitus on autophagy status in the rat pulmonary tissue. Methods: In this study, 20 male Wistar rats were randomly allocated into two groups as follows: control and diabetic groups. To induce type 2 diabetes mellitus, rats received a combination of streptozotocin (STZ) and a high-fat diet. After confirmation of diabetic condition, rats were maintained for 8 weeks and euthanized for further analyses. The pathological changes were assessed using H&E staining. We also measured transforming growth factor-β (TGF-β), bronchoalveolar lavage fluid (BALF), and tumor necrosis factor-α (TNF-α) in the lungs using ELISA and real-time PCR analyses, respectively. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were monitored in diabetic lungs to assess oxidative status. We also measured the expression of becline-1, LC3, and P62 to show autophagic response under diabetic conditions. Using immunofluorescence staining, protein levels of LC3 was also monitored. Results: H&E staining showed pathological changes in diabetic rats coincided with the increase of TNF-α (~1.4-fold) and TGF-β (~1.3-fold) compared to those in the normal rats (P<0.05). The levels of MDA (5.6 ± 0.4 versus 6.4 ± 0.27 nM/mg protein) were increased while SOD (4.2 ± 0.28 versus 3.8 ± 0.13 U/mL) activity decreased in the diabetic rats (P<0.05). Real-time polymerase chain reaction (PCR) analysis showed the up-regulation of Becline-1 (~1.35-fold) and LC3 (~2-fold) and down-regulation of P62 (~0.8-fold) (P<0.05), showing incomplete autophagic flux. We noted the increase of LC3+ cells in diabetic condition compared to that in the control samples. Conclusion: The prolonged diabetic condition could inhibit the normal activity of autophagy flux, thereby increasing pathological outcomes.
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Affiliation(s)
- Mohammad Ghader Bayazidi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Rezaie
- Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Hassanpour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Ahmadi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran,Corresponding author: Mahdi Ahmadi,
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16
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Isaković J, Šerer K, Barišić B, Mitrečić D. Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force? Front Bioeng Biotechnol 2023; 11:1139359. [PMID: 36926687 PMCID: PMC10011535 DOI: 10.3389/fbioe.2023.1139359] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Neurological disorders are recognized as major causes of death and disability worldwide. Because of this, they represent one of the largest public health challenges. With awareness of the massive burden associated with these disorders, came the recognition that treatment options were disproportionately scarce and, oftentimes, ineffective. To address these problems, modern research is increasingly looking into novel, more effective methods to treat neurological patients; one of which is cell-based therapies. In this review, we present a critical analysis of the features, challenges, and prospects of one of the stem cell types that can be employed to treat numerous neurological disorders-mesenchymal stem cells (MSCs). Despite the fact that several studies have already established the safety of MSC-based treatment approaches, there are still some reservations within the field regarding their immunocompatibility, heterogeneity, stemness stability, and a range of adverse effects-one of which is their tumor-promoting ability. We additionally examine MSCs' mechanisms of action with respect to in vitro and in vivo research as well as detail the findings of past and ongoing clinical trials for Parkinson's and Alzheimer's disease, ischemic stroke, glioblastoma multiforme, and multiple sclerosis. Finally, this review discusses prospects for MSC-based therapeutics in the form of biomaterials, as well as the use of electromagnetic fields to enhance MSCs' proliferation and differentiation into neuronal cells.
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Affiliation(s)
- Jasmina Isaković
- Omnion Research International, Zagreb, Croatia.,Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Klara Šerer
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Barbara Barišić
- University of Zagreb School of Dental Medicine, Zagreb, Croatia
| | - Dinko Mitrečić
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia.,Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
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17
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Fayyazpour P, Alizadeh E, Hosseini V, Kalantary-Charvadeh A, Niafar M, Sadra V, Norouzi Z, Saebnazar A, Mehdizadeh A, Darabi M. Fatty acids of type 2 diabetic serum decrease the stemness properties of human adipose-derived mesenchymal stem cells. J Cell Biochem 2022; 123:1157-1170. [PMID: 35722966 DOI: 10.1002/jcb.30270] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 03/26/2022] [Accepted: 04/20/2022] [Indexed: 11/11/2022]
Abstract
In type 2 diabetes, dyslipidemia and increased serum free fatty acids (FFAs) exacerbate the development of the disease through a negative effect on insulin secretion. Adipose-derived mesenchymal stem cells (AdMSCs) play a key role in regenerative medicine, and these cells can potentially be applied as novel therapeutic resources in the treatment of diabetes. In this study, AdMSCs were treated with diabetic or nondiabetic serum FFAs isolated from women of menopausal age. Serum FFAs were analyzed using gas-liquid chromatography. The expression level of the stemness markers CD49e and CD90 and the Wnt signaling target genes Axin-2 and c-Myc were evaluated using real-time PCR. The proliferation rate and colony formation were also assessed using a BrdU assay and crystal violet staining, respectively. The level of glutathione was assessed using cell fluorescence staining. Compared to nondiabetic serum, diabetic serum contained a higher percentage of oleate (1.5-fold, p < 0.01). In comparison with nondiabetic FFAs, diabetic FFAs demonstrated decreasing effects on the expression of CD90 (-51%, p < 0.001) and c-Myc (-48%, p < 0.05), and proliferation rate (-35%, p < 0.001), colony formation capacity (-50%, p < 0.01), and GSH levels (-62%, p < 0.05). The negative effect of the FFAs of diabetic serum on the stemness characteristics may impair the regenerative capabilities of AdMSCs.
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Affiliation(s)
- Parisa Fayyazpour
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Hosseini
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ashkan Kalantary-Charvadeh
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mitra Niafar
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahideh Sadra
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Norouzi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysan Saebnazar
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masoud Darabi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany
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18
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Ginsenoside Rh4 Inhibits Colorectal Cancer Cell Proliferation by Inducing Ferroptosis via Autophagy Activation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6177553. [PMID: 35677385 PMCID: PMC9168088 DOI: 10.1155/2022/6177553] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 12/18/2022]
Abstract
Colorectal cancer (CRC) is a severe threat to human health. Ginsenosides such as ginsenoside Rh4 have been widely studied in the antitumor field. Here, we investigated the antiproliferative activity and mechanism of Rh4 against CRC in vivo and in vitro. The CRC xenograft model showed that Rh4 inhibited xenograft tumor growth with few side effects (p < 0.05). As determined by MTT colorimetric assays, Western blotting, and immunohistochemical analysis, Rh4 effectively inhibited CRC cell proliferation through autophagy and ferroptosis (p < 0.05). Rh4 significantly upregulated autophagy and ferroptosis marker expression in CRC cells and xenograft tumor tissues in the present study (p < 0.05). Interestingly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed Rh4-induced ferroptosis (p < 0.05). Moreover, the autophagy inhibitor 3-methyladenine (3-MA) also reversed Rh4-induced ferroptosis (p < 0.05). These results indicate that Rh4-induced ferroptosis is regulated via the autophagy pathway. In addition, Rh4 increased reactive oxygen species (ROS) accumulation, leading to the activation of the ROS/p53 signaling pathway (p < 0.05). Transcriptome sequencing also confirmed this (p < 0.05). Moreover, the ROS scavenger N-acetyl-cysteine (NAC) reversed the inhibitory effect of Rh4 on CRC cells (p < 0.05). Therefore, this study proves that Rh4 inhibits cancer cell proliferation by activating the ROS/p53 signaling pathway and activating autophagy to induce ferroptosis, which provides necessary scientific evidence of the great anticancer potential of Rh4.
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19
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Sadat-Ebrahimi SR, Amini H, Rahbarghazi R, Habibollahi P, Ghaderi S, Rajabi H, Rezabakhsh A. Putative therapeutic impacts of cardiac CTRP9 in ischaemia/reperfusion injury. J Cell Mol Med 2022; 26:3120-3132. [PMID: 35535510 PMCID: PMC9170823 DOI: 10.1111/jcmm.17355] [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: 02/16/2022] [Revised: 04/18/2022] [Accepted: 04/22/2022] [Indexed: 11/28/2022] Open
Abstract
Recently, cytokines belonging to C1q/tumour necrosis factor‐related proteins (CTRPs) superfamily have attracted increasing attention due to multiple metabolic functions and desirable anti‐inflammatory effects. These various molecular effectors exhibit key roles upon the onset of cardiovascular diseases, making them novel adipo/cardiokines. This review article aimed to highlight recent findings correlated with therapeutic effects and additional mechanisms specific to the CTRP9, particularly in cardiac ischaemia/reperfusion injury (IRI). Besides, the network of the CTPR9 signalling pathway and its possible relationship with IRI were discussed. Together, the discovery of all involved underlying mechanisms could shed light to alleviate the pathological sequelae after the occurrence of IRI.
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Affiliation(s)
| | - Hassan Amini
- Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Applied Cell Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Paria Habibollahi
- Department of Pharmacology and Toxicology, Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahrouz Ghaderi
- Institute of Molecular Medicine III, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
| | - Hadi Rajabi
- Koç University Research Center for Translational Medicine (KUTTAM), Koç University, School of Medicine, Istanbul, Turkey
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Emergency Medicine & Trauma Care Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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20
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Mastrogiacomo M, Nardini M, Collina MC, Di Campli C, Filaci G, Cancedda R, Odorisio T. Innovative Cell and Platelet Rich Plasma Therapies for Diabetic Foot Ulcer Treatment: The Allogeneic Approach. Front Bioeng Biotechnol 2022; 10:869408. [PMID: 35586557 PMCID: PMC9108368 DOI: 10.3389/fbioe.2022.869408] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
Abstract
Cutaneous chronic wounds are a major global health burden in continuous growth, because of population aging and the higher incidence of chronic diseases, such as diabetes. Different treatments have been proposed: biological, surgical, and physical. However, most of these treatments are palliative and none of them can be considered fully satisfactory. During a spontaneous wound healing, endogenous regeneration mechanisms and resident cell activity are triggered by the released platelet content. Activated stem and progenitor cells are key factors for ulcer healing, and they can be either recruited to the wound site from the tissue itself (resident cells) or from elsewhere. Transplant of skin substitutes, and of stem cells derived from tissues such as bone marrow or adipose tissue, together with platelet-rich plasma (PRP) treatments have been proposed as therapeutic options, and they represent the today most promising tools to promote ulcer healing in diabetes. Although stem cells can directly participate to skin repair, they primarily contribute to the tissue remodeling by releasing biomolecules and microvesicles able to stimulate the endogenous regeneration mechanisms. Stem cells and PRP can be obtained from patients as autologous preparations. However, in the diabetic condition, poor cell number, reduced cell activity or impaired PRP efficacy may limit their use. Administration of allogeneic preparations from healthy and/or younger donors is regarded with increasing interest to overcome such limitation. This review summarizes the results obtained when these innovative treatments were adopted in preclinical animal models of diabetes and in diabetic patients, with a focus on allogeneic preparations.
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Affiliation(s)
- Maddalena Mastrogiacomo
- Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università degli Studi di Genova, Genova, Italy
- *Correspondence: Maddalena Mastrogiacomo,
| | - Marta Nardini
- Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università degli Studi di Genova, Genova, Italy
| | - Maria Chiara Collina
- Unità Operativa Semplice Piede Diabetico e Ulcere Cutanee, IDI-IRCCS, Roma, Italy
| | - Cristiana Di Campli
- Unità Operativa Semplice Piede Diabetico e Ulcere Cutanee, IDI-IRCCS, Roma, Italy
| | - Gilberto Filaci
- Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università degli Studi di Genova, Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Ranieri Cancedda
- Emeritus Professor, Università degli Studi di Genova, Genova, Italy
| | - Teresa Odorisio
- Laboratorio di Biologia Molecolare e Cellulare, IDI-IRCCS, Roma, Italy
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21
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The Effect of Diabetes Mellitus on IGF Axis and Stem Cell Mediated Regeneration of the Periodontium. Bioengineering (Basel) 2021; 8:bioengineering8120202. [PMID: 34940355 PMCID: PMC8698546 DOI: 10.3390/bioengineering8120202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 11/29/2021] [Indexed: 11/16/2022] Open
Abstract
Periodontitis and diabetes mellitus (DM) are two of the most common and challenging health problems worldwide and they affect each other mutually and adversely. Current periodontal therapies have unpredictable outcome in diabetic patients. Periodontal tissue engineering is a challenging but promising approach that aims at restoring periodontal tissues using one or all of the following: stem cells, signalling molecules and scaffolds. Mesenchymal stem cells (MSCs) and insulin-like growth factor (IGF) represent ideal examples of stem cells and signalling molecules. This review outlines the most recent updates in characterizing MSCs isolated from diabetics to fully understand why diabetics are more prone to periodontitis that theoretically reflect the impaired regenerative capabilities of their native stem cells. This characterisation is of utmost importance to enhance autologous stem cells based tissue regeneration in diabetic patients using both MSCs and members of IGF axis.
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22
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Xu J, Zuo C. The Fate Status of Stem Cells in Diabetes and its Role in the Occurrence of Diabetic Complications. Front Mol Biosci 2021; 8:745035. [PMID: 34796200 PMCID: PMC8592901 DOI: 10.3389/fmolb.2021.745035] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/20/2021] [Indexed: 12/19/2022] Open
Abstract
Diabetes mellitus (DM) is becoming a growing risk factor for public health worldwide. It is a very common disease and is widely known for its susceptibility to multiple complications which do great harm to the life and health of patients, some even lead to death. To date, there are many mechanisms for the complications of diabetes, including the generation of reactive oxygen species (ROS) and the abnormal changes of gas transmitters, which ultimately lead to injuries of cells, tissues and organs. Normally, even if injured, the body can quickly repair and maintain its homeostasis. This is closely associated with the repair and regeneration ability of stem cells. However, many studies have demonstrated that stem cells happen to be damaged under DM, which may be a nonnegligible factor in the occurrence and progression of diabetic complications. Therefore, this review summarizes how diabetes causes the corresponding complications by affecting stem cells from two aspects: stem cells dysfunctions and stem cells quantity alteration. In addition, since mesenchymal stem cells (MSCs), especially bone marrow mesenchymal stem cells (BMMSCs), have the advantages of strong differentiation ability, large quantity and wide application, we mainly focus on the impact of diabetes on them. The review also puts forward the basis of using exogenous stem cells to treat diabetic complications. It is hoped that through this review, researchers can have a clearer understanding of the roles of stem cells in diabetic complications, thus promoting the process of using stem cells to treat diabetic complications.
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Affiliation(s)
- Jinyi Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chengguo Zuo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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23
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Aydinlik S, Uvez A, Kiyan HT, Gurel-Gurevin E, Yilmaz VT, Ulukaya E, Armutak EI. Palladium (II) complex and thalidomide intercept angiogenic signaling via targeting FAK/Src and Erk/Akt/PLCγ dependent autophagy pathways in human umbilical vein endothelial cells. Microvasc Res 2021; 138:104229. [PMID: 34339726 DOI: 10.1016/j.mvr.2021.104229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 07/18/2021] [Accepted: 07/26/2021] [Indexed: 12/25/2022]
Abstract
The current study assessed the effects of the thalidomide and palladium (II) saccharinate complex of terpyridine on the suppression of angiogenesis-mediated cell proliferation. The viability was assessed after treatment with palladium (II) complex (1.56-100 μM) and thalidomide (0.1-400 μM) alone by using ATP assay for 48 h. Palladium (II) complex was found to inhibit growth statistically significant in a dose-dependent manner in HUVECs and promoted PARP-1 cleavage through the production of ROS. On the other hand, thalidomide did not cause any significant change in cell viability. Moreover, cell death was observed to be manifested as late apoptosis due to Annexin V/SYTOX staining after palladium (II) complex treatment however, thalidomide did not demonstrate similar results. Thalidomide and palladium (II) complex also suppressed HUVEC migration and capillary-like structure tube formation in vitro in a time-dependent manner. Palladium (II) complex (5 mg/ml) treatment showed a strong antiangiogenic effect similar to positive control thalidomide (5 mg/ml) and successfully disrupted the vasculature and reduced the thickness of the vessels compared to control (agar). Furthermore, suppression of autophagy enhanced the cell death and anti-angiogenic effect of thalidomide and palladium (II) complex. We also showed that being treated with thalidomide and palladium (II) complex inhibited phosphorylation of the signaling regulators downstream of the VEGFR2. These results provide evidence for the regulation of endothelial cell functions that are relevant to angiogenesis through the suppression of the FAK/Src/Akt/ERK1/2 signaling pathway. Our results also indicate that PLC-γ1 phosphorylation leads to activation of p-Akt and p-Erk1/2 which cause stimulation on cell proliferation at lower doses. Hence, we demonstrated that palladium (II) and thalidomide can induce cell death via the Erk/Akt/PLCγ signaling pathway and that this pathway might be a novel mechanism.
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Affiliation(s)
- Seyma Aydinlik
- Department of Biology, Faculty of Arts and Science, Uludag University, Bursa, Turkey
| | - Ayca Uvez
- Faculty of Veterinary Medicine, Department of Histology and Embryology, Istanbul University-Cerrahpasa, 34500 Buyukcekmece/Istanbul, Turkey
| | - Hulya Tuba Kiyan
- Department of Pharmacognosy, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey
| | - Ebru Gurel-Gurevin
- Department of Biology, Faculty of Science, Istanbul University, 34134 Istanbul, Turkey
| | - Veysel Turan Yilmaz
- Department of Chemistry, Faculty of Arts and Science, Uludag University, Bursa, Turkey
| | - Engin Ulukaya
- Department of Clinical Biochemistry, Faculty of Medicine, Istinye University, Istanbul, Turkey
| | - Elif Ilkay Armutak
- Faculty of Veterinary Medicine, Department of Histology and Embryology, Istanbul University-Cerrahpasa, 34500 Buyukcekmece/Istanbul, Turkey.
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24
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Shen C, Lu Y, Zhang J, Li Y, Zhang Y, Fan D. c-Casitas b-Lineage Lymphoma Downregulation Improves the Ability of Long-term Cultured Mesenchymal Stem Cells for Promoting Angiogenesis and Diabetic Wound Healing. Cell Transplant 2021; 30:963689721989605. [PMID: 33588607 PMCID: PMC7894690 DOI: 10.1177/0963689721989605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The chronic wound induced by diabetes has poor efficacy and could lead to amputation. The repair function of mesenchymal stem cells (MSCs) impaired after long-term culture in vitro. Studies have shown that the proto-oncogene c-Casitas b-lineage lymphoma (c-Cbl) can regulate receptor- and non-receptor tyrosine kinase, which was also involved in the angiogenesis process. This study aimed to explore the regulative effect of c-Cbl on the proangiogenic functions of long-term cultured MSCs and evaluate its pro-healing effect on diabetic wounds. In this study, the c-Cbl level was downregulated by locked nucleic acid–modified antisense oligonucleotide gapmers (LNA Gapmers). We detected the effect of c-Cbl downregulation on long-term cultured MSCs in terms of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal, cellular proliferation, senescence, migration, and angiogenic factors paracrine activity in vitro. In vivo, we observed the pro-healing effect of long-term cultured MSCs, with or without c-Cbl downregulation, on the diabetic wound. We found that the phosphorylation level of c-Cbl increased and that of Akt decreased in passage 10 (P10) MSCs compared with passage 3 (P3) MSCs (P < 0.05). Additionally, the proliferation, paracrine, and migration capacity of P10 MSCs decreased significantly, accompanied by the increase of cellular senescence (P < 0.05). However, these functions, including PI3K/Akt activity of P10 MSCs, have been improved by c-Cbl downregulation (P < 0.05). Compared with P10 MSCs treatment, treatment with c-Cbl downregulated P10 MSCs accelerated diabetic wound healing, as defined by a more rapid wound closure (P < 0.05), more neovascularization (P < 0.05), and higher scores of wound histological assessment (P < 0.05) in a diabetic rat model. Our findings suggested that c-Cbl downregulation could attenuate the impairment of proangiogenic functions in MSCs induced by long-term culture in vitro and improve the effect of long-term cultured MSCs in promoting diabetic wound healing.
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Affiliation(s)
- Chengcheng Shen
- Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yuangang Lu
- Department of Plastic and Cosmetic Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jianghe Zhang
- Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yujie Li
- Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yiming Zhang
- Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Dongli Fan
- Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
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25
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Wu P, Zhang X, Hu Y, Liu D, Song J, Xu W, Tan H, Lu R, Zheng L. Co-culture with Endothelial Progenitor Cells promotes the Osteogenesis of Bone Mesenchymal Stem Cells via the VEGF-YAP axis in high-glucose environments. Int J Med Sci 2021; 18:1628-1638. [PMID: 33746579 PMCID: PMC7976568 DOI: 10.7150/ijms.52316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 01/11/2021] [Indexed: 11/05/2022] Open
Abstract
Patients with type 2 diabetes mellitus (T2DM) have a high risk of fracture and experience poor bone healing. In recent years, bone mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs) have become the most commonly used cells in cell therapy and tissue engineering. In this study, we found that high glucose levels had a negative effect on the differentiation of BMSCs and EPCs. Considering that EPCs-BMSCs sheets can provide endothelial cells and osteoblastic cells, we transplanted cell sheets into T2DM rats with bilateral skull defects. The outcomes of the in vivo study revealed that EPCs-BMSCs sheets promoted ossification, which was verified by micro-CT and immunohistochemistry (IHC) analyses. Furthermore, we detected the VEGF content in the culture supernatant using an enzyme-linked immunosorbent assay (ELISA). The results showed that the BMSCs co-cultured with EPCs presented a higher level of VEGF than other cells. To assess the differentiation and migration of BMSCs exposed to VEGF, ALP staining, scratch assay and qRT-PCR analysis were performed. In addition, we used immunofluorescence and western blotting analysis to further explore the related mechanisms. The results showed that cells cultured with VEGF had a stronger actin cytoskeleton and a greater amount of nuclear and total YAP than cells cultured without VEGF. Taken together, our results indicate that co-culture with EPCs could promote the osteogenesis of BMSCs partially via VEGF. Furthermore, YAP and F-actin play important roles in this process.
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Affiliation(s)
- Peilian Wu
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Xia Zhang
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- West china dental hospital of Chongqing, Chongqing, 401147, China
| | - Yun Hu
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Dongrong Liu
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Jinlin Song
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Wenjie Xu
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Hao Tan
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Rui Lu
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Leilei Zheng
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
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26
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Ribot J, Denoeud C, Frescaline G, Landon R, Petite H, Pavon-Djavid G, Bensidhoum M, Anagnostou F. Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells. Cells 2021; 10:268. [PMID: 33572905 PMCID: PMC7912056 DOI: 10.3390/cells10020268] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/16/2022] Open
Abstract
Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.
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Affiliation(s)
- Jonathan Ribot
- Université de Paris, CNRS, INSERM, B3OA, 75010 Paris, France; (J.R.); (C.D.); (G.F.); (R.L.); (H.P.); (M.B.)
| | - Cyprien Denoeud
- Université de Paris, CNRS, INSERM, B3OA, 75010 Paris, France; (J.R.); (C.D.); (G.F.); (R.L.); (H.P.); (M.B.)
| | - Guilhem Frescaline
- Université de Paris, CNRS, INSERM, B3OA, 75010 Paris, France; (J.R.); (C.D.); (G.F.); (R.L.); (H.P.); (M.B.)
| | - Rebecca Landon
- Université de Paris, CNRS, INSERM, B3OA, 75010 Paris, France; (J.R.); (C.D.); (G.F.); (R.L.); (H.P.); (M.B.)
| | - Hervé Petite
- Université de Paris, CNRS, INSERM, B3OA, 75010 Paris, France; (J.R.); (C.D.); (G.F.); (R.L.); (H.P.); (M.B.)
| | - Graciela Pavon-Djavid
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Université Sorbonne Paris Nord, 93430 Villetaneuse, France;
| | - Morad Bensidhoum
- Université de Paris, CNRS, INSERM, B3OA, 75010 Paris, France; (J.R.); (C.D.); (G.F.); (R.L.); (H.P.); (M.B.)
| | - Fani Anagnostou
- Université de Paris, CNRS, INSERM, B3OA, 75010 Paris, France; (J.R.); (C.D.); (G.F.); (R.L.); (H.P.); (M.B.)
- Department of Periodontology, Service of Odontology–Pitié Salpêtrière Hospital, AP-HP et U.F.R. of Odontology, 75013 Paris, France
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27
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Lesmana R, Felia Yusuf I, Goenawan H, Achadiyani A, Khairani AF, Nur Fatimah S, Supratman U. Low Dose of β-Carotene Regulates Inflammation, Reduces Caspase Signaling, and Correlates with Autophagy Activation in Cardiomyoblast Cell Lines. Med Sci Monit Basic Res 2020; 26:e928648. [PMID: 33361744 PMCID: PMC7780889 DOI: 10.12659/msmbr.928648] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Background Excessive reactive oxygen species (ROS) stimulate mitochondrial damage that causes degenerative diseases such as cardiovascular disease (CVD). β-carotene (BC), a natural antioxidant able to counteract free radicals, acts as a cytoprotective agent. However, knowledge of the role of BC on cardiomyoblasts is limited. In this study, we explored its role on COX4, Tom20, Nfr1, Nrf2, Nf-κB, LC3, p62, caspase 3, and caspase 9 and its association with cardiomyoblast viability and survival. Material/Methods H9C2 cell lines were seeded, cultivated until 90% to 100% confluency, and treated with various doses of BC: 10 μM, 1 μM, 0.1 μM, and 0.01 μM. After 24 h, the cells were harvested, lyzed, and tested for specific related protein expressions from each dose. Results Low-dose BC induced autophagy most effectively at 1 μM, 0.1 μM, and 0.01 μM, as indicated by a decrease of LC3II and p62 levels. We observed that Nf-κB protein levels were suppressed; Nrf2 was stimulated, but Nrf1 was not altered significantly. Further, low-dose BC might stimulate cell viability by reducing apoptotic signals of caspase 3 and 9. Notably, low-dose BC also showed potential to increase Tom20 protein levels. Conclusions Low-dose BC supplementation shows beneficial effects, especially at 0.01 μM, by reducing inflammation through the suppression of Nf-κB and increase of Nrf2 level. Autophagy as a cellular maintenance mechanism was also stimulated, and the amount of the mitochondria marker Tom20 increased. Taken together, results showed that specific low-dose BC is effective and might improve cell viability by stimulating autophagy, inhibiting proinflammatory factors, and suppressing apoptosis.
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Affiliation(s)
- Ronny Lesmana
- Physiology Division, Department of Biomedical Science, Faculty of Medicine, University Padjadjaran, Jatinangor, Indonesia.,Division of Biological Activity, Central Laboratory, University Padjadjaran, Bandung, Indonesia.,Center of Excellence in Higher Education for Pharmaceutical Care Innovation, University Padjadjaran, Bandung, Indonesia
| | - Inez Felia Yusuf
- Postgraduate Program of Anti-Aging and Aesthetics Medicine, Faculty of Medicine, University Padjadjaran, Bandung, Indonesia
| | - Hanna Goenawan
- Physiology Division, Department of Biomedical Science, Faculty of Medicine, University Padjadjaran, Bandung, Indonesia.,Division of Biological Activity, Central Laboratory, University Padjadjaran, Bandung, Indonesia
| | - Achadiyani Achadiyani
- Cell Biology Division, Department of Biomedical Science, Faculty of Medicine, University Padjadjaran, Jatinangor, Indonesia
| | - Astrid Feinisa Khairani
- Postgraduate Program of Anti-Aging and Aesthetics Medicine, Faculty of Medicine, University Padjadjaran, Bandung, Indonesia.,Cell Biology Division, Department of Biomedical Science, Faculty of Medicine, University Padjadjaran, Jatinangor, Indonesia
| | - Siti Nur Fatimah
- Department of Medical Nutrition, Faculty of Medicine, University Padjadjaran, Bandung, Indonesia
| | - Unang Supratman
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, University Padjadjaran, Bandung, Indonesia
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28
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Ahmadian S, Mahdipour M, Pazhang M, Sheshpari S, Mobarak H, Bedate AM, Rahbarghazi R, Nouri M. Effectiveness of Stem Cell Therapy in the Treatment of Ovarian Disorders and Female Infertility: A Systematic Review. Curr Stem Cell Res Ther 2020; 15:173-186. [PMID: 31746298 DOI: 10.2174/1574888x14666191119122159] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/22/2019] [Accepted: 10/29/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Infertility is a major problem worldwide. Various strategies are being used to develop better treatments for infertility and The most trending strategy is the stem cell therapy. In this study, the literature on stem cell therapy for ovarian disorders is summarized with analysis of current developments. OBJECTIVE Different published studies on stem cell-based therapy for the treatment of various types of ovarian insufficiency and disorders such as Premature Ovarian Insufficiency (POI) in the affected female population in animal or human clinical studies are systematically reviewed. METHODS We monitored five databases, including PubMed, Cochrane, Embase, Scopus, and ProQuest. A comprehensive online search was done using the criteria targeting the application of stem cells in animal models for menopause. Two independent reviewers carefully evaluated titles and abstracts of studies. The stem cell type, source, dosage, route of administration were highlighted in various POI animals models. Non-relevant and review articles were excluded. OUTCOMES 648 published studies were identified during the initial comprehensive search process from which 41 were selected according to designed criteria. Based on our analysis, stem cells could accelerate ovarian tissues rejuvenation, regulate systemic sex-related hormones levels and eventually increase fertility rate. CONCLUSION The evidence suggests that stem cell-based therapies could be considered as an alternative modality to deal with women undergoing POI.
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Affiliation(s)
- Shahin Ahmadian
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biology, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Pazhang
- Department of Biology, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran
| | - Sepideh Sheshpari
- Department of Midwifery, Faculty of Nursing and Midwifery, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Halimeh Mobarak
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Alberto Miranda Bedate
- Laboratory for Translational Immunology (LTI), Universitair Medisch Centrum Utrecht, (UMCU), Utrecht, Netherlands
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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29
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Han Q, Niu X, Hou R, Li J, Liu Y, Li X, Li J, Li Y, Zhang K, Wu Y. Dermal mesenchymal stem cells promoted adhesion and migration of endothelial cells by integrin in psoriasis. Cell Biol Int 2020; 45:358-367. [PMID: 33079476 DOI: 10.1002/cbin.11492] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 07/09/2020] [Accepted: 10/18/2020] [Indexed: 01/12/2023]
Abstract
The unusual dilatation of dermal capillaries and angiogenesis played important roles in psoriasis. Some genes and proteins of dermal mesenchymal stem cells (DMSCs) from psoriasis are abnormal and related to the function of endothelial cells (ECs). The present study was aimed to evaluate whether psoriatic DMSCs could affect adhesion and migration of ECs through neovascularization-related integrins in psoriasis. Human DMSCs, collected from psoriasis lesions and healthy skin, respectively, were cocultured with human umbilical vein endothelial cells (HUVECs). The expression levels of three integrins, that is, αvβ3, αvβ5, and α5β1 in HUVECs were tested by quantitative real-time polymerase chain reaction and Western blot analysis. The adhesion and migration of HUVECs were detected by adhesion assay and migration assay. The results showed that in psoriasis group, the expression of αVβ3 and α5β1 of HUVECs markedly increased 2.50- and 3.71-fold in messenger RNA levels, and significantly increased 1.63- and 1.92-fold in protein levels, comparing to healthy control group (all p < .05). But β5 was not significantly different between the two groups (p > .05). In addition, compared with control, psoriatic DMSCs promoted HUVECs adhesion by 1.62-fold and migration by 2.91-fold (all p < .05). In conclusion, psoriatic DMSCs impact HUVECs adhesion and migration by upregulating the expression of integrins αVβ3 and α5β1.
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Affiliation(s)
- Qixin Han
- Dermatology Department, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xuping Niu
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ruixia Hou
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Junqin Li
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yamin Liu
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaofang Li
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Juan Li
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yan Li
- English Department, School of Fundamental Sciences, China Medical University, Shenyang, Liaoning, China
| | - Kaiming Zhang
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yan Wu
- Dermatology Department, The First Hospital of China Medical University, Shenyang, Liaoning, China
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30
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Huo Y, Chen W, Zheng X, Zhao J, Zhang Q, Hou Y, Cai Y, Lu X, Jin X. The protective effect of EGF-activated ROS in human corneal epithelial cells by inducing mitochondrial autophagy via activation TRPM2. J Cell Physiol 2020; 235:7018-7029. [PMID: 32083315 DOI: 10.1002/jcp.29597] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 01/16/2020] [Indexed: 01/03/2023]
Abstract
Oxidative stress is a major pathogenesis of some ocular surface diseases. Our previous study demonstrated that epidermal growth factor (EGF)-activated reactive oxygen species (ROS) could protect against human corneal epithelial cell (HCE) injury. In the present study, we aimed to explore the role and mechanisms of oxidative stress and mitochondrial autophagy in HCE cells subjected to scratch injury. CCK-8 assays, EdU assays, Western blot analysis, wound-healing assays, and flow cytometry were conducted to determine cell viability, proliferation, protein expression, cell apoptosis, and intracellular ROS levels, respectively. The results showed that EGF could promote damage repair and inhibit cell apoptosis in scratch injured HCE cells by upregulating ROS (**p < .01, ***p < .001). EGF also induced mitochondrial autophagy and alleviated mitochondrial damage. Interestingly, the combination of the mitochondrial autophagy inhibitor and mitochondrial division inhibitor 1 (MDIVI-1) with EGF could reduce cell proliferation, viability, and the ROS level (*p < .05, **p < .01, ***p < .001). Treatment using the ROS inhibitor N-acetyl- l-cysteine abrogated the increase in mitochondrial membrane potential after EGF treatment. (*p < .05). Taken together, these findings indicated that EGF plays an important role in HCE damage repair and could activate ROS to protect against HCE injury by inducing mitochondrial autophagy via activation of TRPM2.
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Affiliation(s)
- Yanan Huo
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wei Chen
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaoxiao Zheng
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jinchuan Zhao
- Zhejiang Institute of Medical Device Supervision and Testing, Hangzhou, Zhejiang, China
| | - Qi Zhang
- Zhejiang Institute of Medical Device Supervision and Testing, Hangzhou, Zhejiang, China
| | - Yuerou Hou
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Ying Cai
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xuemei Lu
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiuming Jin
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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31
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Sun Y, Song L, Zhang Y, Wang H, Dong X. Adipose stem cells from type 2 diabetic mice exhibit therapeutic potential in wound healing. Stem Cell Res Ther 2020; 11:298. [PMID: 32680569 PMCID: PMC7368682 DOI: 10.1186/s13287-020-01817-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/04/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
Background Diabetic patients suffer from impaired wound healing. Mesenchymal stem cell (MSC) therapy represents a promising approach toward improving skin wound healing through the release of soluble growth factors and cytokines that stimulate new vessel formation and modulate inflammation. Whether adipose tissue-derived MSCs (ASCs) from type 2 diabetes (T2D) donors are suitable for skin damage repair remains largely unknown. Methods In this study, we compared the phenotype and functionality of ASCs harvested from high-fat diet (HFD) and streptozotocin (STZ)-induced T2D or control mice, and assessed their abilities to promote wound healing in an excisional wound splinting mouse model with T2D. Results T2D ASCs expressed similar cellular markers as control ASCs but secreted less hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β). T2D ASCs were somewhat less effective in promoting healing of the wound, as manifested by slightly reduced re-epithelialization, cutaneous appendage regeneration, and collagen III deposition in wound tissues. In vitro, T2D ASCs promoted proliferation and migration of skin fibroblasts to a comparable extent as control ASCs via suppression of inflammation and macrophage infiltration. Conclusions From these findings, we conclude that, although ASCs from T2D mice are marginally inferior to control ASCs, they possess comparable therapeutic effects in wound healing.
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Affiliation(s)
- Yongfa Sun
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China
| | - Lili Song
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China
| | - Yong Zhang
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China
| | - Hongjun Wang
- Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Xiao Dong
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China.
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Electroacupuncture Relieves Suppression of Autophagy in Interstitial Cells of Cajal of Diabetic Gastroparesis Rats. Can J Gastroenterol Hepatol 2020; 2020:7920715. [PMID: 32211350 PMCID: PMC7060882 DOI: 10.1155/2020/7920715] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 01/13/2020] [Accepted: 01/16/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The incidence of diabetic gastroparesis (DGP) is mainly blamed to abnormity of interstitial cells of Cajal (ICCs). Autophagy could degrade damaged proteins and organelles to keep intracellular homeostasis, and it could directly influence structure and number of cells. In this study, we aimed to figure out the relationship between DGP and autophagy of ICCs. METHODS Sixty Sprague-Dawley (SD) rats were randomly divided into normal control group (NC, 10) and modeling group (50). Rats in the modeling group were injected 2% streptozotocin (STZ) and fed with high-glucose and high-fat diet for 8 weeks in order to establish DGP rat model. After modeling, 30 successfully modeled rats were randomly selected and separated into diabetic gastroparesis group (DGP, 10), GDP rats with electroacupuncture group (EA, 10), and GDP rats with metoclopramide group (MP, 10). When the intervention was completed, blood glucose was measured by ONE TOUCH glucometer and gastrointestinal propulsive rate was detected through measuring optical density. Autophagosomes were observed under transmission electron microscope (TEM). The expression of LC3 protein and P62 protein was measured by Western blot. When ICCs were transfected with GFP-RFP-LC3 plasmid, autophagy flux was observed by laser scanning confocal microscope. RESULTS (1) After intervention, compared with blood glucose of rats in the NC group, all of the DGP, EA, and MP groups were remarkably increased (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01); compared with the DGP group, the blood glucose of the EA and MP groups was decreased greatly (P < 0.01). (2) Compared with gastrointestinal propulsive rate of rats in the NC group, no matter gastric emptying rate or intestinal propulsive rate, the EA and MP groups were significantly reduced (P < 0.01); compared with the NC group, gastric emptying rate and intestinal propulsive rate in the EA group were obviously decreased (P < 0.05, P < 0.01); compared with the DGP group, the EA and MP groups were increased significantly (P < 0.01). (3) Compared with the NC group, intensity of RFP and GFP in the DGP group was obviously increased (P < 0.05, P < 0.01), in other words, the DGP group accompanying suppression of autophagy; compared with the DGP group, intensity of RFP and GFP in the EA group was decreased significantly (P < 0.05, P < 0.01). (4) There was no autophagosome in the NC group, and an autophagosome existed in the DGP group. Both EA and MP groups found autophagy. (5) When coming to LC3 II/LC3 I, compared with the NC group, the ratio was enhanced in the DGP and EA groups (P < 0.01, P < 0.05); compared with the DGP group, LC3 II/LC3 I was dramatically decreased in the MP and EA groups (P < 0.01). (6) As the substrate of degradation, the expression of P62 in the other three groups was significantly increased (P < 0.01) compared with the NC group; compared with the DGP group, the amount of P62 in the EA and MP groups was reduced greatly (P < 0.01). CONCLUSION The impaired autophagy flux in ICCs is the pathological basis of diabetic gastroparesis, blaming to fusion dysfunction of autophagosome and lysosome and electroacupuncture (EA) could ease the suppression of autophagy to improve gastric motility.
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Paul S, Chakrabarty S, Ghosh S, Nag D, Das A, Dastidar DG, Dasgupta M, Dutta N, Kumari M, Pal M, Chakrabarti G. Targeting cellular microtubule by phytochemical apocynin exhibits autophagy-mediated apoptosis to inhibit lung carcinoma progression and tumorigenesis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 67:153152. [PMID: 31887479 DOI: 10.1016/j.phymed.2019.153152] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/06/2019] [Accepted: 12/15/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Lung cancer is the leading cause of cancer-related deaths worldwide. Several targets have been identified for lung cancer therapy, amongst which 'Microtubule' and its dynamics are the most widely studied and used in therapy. Tubulin-microtubule polymer dynamics are highly sought after targets in the field of anti-cancer drug designing. Natural compounds are important sources for developing anticancer therapeutics owing to their efficacy and lower cytotoxicity. Evidence suggested that therapeutic targeting of microtubule by natural compounds is amongst the most widely used interventions in numerous cancer therapies including lung cancer. PURPOSE To determine the efficacy of apocynin (a natural compound) in suppressing the progression of lung carcinoma both in vitro and in vivo, along with the identification of targets and the underlying mechanism for developing a novel therapeutic approach. METHODS We have demonstrated themicrotubule depolymerizing role of apocynin by established protocols in cellular and cell-free system. The efficacy of apocynin to inhibit lung carcinoma progression was studied on A549 cells.The tumoricidal ability of apocynin was studied in BALB/c mice model as well.Mice were classified into 4 groups namely-group II mice as tumor control; group III-IV mice asalso tumor-induced but treated with differential apocynin doses whereas group I mice were kept as normal. RESULTS Apocynin, showed selective cytotoxicity towards lung cancer cells rather than normal lung fibroblast cells. Apocynin inhibited oncogenic properties including growth, proliferation (p < 0.05), colony formation (p < 0.05), invasion (p < 0.05) and spheroid formation (p < 0.05) in lung cancer cells. Apart from other established properties, apocynin was found to be a novel and potent component to bind with tubulin and depolymerize cellular microtubule network. Apocynin mediated cellular microtubule depolymerization was the driving mechanism to trigger autophagy-mediated apoptotic cell death (p < 0.05) which in turn retarded lung cancer progression. Furthermore, apocynin showed tumoricidal characteristics to inhibit lung tumorigenesis in mice as well. CONCLUSION Targeting tubulin-microtubule equilibrium with apocynin could be the key regulator to catastrophe cellular catabolic processes to mitigate lung carcinoma. Thus, apocynin could be a potential therapeutic agent for lung cancer treatment.
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Affiliation(s)
- Santanu Paul
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal 700019, India.
| | - Subhendu Chakrabarty
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal 700019, India; Deapartment of Microbiology, M.U.C Women's College, University of Burdwan, Burdwan 713104, India
| | - Suvranil Ghosh
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Rd, Scheme VIIM, Kolkata, West Bengal 700054, India
| | - Debasish Nag
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal 700019, India
| | - Amlan Das
- Department of Chemistry, National Institute of Technology, Ravangla, South Sikkim 737139, India
| | - Debabrata Ghosh Dastidar
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal 700019, India; Division of Pharmaceutics, Guru Nanak Institute of Pharmaceutical Science and Technology, Panihati, Kolkata, West Bengal 700114, India
| | - Moumita Dasgupta
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal 700019, India
| | - Naibedya Dutta
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Rd, Scheme VIIM, Kolkata, West Bengal 700054, India
| | - Mandavi Kumari
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal 700019, India
| | - Mahadeb Pal
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Rd, Scheme VIIM, Kolkata, West Bengal 700054, India
| | - Gopal Chakrabarti
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal 700019, India.
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Murray CE, Coleman CM. Impact of Diabetes Mellitus on Bone Health. Int J Mol Sci 2019; 20:ijms20194873. [PMID: 31575077 PMCID: PMC6801685 DOI: 10.3390/ijms20194873] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 12/21/2022] Open
Abstract
Long-term exposure to a diabetic environment leads to changes in bone metabolism and impaired bone micro-architecture through a variety of mechanisms on molecular and structural levels. These changes predispose the bone to an increased fracture risk and impaired osseus healing. In a clinical practice, adequate control of diabetes mellitus is essential for preventing detrimental effects on bone health. Alternative fracture risk assessment tools may be needed to accurately determine fracture risk in patients living with diabetes mellitus. Currently, there is no conclusive model explaining the mechanism of action of diabetes mellitus on bone health, particularly in view of progenitor cells. In this review, the best available literature on the impact of diabetes mellitus on bone health in vitro and in vivo is summarised with an emphasis on future translational research opportunities in this field.
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Affiliation(s)
- Cliodhna E Murray
- Regenerative Medicine Institute, National University of Ireland, Galway, Biomedical Sciences Building, Dangan, Newcastle Road, Galway City, County Galway, H91W2TY, Ireland.
| | - Cynthia M Coleman
- Regenerative Medicine Institute, National University of Ireland, Galway, Biomedical Sciences Building, Dangan, Newcastle Road, Galway City, County Galway, H91W2TY, Ireland.
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Mesenchymal Stem Cells in Homeostasis and Systemic Diseases: Hypothesis, Evidences, and Therapeutic Opportunities. Int J Mol Sci 2019; 20:ijms20153738. [PMID: 31370159 PMCID: PMC6696100 DOI: 10.3390/ijms20153738] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 07/29/2019] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are present in all organs and tissues, playing a well-known function in tissue regeneration. However, there is also evidence indicating a broader role of MSCs in tissue homeostasis. In vivo studies have shown MSC paracrine mechanisms displaying proliferative, immunoregulatory, anti-oxidative, or angiogenic activity. In addition, recent studies also demonstrate that depletion and/or dysfunction of MSCs are associated with several systemic diseases, such as lupus, diabetes, psoriasis, and rheumatoid arthritis, as well as with aging and frailty syndrome. In this review, we hypothesize about the role of MSCs as keepers of tissue homeostasis as well as modulators in a variety of inflammatory and degenerative systemic diseases. This scenario opens the possibility for the use of secretome-derived products from MSCs as new therapeutic agents in order to restore tissue homeostasis, instead of the classical paradigm "one disease, one drug".
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Mastrolia I, Foppiani EM, Murgia A, Candini O, Samarelli AV, Grisendi G, Veronesi E, Horwitz EM, Dominici M. Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review. Stem Cells Transl Med 2019; 8:1135-1148. [PMID: 31313507 PMCID: PMC6811694 DOI: 10.1002/sctm.19-0044] [Citation(s) in RCA: 203] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 06/17/2019] [Indexed: 02/06/2023] Open
Abstract
Identified 50 years ago, mesenchymal stromal/stem cells (MSCs) immediately generated a substantial interest among the scientific community because of their differentiation plasticity and hematopoietic supportive function. Early investigations provided evidence of a relatively low engraftment rate and a transient benefit for challenging congenital and acquired diseases. The reasons for these poor therapeutic benefits forced the entire field to reconsider MSC mechanisms of action together with their ex vivo manipulation procedures. This phase resulted in advances in MSCs processing and the hypothesis that MSC‐tissue supportive functions may be prevailing their differentiation plasticity, broadening the spectrum of MSCs therapeutic potential far beyond their lineage‐restricted commitments. Consequently, an increasing number of studies have been conducted for a variety of clinical indications, revealing additional challenges and suggesting that MSCs are still lagging behind for a solid clinical translation. For this reason, our aim was to dissect the current challenges in the development of still promising cell types that, after more than half a century, still need to reach their maturity. stem cells translational medicine2019;8:1135–1148
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Affiliation(s)
- Ilenia Mastrolia
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Elisabetta Manuela Foppiani
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA
| | - Alba Murgia
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | | | - Anna Valeria Samarelli
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Elena Veronesi
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Technopole of Mirandola TPM, Mirandola, Modena, Italy
| | - Edwin M Horwitz
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA
| | - Massimo Dominici
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Rigenerand srl, Medolla, Modena, Italy.,Technopole of Mirandola TPM, Mirandola, Modena, Italy
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Treatment of cancer stem cells from human colon adenocarcinoma cell line HT-29 with resveratrol and sulindac induced mesenchymal-endothelial transition rate. Cell Tissue Res 2019; 376:377-388. [DOI: 10.1007/s00441-019-02998-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 01/21/2019] [Indexed: 02/07/2023]
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Mahmoud M, Abu-Shahba N, Azmy O, El-Badri N. Impact of Diabetes Mellitus on Human Mesenchymal Stromal Cell Biology and Functionality: Implications for Autologous Transplantation. Stem Cell Rev Rep 2019; 15:194-217. [DOI: 10.1007/s12015-018-9869-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Fijany A, Sayadi LR, Khoshab N, Banyard DA, Shaterian A, Alexander M, Lakey JRT, Paydar KZ, Evans GRD, Widgerow AD. Mesenchymal stem cell dysfunction in diabetes. Mol Biol Rep 2018; 46:1459-1475. [PMID: 30484107 DOI: 10.1007/s11033-018-4516-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 11/22/2018] [Indexed: 02/08/2023]
Abstract
Diabetes mellitus (DM) is a chronic disease that results in a variety of systemic complications. Recently, stem cell-based therapies have been proposed as potential modalities to manage DM related complications. Mesenchymal stem cell (MSC) based therapies are often considered as an ideal stem cell-based treatment for DM management due to their immunosuppressive characteristics, anti-inflammatory properties and differentiation potential. While MSCs show tremendous promise, the underlying functional deficits of MSCs in DM patients is not well understood. Using the MEDLINE database to define these functional deficits, our search yielded 1826 articles of which 33 met our inclusion criteria. This allowed us to review the topic and illuminate four major molecular categories by which MSCs are compromised in both Type 1 DM and Type II DM models which include: (1) changes in angiogenesis/vasculogenesis, (2) altered pro-inflammatory cytokine secretion, (3) increased oxidative stress markers and (4) impaired cellular differentiation and decreased proliferation. Knowledge of the deficits in MSC function will allow us to more clearly assess the efficacy of potential biologic therapies for reversing these dysfunctions when treating the complications of diabetic disease.
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Affiliation(s)
- Arman Fijany
- UC Irvine Department of Plastic Surgery, Center for Tissue Engineering, Orange, CA, USA
| | - Lohrasb R Sayadi
- UC Irvine Department of Plastic Surgery, Center for Tissue Engineering, Orange, CA, USA
| | - Nima Khoshab
- UC Irvine Department of Plastic Surgery, Center for Tissue Engineering, Orange, CA, USA
| | - Derek A Banyard
- UC Irvine Department of Plastic Surgery, Center for Tissue Engineering, Orange, CA, USA
| | - Ashkaun Shaterian
- UC Irvine Department of Plastic Surgery, Center for Tissue Engineering, Orange, CA, USA
| | - Michael Alexander
- UC Irvine Department of Surgery & Biomedical Engineering, Orange, CA, USA
| | | | - Keyianoosh Z Paydar
- UC Irvine Department of Plastic Surgery, Center for Tissue Engineering, Orange, CA, USA
| | - Gregory R D Evans
- UC Irvine Department of Plastic Surgery, Center for Tissue Engineering, Orange, CA, USA.,UC Irvine Department of Surgery & Biomedical Engineering, Orange, CA, USA
| | - Alan D Widgerow
- UC Irvine Department of Plastic Surgery, Center for Tissue Engineering, Orange, CA, USA. .,UC Irvine Department of Surgery & Biomedical Engineering, Orange, CA, USA. .,University of California, Irvine Suite 108a Building 55, 101 S. City Dr., Orange, CA, 92868, USA.
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Hassanpour M, Rezabakhsh A, Pezeshkian M, Rahbarghazi R, Nouri M. Distinct role of autophagy on angiogenesis: highlights on the effect of autophagy in endothelial lineage and progenitor cells. Stem Cell Res Ther 2018; 9:305. [PMID: 30409213 PMCID: PMC6225658 DOI: 10.1186/s13287-018-1060-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Autophagy plays a critical role in the dynamic growth of each cell through different conditions. It seems that this intracellular mechanism acts as a two-edged sword against the numerous cell insults. Previously, autophagy was described in the context of cell activity and behavior, but little knowledge exists related to the role of autophagy in endothelial cells, progenitors, and stem cells biology from different tissues. Angiogenic behavior of endothelial lineage and various stem cells are touted as an inevitable feature in the restoration of different damaged tissues and organs. This capacity was found to be dictated by autophagy signaling pathway. This review article highlights the fundamental role of cell autophagic response in endothelial cells function, stem cells dynamic, and differentiation rate. It seems that elucidation of the mechanisms related to pro- and/or anti-angiogenic potential of autophagy inside endothelial cells and stem cells could help us to modulate stem cell therapeutic feature post-transplantation.
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Affiliation(s)
- Mehdi Hassanpour
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St., Tabriz, 5166614756 Iran
- Stem Cell And Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Emergency Medicine Research Team, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masoud Pezeshkian
- Department of Applied Drug Research, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St., Tabriz, 5166614756 Iran
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St., Tabriz, 5166614756 Iran
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Montazersaheb S, Kabiri F, Saliani N, Nourazarian A, Avci ÇB, Rahbarghazi R, Nozad Charoudeh H. Prolonged incubation with Metformin decreased angiogenic potential in human bone marrow mesenchymal stem cells. Biomed Pharmacother 2018; 108:1328-1337. [PMID: 30372835 DOI: 10.1016/j.biopha.2018.09.135] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 09/20/2018] [Accepted: 09/24/2018] [Indexed: 12/15/2022] Open
Abstract
Metformin is commonly prescribed as a hypoglycemic agent following the onset of type 2 diabetes mellitus. This study aimed to investigate pro- and/or anti-angiogenic effects of Metformin on human bone marrow mesenchymal stem cells. Cells were incubated with different doses of Metformin including 0.5, 1, 10, 50, 100, 200 and 500 μM for 14 days. Cell viability and total fatty acids profile were examined by MTT and gas chromatography methods. Differentiation of cells to endothelial lineage was studied by monitoring the expression of VEGFR-2 and Tie-2 receptors and VE-cadherin via real-time PCR and western blotting. Angiogenic potential and migration of cells were assessed by tubulogenesis and Transwell migration assays. PCR array was performed to analyze mTOR signaling. CD133+ and VEGFR-2+ cells were detected in blood samples of non-diabetic control, diabetic subjects and diabetics received Metformin. Metformin dose-dependently reduced cell survival. Decreased content of palmitate and oleate coincided increased level of stearate, palmitoleate, and linoleate (p < 0.05). Metformin decreased the angiogenic potential of cells by decreasing VEGFR-2 and Tie-2 expression (p < 0.05). The protein level of VE-cadherin decreased in cells received Metformin. Compared to the control, Metformin blunted the expression of VEGF subtypes and directed cells to energy status by induction of PRKAA1, PRKAB2, and PRKAG1 genes (p < 0.05). Non-significant differences were observed regarding the number of CD133 and VEGFR-2 cells in blood samples (p > 0.05). These data support a notion that Metformin could blunt the angiogenic behavior of human mesenchymal stem cells by modulating mTOR signaling pathway.
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Affiliation(s)
- Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fahimeh Kabiri
- Department of Developmental Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Negar Saliani
- Department of Cellular and Molecular Biology, School of Biology, College of Sciences, University of Tehran, Tehran, Iran
| | - Alireza Nourazarian
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Çıgır Biray Avci
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Novinbahador T, Nourazarian A, Asgharzadeh M, Rahbarghazi R, Avci ÇB, Bagca BG, Ozates NP, Karbasforoush S, Khaki‐Khatibi F. Docosahexaenoic acid attenuates the detrimental effect of palmitic acid on human endothelial cells by modulating genes from the atherosclerosis signaling pathway. J Cell Biochem 2018; 119:9752-9763. [DOI: 10.1002/jcb.27294] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/26/2018] [Indexed: 12/22/2022]
Affiliation(s)
- Tannaz Novinbahador
- Drug Applied Research Center Tabriz University of Medical Sciences Tabriz Iran
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Alireza Nourazarian
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Mohammad Asgharzadeh
- Biotechnology Research Center and Department of Laboratory Sciences, Faculty of Paramedical Sciences Tabriz University of Medical Sciences Tabriz Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center Tabriz University of Medical Sciences Tabriz Iran
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences Tabriz University of Medical Sciences Tabriz Iran
| | - Çıgır Biray Avci
- Department of Medical Biology, Faculty of Medicine Ege University Izmir Turkey
| | - Bakiye Goker Bagca
- Department of Medical Biology, Faculty of Medicine Ege University Izmir Turkey
| | | | - Saeede Karbasforoush
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Fatemeh Khaki‐Khatibi
- Drug Applied Research Center Tabriz University of Medical Sciences Tabriz Iran
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
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43
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Diabetic sera disrupted the normal exosome signaling pathway in human mesenchymal stem cells in vitro. Cell Tissue Res 2018; 374:555-565. [DOI: 10.1007/s00441-018-2895-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 07/08/2018] [Indexed: 01/23/2023]
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Khaksar M, Sayyari M, Rezaie J, Pouyafar A, Montazersaheb S, Rahbarghazi R. High glucose condition limited the angiogenic/cardiogenic capacity of murine cardiac progenitor cells in in vitro and in vivo milieu. Cell Biochem Funct 2018; 36:346-356. [PMID: 30051492 DOI: 10.1002/cbf.3354] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 06/19/2018] [Accepted: 07/02/2018] [Indexed: 12/21/2022]
Abstract
Murine c-kit+ cardiac cells were isolated and enriched by magnetic activated cell sorting technique. c-kit+ cells viability and colony-forming activity were evaluated by MTT and clonogenic assay. c-kit+ cells were exposed to endothelial, pericyte, and cardiomyocyte induction media containing 30mM glucose for 7 days. We monitored the level of endothelial (VE-cadherin, CD31, and vWF), pericyte (NG2 , α-SMA, and PDGFR-β), and cardiomyocyte markers (cTnT) using flow cytometry, real-time Polymerase Chain Reaction (PCR), and Enzyme-Linked Immunosorbent Assay (ELISA) analyses. Ultrastructural changes were studied by transmission electron microscopy (TEM) in cells treated with 5-Azacytidine and 30mM glucose. Matrigel plug assay was performed to determine the angio/cardiogenic property of c-kit+ cells in a diabetic mouse model. Glucose of 30mM decreased c-kit+ cells viability and clonogenicity (P < 0.05). The transdifferentiation capacity of c-kit+ cells into the endothelial lineage, pericytes, and cardiomyocytes were reduced through the inhibition of related genes (P < 0.05). TEM analysis revealed cardiomyocyte differentiation rate in c-kit+ cells coincided with an increased intracellular lipid accumulation and reduced number of mitochondria. Similar to in vitro condition, the angiogenic capacity of c-kit+ cells was aborted in vivo indicated by reduced NG2 , α-SMA, CD31, and vWF levels. High glucose condition reduces the angio/cardiogenic capacity of cardiac c-kit+ cells in vitro and in vivo. SIGNIFICANCE OF THE STUDY: High glucose condition seen in diabetes mellitus could affect the regenerative potential of cardiac tissue. The current experiment showed that the exposure of murine cardiac progenitor cells (CD117+ cells) to condition containing 30mM glucose could decrease the differentiation properties into endothelial cells, pericytes, and mature cardiomyocytes in vitro and in vivo. Our finding confirmed that the angiogenic/cardiogenic potential cardiac progenitor cells decrease under treatment with high glucose content as seen in the diabetic condition.
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Affiliation(s)
- Majid Khaksar
- Department of Pathology, Faculty of Veterinary Medicine, University of Shiraz, Shiraz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mansour Sayyari
- Department of Pathology, Faculty of Veterinary Medicine, University of Shiraz, Shiraz, Iran
| | - Jafar Rezaie
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayda Pouyafar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Faculty of Advanced Medical Sciences, Department of Applied Cell Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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45
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Che Y, Wang ZP, Yuan Y, Zhang N, Jin YG, Wan CX, Tang QZ. Role of autophagy in a model of obesity: A long‑term high fat diet induces cardiac dysfunction. Mol Med Rep 2018; 18:3251-3261. [PMID: 30066870 PMCID: PMC6102660 DOI: 10.3892/mmr.2018.9301] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 01/19/2018] [Indexed: 12/13/2022] Open
Abstract
Obesity may induce end-organ damage through metabolic syndrome, and autophagy serves a vital role in the pathogenesis of metabolic syndrome. The purpose of the present study was to define the roles of autophagy and mitophagy in high fat diet (HFD)-induced cardiomyopathy. Male, 8 week-old C57BL/6 mice were fed either a HFD (60% kcal) or a diet of normal chow (NC; 10% kcal) for 42 weeks. Glucose tolerance tests were performed during the feeding regimes. Blood samples were collected for assaying serum triglyceride with the glycerol-3-phosphate oxidase phenol and aminophenazone (PAP) method and total cholesterol was tested with the cholesterol oxidase-PAP method. Myocardial function was assessed using echocardiography and hemodynamic analyses. Western blot analysis was employed to evaluate endoplasmic reticulum stress (ERS), autophagy and mitochondrial function. Electron microscopy was used to assess the number of lipid droplets and the degree of autophagy within the myocardium. The body weight and adipose tissue weight of mice fed the HFD were increased compared with the NC mice. The serum levels of blood glucose, total cholesterol and triglyceride were significantly increased following 42 weeks of HFD feeding. The results of the glucose tolerance tests additionally demonstrated metabolic dysregulation in HFD mice. In addition, HFD mice exhibited hemodynamic and echocardiographic evidence of impaired diastolic and systolic function, including alterations in the cardiac output, end-diastolic pressure, end-diastolic volume and left ventricular relaxation time constant (tau) following HFD intake. Furthermore, a HFD resulted in increased ERS, and a downregulation of the autophagy and mitophagy level. The present study investigated cardiac function in obese HFD-fed mice. These results aid the pursuit of novel therapeutic targets to combat obesity-associated cardiomyopathy.
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Affiliation(s)
- Yan Che
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhao-Peng Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yuan Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ning Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ya-Ge Jin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Chun-Xia Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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46
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Wang M, Song L, Strange C, Dong X, Wang H. Therapeutic Effects of Adipose Stem Cells from Diabetic Mice for the Treatment of Type 2 Diabetes. Mol Ther 2018; 26:1921-1930. [PMID: 30005867 DOI: 10.1016/j.ymthe.2018.06.013] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/30/2018] [Accepted: 06/12/2018] [Indexed: 02/07/2023] Open
Abstract
To assess the potential therapeutic effects of adipose tissue-derived mesenchymal stem cells (ASCs) for the treatment of type 2 diabetes (T2D), we compared the phenotype and functionality of ASCs isolated from high-fat diet and streptozotocin (STZ)-induced T2D and the leptin receptor-deficient (db/db) mice with cells from healthy C57BL/6 mice. ASCs from T2D or db/db mice showed similar expression patterns of cellular markers and abilities to differentiate into adipocytes, osteoblasts, and chondrocytes. However, the rate of proliferation was reduced. ASCs from db/db mice secreted less hepatocyte growth factor (HGF). T2D mice receiving a single intravenous injection of T2D or db/db ASCs showed increased insulin sensitivity, reduced inflammation and fat content in adipose tissue and the liver and increased pancreatic β cell mass through 5 weeks post-infusion. Our data show that, although ASCs from T2D or db/db mice had inferior proliferative capacity compared to cells from healthy controls, improved insulin sensitivity and less β cell death was seen in T2D mice receiving mesenchymal stem cell (MSC) therapy. This study offers evidence that ASCs from diabetic donors have the potential to be used for cell therapy in the treatment of insulin resistance and T2D.
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Affiliation(s)
- Mengmeng Wang
- College of Life Science, Qingdao Agricultural University, Qingdao, Shandong 266109, China
| | - Lili Song
- China Agricultural University, Beijng 100094, China
| | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Xiao Dong
- College of Life Science, Qingdao Agricultural University, Qingdao, Shandong 266109, China.
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
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47
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van Rhijn-Brouwer FCC, Gremmels H, Fledderus JO, Verhaar MC. Mesenchymal Stromal Cell Characteristics and Regenerative Potential in Cardiovascular Disease: Implications for Cellular Therapy. Cell Transplant 2018; 27:765-785. [PMID: 29895169 PMCID: PMC6047272 DOI: 10.1177/0963689717738257] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Administration of mesenchymal stromal cells (MSCs) is a promising strategy to treat cardiovascular disease (CVD). As progenitor cells may be negatively affected by both age and comorbidity, characterization of MSC function is important to guide decisions regarding use of allogeneic or autologous cells. Definitive answers on which factors affect MSC function can also aid in selecting which MSC donors would yield the most therapeutically efficacious MSCs. Here we provide a narrative review of MSC function in CVD based on a systematic search. A total of 41 studies examining CVD-related MSC (dys)function were identified. These data show that MSC characteristics and regenerative potential are often affected by CVD. However, studies presented conflicting results, and directed assessment of MSC parameters relevant to regenerative medicine applications was lacking in many studies. The predictive ability of in vitro assays for in vivo efficacy was rarely assessed. There was no correlation between quality of study reporting and study findings. Age mismatch was also not associated with study findings or effect size. Future research should focus on assays that assess regenerative potential in MSCs and parameters that relate to clinical success.
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Affiliation(s)
- F C C van Rhijn-Brouwer
- 1 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - H Gremmels
- 1 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - J O Fledderus
- 1 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - M C Verhaar
- 1 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
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48
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Salimi L, Rahbarghazi R, Jafarian V, Biray Avci Ç, Goker Bagca B, Pinar Ozates N, Khaksar M, Nourazarian A. Heat shock protein 70 modulates neural progenitor cells dynamics in human neuroblastoma SH-SY5Y cells exposed to high glucose content. J Cell Biochem 2018; 119:6482-6491. [PMID: 29345335 DOI: 10.1002/jcb.26679] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 01/17/2018] [Indexed: 01/21/2023]
Abstract
In the current experiment, detrimental effects of high glucose condition were investigated on human neuroblastoma cells. Human neuroblastoma cell line SH-SY5Y were exposed to 5, 40, and 70 mM glucose over a period of 72 h. Survival rate and the proliferation of cells were analyzed by MTT and BrdU incorporation assays. Apoptosis was studied by the assays of flow cytometry and PCR array. In order to investigate the trans-differentiation capacity of the cell into mature neurons, we used immunofluorescence imaging to follow NeuN protein level. The transcription level of HSP70 was shown by real-time PCR analysis. MMP-2 and -9 activities were shown by gelatin Zymography. According to data from MTT and BrdU incorporation assay, 70 mM glucose reduced cell viability and proliferation rate as compared to control (5 mM glucose) and cells treated with 40 mM glucose (P < 0.05). Cell exposure to 70 mM glucose had potential to induced apoptosis after 72 h (P < 0.05). Our results also demonstrated the sensitivity of SH-SY5Y cells to detrimental effects of high glucose condition during trans-differentiation into mature neuron-like cells. Real-time PCR analysis confirmed the expression of HSP70 in cells under high content glucose levels, demonstrating the possible cell compensatory response to an insulting condition (pcontrol vs 70 mM group <0.05). Both MMP-2 and -9 activities were reduced in cells being exposed to 70 mM glucose. High glucose condition could abrogate the dynamics of neural progenitor cells. The intracellular level of HSP70 was proportional to cell damage in high glucose condition.
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Affiliation(s)
- Leila Salimi
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahab Jafarian
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
| | - Çıgır Biray Avci
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Bakiye Goker Bagca
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | | | - Majid Khaksar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Nourazarian
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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49
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Low-level laser irradiation at a high power intensity increased human endothelial cell exosome secretion via Wnt signaling. Lasers Med Sci 2018; 33:1131-1145. [PMID: 29603107 DOI: 10.1007/s10103-018-2495-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 03/22/2018] [Indexed: 01/08/2023]
Abstract
The distinct role of low-level laser irradiation (LLLI) on endothelial exosome biogenesis remains unclear. We hypothesize that laser irradiation of high dose in human endothelial cells (ECs) contributes to the modulation of exosome biogenesis via Wnt signaling pathway. When human ECs were treated with LLLI at a power density of 80 J/cm2, the survival rate reduced. The potential of irradiated cells to release exosomes was increased significantly by expressing genes CD63, Alix, Rab27a, and b. This occurrence coincided with an enhanced acetylcholine esterase activity, pseudopodia formation, and reduced zeta potential value 24 h post-irradiation. Western blotting showed the induction of LC3 and reduced level of P62, confirming autophagy response. Flow cytometry and electron microscopy analyses revealed the health status of the mitochondrial function indicated by normal ΔΨ activity without any changes in the transcription level of PINK1 and Optineurin. When cells exposed to high power laser irradiation, p-Akt/Akt ratio and in vitro tubulogenesis capacity were blunted. PCR array and bioinformatics analyses showed the induction of transcription factors promoting Wnt signaling pathways and GTPase activity. Thus, LLLI at high power intensity increased exosome biogenesis by the induction of autophagy and Wnt signaling. LLLI at high power intensity increases exosome biogenesis by engaging the transcription factors related to Wnt signaling and autophagy stimulate.
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50
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Xu YX, Huang C, Liu M, Chen N, Chen W, Yang C, Zhao Y, Li X, Duan J, Liu S, Yang S. Survivin regulated by autophagy mediates hyperglycemia-induced vascular endothelial cell dysfunction. Exp Cell Res 2018; 364:152-159. [DOI: 10.1016/j.yexcr.2018.01.037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 12/21/2017] [Accepted: 01/28/2018] [Indexed: 12/11/2022]
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