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Chen HM, Li H, Lin MX, Fan WJ, Zhang Y, Lin YT, Wu SX. Research Progress for RNA Modifications in Physiological and Pathological Angiogenesis. Front Genet 2022; 13:952667. [PMID: 35937999 PMCID: PMC9354963 DOI: 10.3389/fgene.2022.952667] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/20/2022] [Indexed: 12/04/2022] Open
Abstract
As a critical layer of epigenetics, RNA modifications demonstrate various molecular functions and participate in numerous biological processes. RNA modifications have been shown to be essential for embryogenesis and stem cell fate. As high-throughput sequencing and antibody technologies advanced by leaps and bounds, the association of RNA modifications with multiple human diseases sparked research enthusiasm; in addition, aberrant RNA modification leads to tumor angiogenesis by regulating angiogenesis-related factors. This review collected recent cutting-edge studies focused on RNA modifications (N6-methyladenosine (m6A), N5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), and pseudopuridine (Ψ)), and their related regulators in tumor angiogenesis to emphasize the role and impact of RNA modifications.
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Affiliation(s)
- Hui-Ming Chen
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Hang Li
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Meng-Xian Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Wei-Jie Fan
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yi Zhang
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yan-Ting Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
- *Correspondence: Shu-Xiang Wu, ; Yan-Ting Lin,
| | - Shu-Xiang Wu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
- *Correspondence: Shu-Xiang Wu, ; Yan-Ting Lin,
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Xiang D, Li Y, Cao Y, Huang Y, Zhou L, Lin X, Qiao Y, Li X, Liao D. Different Effects of Endothelial Extracellular Vesicles and LPS-Induced Endothelial Extracellular Vesicles on Vascular Smooth Muscle Cells: Role of Curcumin and Its Derivatives. Front Cardiovasc Med 2021; 8:649352. [PMID: 34150863 PMCID: PMC8210670 DOI: 10.3389/fcvm.2021.649352] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/07/2021] [Indexed: 12/25/2022] Open
Abstract
Background: During the progression of atherosclerosis (AS), the vascular endothelial and smooth muscle cells are reciprocally regulated by extracellular vesicles (EVs). EVs have different effects on pathological and physiological processes due to the different cargoes contained in EVs. Purpose: To study the effects of endothelial cells-derived EVs on normal and inflammatory conditions. To investigate the effects of curcumin and curcumin derivatives (Nicotinic-curcumin) on endothelial EVs. Methods: EVs were isolated from human umbilical vein endothelial cells (HUVECs) by ultracentrifugation. To examined the effect of normal and LPS-induced endothelial cells-derived EVs on the proliferation of human aortic smooth muscle cells (HASMCs), the CCK-8 assay was performed. Transwell and wound healing assays were conducted to assess cell migration. The effects of EVs on lipid accumulation following treatment with oxidized low-density lipoprotein (Ox-LDL) were evaluated with the oil red O staining assay and HPLC. The number of EVs was calculated using the nanoparticle tracking analysis (NTA) and BCA. The expression levels of Rab27a and Rab27b that regulate the EVs secretion were measured by Western blotting assay. The differential expression of miRNAs in endothelial EVs and LPS-induced endothelial EVs was analyzed using miRNA-Sequencing (miRNA-Seq) and RT-PCR. Results: Treatment with endothelial EVs reduced the proliferation and migration of HASMCs as well as lipid accumulation in HASMCs. However, treatment with LPS-induced endothelial EVs did not inhibit the migration of HASMCs or lipid accumulation, instead it promoted the proliferation of HASMCs. Treatment with the two types of EVs induced differential expression of several miRNAs, including miR-92a-3p, miR-126-5p, miR-125a-3p, miR-143-3p, etc. Moreover, 1 μg/mL LPS induction greatly increased secretion of endothelial EVs. Treatment with curcumin and nicotinic-curcumin reduced endothelial EVs secretion, possibly by inhibiting inflammation. Conclusion: Endothelial EVs may confer beneficial effects on atherosclerosis by regulating vascular smooth muscle cell (VSMCs), whereas pro-inflammatory factors may disrupt this effect.
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Affiliation(s)
| | - Yamei Li
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Yuling Cao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Ying Huang
- The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Lili Zhou
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Xiulian Lin
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Yong Qiao
- The Third Hospital of Changsha, Changsha, China
| | - Xin Li
- The Third Hospital of Changsha, Changsha, China
| | - Duanfang Liao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
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Khan S, Ahmad SS, Kamal MA. Diabetic Cardiomyopathy: From Mechanism to Management in a Nutshell. Endocr Metab Immune Disord Drug Targets 2020; 21:268-281. [PMID: 32735531 DOI: 10.2174/1871530320666200731174724] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 06/03/2020] [Accepted: 07/06/2020] [Indexed: 11/22/2022]
Abstract
Diabetic cardiomyopathy (DCM) is a significant complication of diabetes mellitus characterized by gradually failing heart with detrimental cardiac remodelings, such as fibrosis and diastolic and systolic dysfunction, which is not directly attributable to coronary artery disease. Insulin resistance and resulting hyperglycemia is the main trigger involved in the initiation of diabetic cardiomyopathy. There is a constellation of many pathophysiological events, such as lipotoxicity, oxidative stress, inflammation, inappropriate activation of the renin-angiotensin-aldosterone system, dysfunctional immune modulation promoting increased rate of cardiac cell injury, apoptosis, and necrosis, which ultimately culminates into interstitial fibrosis, cardiac stiffness, diastolic dysfunction, initially, and later systolic dysfunction too. These events finally lead to clinical heart failure of DCM. Herein, The pathophysiology of DCM is briefly discussed. Furthermore, potential therapeutic strategies currently used for DCM are also briefly mentioned.
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Affiliation(s)
- Shahzad Khan
- Department of Pathophysiology, Wuhan University School of Medicine, Hubei, Wuhan, China
| | - Syed S Ahmad
- Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, India
| | - Mohammad A Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
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Sim J, Kim Y, Kim H, Bang S, Jee S, Park S, Shin SJ, Jang K. Loss of MTUS1 Expression Is Associated With Poor Prognosis in Patients With Gallbladder Carcinoma. In Vivo 2020; 34:125-132. [PMID: 31882471 DOI: 10.21873/invivo.11753] [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: 09/26/2019] [Revised: 10/14/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIM Microtubule-associated scaffold protein 1 (MTUS1) acts as tumor suppressor in several cancer types. This study assessed the relationship between clinicopathological characteristics and expression of microRNA candidates based on MTUS1 expression in gallbladder cancer (GBC). MATERIALS AND METHODS MTUS1 expression was evaluated by immunohistochemical staining of tissue microarrays from 109 cases of GBC. The association of MTUS1 expression with clinicopathological factors was explored. Two microRNA candidates (miR-19a-3p, and miR-19b-3p), which were identified by a literature review and computational analysis, were assessed in GBC tissue samples by quantitative real-time polymerase chain reaction. RESULTS Low MTUS1 expression in GBC was associated with high histological grade, perineural invasion, lymphovascular invasion, high T-stage, advanced TNM stage, poorer disease-free survival, and poorer cancer-specific survival. No statistical association between MTUS1 expression and expression of microRNA candidates was observed. CONCLUSION MTUS1 may act as tumor suppressor and might be a potential biomarker for predicting prognosis in GBC.
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Affiliation(s)
- Jongmin Sim
- Department of Pathology, Samsung Medical Center, Seoul, Republic of Korea
| | - Yeseul Kim
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Hyungsung Kim
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Seongsik Bang
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Seungyun Jee
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Seongun Park
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Su-Jin Shin
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Kiseok Jang
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
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van der Kwast RV, Quax PH, Nossent AY. An Emerging Role for isomiRs and the microRNA Epitranscriptome in Neovascularization. Cells 2019; 9:cells9010061. [PMID: 31881725 PMCID: PMC7017316 DOI: 10.3390/cells9010061] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/19/2019] [Accepted: 12/21/2019] [Indexed: 02/06/2023] Open
Abstract
Therapeutic neovascularization can facilitate blood flow recovery in patients with ischemic cardiovascular disease, the leading cause of death worldwide. Neovascularization encompasses both angiogenesis, the sprouting of new capillaries from existing vessels, and arteriogenesis, the maturation of preexisting collateral arterioles into fully functional arteries. Both angiogenesis and arteriogenesis are highly multifactorial processes that require a multifactorial regulator to be stimulated simultaneously. MicroRNAs can regulate both angiogenesis and arteriogenesis due to their ability to modulate expression of many genes simultaneously. Recent studies have revealed that many microRNAs have variants with altered terminal sequences, known as isomiRs. Additionally, endogenous microRNAs have been identified that carry biochemically modified nucleotides, revealing a dynamic microRNA epitranscriptome. Both types of microRNA alterations were shown to be dynamically regulated in response to ischemia and are able to influence neovascularization by affecting the microRNA’s biogenesis, or even its silencing activity. Therefore, these novel regulatory layers influence microRNA functioning and could provide new opportunities to stimulate neovascularization. In this review we will highlight the formation and function of isomiRs and various forms of microRNA modifications, and discuss recent findings that demonstrate that both isomiRs and microRNA modifications directly affect neovascularization and vascular remodeling.
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Affiliation(s)
- Reginald V.C.T. van der Kwast
- Department of Surgery and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Paul H.A. Quax
- Department of Surgery and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - A. Yaël Nossent
- Department of Surgery and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Department of Laboratory Medicine and Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria
- Correspondence:
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van der Kwast RVCT, Woudenberg T, Quax PHA, Nossent AY. MicroRNA-411 and Its 5'-IsomiR Have Distinct Targets and Functions and Are Differentially Regulated in the Vasculature under Ischemia. Mol Ther 2019; 28:157-170. [PMID: 31636041 DOI: 10.1016/j.ymthe.2019.10.002] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 09/24/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are posttranscriptional regulators of gene expression. As microRNAs can target many genes simultaneously, microRNAs can regulate complex multifactorial processes, including post-ischemic neovascularization, a major recovery pathway in cardiovascular disease. MicroRNAs select their target mRNAs via full complementary binding with their seed sequence, i.e., nucleotides 2-8 from the 5' end of a microRNA. The exact sequence of a mature microRNA, and thus of its 5' and 3' ends, is determined by two sequential cleavage steps of microRNA precursors, Drosha/DGCR8 and Dicer. When these cleavage steps result in nucleotide switches at the 5' end, forming a so-called 5'-isomiR, this results in a shift in the mature microRNA's seed sequence. The role of 5'-isomiRs in cardiovascular diseases is still unknown. Here, we characterize the expression and function of the 5'-isomiR of miR-411 (ISO-miR-411). ISO-miR-411 is abundantly expressed in human primary vascular cells. ISO-miR-411 has a different "targetome" from WT-miR-411, with only minor overlap. The ISO-miR-411/WT-miR-411 ratio is downregulated under acute ischemia, both in cells and a murine ischemia model, but is upregulated instead in chronically ischemic human blood vessels. ISO-miR-411 negatively influences vascular cell migration, whereas WT-miR-411 does not. Our data demonstrate that isomiR formation is a functional pathway that is actively regulated during ischemia.
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Affiliation(s)
- Reginald V C T van der Kwast
- Department of Surgery, Leiden University Medical Center, Leiden 2333ZA, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Tamar Woudenberg
- Department of Surgery, Leiden University Medical Center, Leiden 2333ZA, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Paul H A Quax
- Department of Surgery, Leiden University Medical Center, Leiden 2333ZA, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - A Yaël Nossent
- Department of Surgery, Leiden University Medical Center, Leiden 2333ZA, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333ZA, the Netherlands; Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria; Department of Internal Medicine II, Medical University of Vienna, Vienna 1090, Austria.
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Qian T, Wang P, Chen Q, Yi S, Liu Q, Wang H, Wang S, Geng W, Liu Z, Li S. The dynamic changes of main cell types in the microenvironment of sciatic nerves following sciatic nerve injury and the influence of let-7 on their distribution. RSC Adv 2018; 8:41181-41191. [PMID: 35559286 PMCID: PMC9091661 DOI: 10.1039/c8ra08298g] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 11/29/2018] [Indexed: 12/13/2022] Open
Abstract
Schwann cells (SCs), fibroblasts and macrophages are the main cells in the peripheral nerve stumps.
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Jansen F, Schäfer L, Wang H, Schmitz T, Flender A, Schueler R, Hammerstingl C, Nickenig G, Sinning JM, Werner N. Kinetics of Circulating MicroRNAs in Response to Cardiac Stress in Patients With Coronary Artery Disease. J Am Heart Assoc 2017; 6:JAHA.116.005270. [PMID: 28751542 PMCID: PMC5586407 DOI: 10.1161/jaha.116.005270] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Background Circulating microRNAs (miRNAs/miRs) are regulated in patients with coronary artery disease. The impact of transient coronary ischemia on circulating miRNA levels is unknown. We aimed to investigate circulating miRNA kinetics in response to cardiac stress in patients with or without significant coronary stenosis. Methods and Results Eighty of 105 screened patients with stable coronary artery disease underwent dobutamine stress echocardiography before coronary angiography. Nine circulating vascular miRNAs (miRNA‐21, miRNA‐26, miRNA‐27a, miRNA‐92a, miRNA‐126‐3p, miRNA‐133a, miRNA‐222, miRNA‐223, and miRNA‐199‐5p) were quantified in plasma by reverse transcription polymerase chain reaction before, immediately after, and 4 and 24 hours after dobutamine stress echocardiography. Quantitative polymerase chain reaction revealed increased miRNA‐21, miRNA‐126‐3p, and miRNA‐222 levels at 24 hours after dobutamine stress echocardiography in all patients. On coronary angiography, significant coronary artery stenoses (>80% diameter stenosis) were found in 41 patients. Stratifying patients according to the prevalence of significant stenoses, patients with stenosis showed an increase of circulating miRNA‐21, miRNA‐126‐3p, and miRNA‐222 in response to cardiac stress. In patients without significant stenoses (<50% diameter stenosis), miRNA‐92a levels gradually increased in response to cardiac stress. Conclusions miRNAs are distinctly released into the circulation in response to cardiac stress depending on the prevalence of significant coronary stenoses.
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Affiliation(s)
- Felix Jansen
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Lisa Schäfer
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Han Wang
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Theresa Schmitz
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Anna Flender
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Robert Schueler
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Christoph Hammerstingl
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Georg Nickenig
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Jan-Malte Sinning
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
| | - Nikos Werner
- Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany
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The Emerging Role of miRNAs and Their Clinical Implication in Biliary Tract Cancer. Gastroenterol Res Pract 2016; 2016:9797410. [PMID: 28115929 PMCID: PMC5223017 DOI: 10.1155/2016/9797410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 10/07/2016] [Accepted: 12/04/2016] [Indexed: 01/17/2023] Open
Abstract
Biliary tract cancers are aggressive malignancies that include gallbladder cancer and tumors of intra- and extrahepatic ducts and have a poor prognosis. Surgical resection remains the main curative therapy. Nevertheless, numerous patients experience recurrence even after radical surgery. This scenario drives the research to identify biliary tract cancer biomarkers despite the limited progress that has been made. Recently, a large number of studies have demonstrated that deregulated expression of microRNAs is closely associated with cancer development and progression. In this review, we highlight the role and importance of microRNAs in biliary tract cancers with an emphasis on utilizing circulating microRNAs as potential biomarkers. Additionally, we report several single-nucleotide polymorphisms in microRNA genes that are associated with the susceptibility of biliary tract tumors.
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Chandra V, Kim JJ, Mittal B, Rai R. MicroRNA aberrations: An emerging field for gallbladder cancer management. World J Gastroenterol 2016; 22:1787-1799. [PMID: 26855538 PMCID: PMC4724610 DOI: 10.3748/wjg.v22.i5.1787] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/12/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer (GBC) is infrequent but most lethal biliary tract malignancy characterized by an advanced stage diagnosis and poor survival rates attributed to absence of specific symptoms and effective treatment options. These necessitate development of early prognostic/predictive markers and novel therapeutic interventions. MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a key role in tumor biology by functioning like tumor suppressor- or onco- genes and their aberrant expression are associated with the pathogenesis of several neoplasms with overwhelming clinical implications. Since miRNA signature is tissue specific, here, we focused on current data concerning the miRNAs aberrations in GBC pathogenesis. In GBC, miRNAs with tumor suppressor activity (miR-135-5p, miR-335, miR-34a, miR-26a, miR-146b-5p, Mir-218-5p, miR-1, miR-145, mir-130a) were found downregulated, while those with oncogenic property (miR-20a, miR-182, mir-155) were upregulated. The expression profile of miRNAs was significantly associated with GBC prognosis and prediction, and forced over-expression/ inhibition of these miRNAs was shown to affect tumor growth and development. Further, differential expression of miRNAs in the blood samples of GBC patients suggest miRNAs as promising noninvasive biomarker. Thus, miRNAs represent potential candidate for GBC management, though many hurdles need to be overcome before miRNAs therapy can be clinically applied to GBC prevention and treatment.
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Brites D, Fernandes A. Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation. Front Cell Neurosci 2015; 9:476. [PMID: 26733805 PMCID: PMC4681811 DOI: 10.3389/fncel.2015.00476] [Citation(s) in RCA: 420] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 11/23/2015] [Indexed: 12/21/2022] Open
Abstract
Patients with chronic inflammation are often associated with the emergence of depression symptoms, while diagnosed depressed patients show increased levels of circulating cytokines. Further studies revealed the activation of the brain immune cell microglia in depressed patients with a greater magnitude in individuals that committed suicide, indicating a crucial role for neuroinflammation in depression brain pathogenesis. Rapid advances in the understanding of microglial and astrocytic neurobiology were obtained in the past 15–20 years. Indeed, recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions, besides their involvement in immune-response generating cytokines. The communication between microglia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), comprising ectosomes and exosomes with a size ranging from 0.1–1 μm, are key players in intercellular signaling. These EVs may carry specific proteins, mRNAs and microRNAs (miRNAs). Transfer of exosomes to neurons was shown to be mediated by oligodendrocytes, microglia and astrocytes that may either be supportive to neurons, or instead disseminate the disease. Interestingly, several recent reports have identified changes in miRNAs in depressed patients, which target not only crucial pathways associated with synaptic plasticity, learning and memory but also the production of neurotrophic factors and immune cell modulation. In this article, we discuss the role of neuroinflammation in the emergence of depression, namely dynamic alterations in the status of microglia response to stimulation, and how their activation phenotypes may have an etiological role in neurodegeneneration, in particular in depressive-like behavior. We will overview the involvement of miRNAs, exosomes, ectosomes and microglia in regulating critical pathways associated with depression and how they may contribute to other brain disorders including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Parkinson’s disease (PD), which share several neuroinflammatory-associated processes. Specific reference will be made to EVs as potential biomarkers and disease monitoring approaches, focusing on their potentialities as drug delivery vehicles, and on putative therapeutic strategies using autologous exosome-based delivery systems to treat neurodegenerative and psychiatric disorders.
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Affiliation(s)
- Dora Brites
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de LisboaLisbon, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de LisboaLisbon, Portugal
| | - Adelaide Fernandes
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de LisboaLisbon, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de LisboaLisbon, Portugal
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12
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Cao WJ, Rosenblat JD, Roth NC, Kuliszewski MA, Matkar PN, Rudenko D, Liao C, Lee PJH, Leong-Poi H. Therapeutic Angiogenesis by Ultrasound-Mediated MicroRNA-126-3p Delivery. Arterioscler Thromb Vasc Biol 2015; 35:2401-11. [PMID: 26381870 DOI: 10.1161/atvbaha.115.306506] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 09/02/2015] [Indexed: 01/15/2023]
Abstract
OBJECTIVE MicroRNAs are involved in many critical functions, including angiogenesis. Ultrasound-targeted microbubble destruction (UTMD) is a noninvasive technique for targeted vascular transfection of plasmid DNA and may be well suited for proangiogenic microRNA delivery. We aimed to investigate UTMD of miR-126-3p for therapeutic angiogenesis in chronic ischemia. APPROACH AND RESULTS The angiogenic potential of miR-126-3p was tested in human umbilical vein endothelial cells in vitro. UTMD of miR-126-3p was tested in vivo in Fischer-344 rats before and after chronic left femoral artery ligation, evaluating target knockdown, miR-126-3p and miR-126-5p expression, phosphorylated Tie2 levels, microvascular perfusion, and vessel density. In vitro, miR-126-3p-transfected human umbilical vein endothelial cells showed repression of sprouty-related protein-1 and phosphatidylinositol-3-kinase regulatory subunit 2, negative regulators of vascular endothelial growth factor and angiopoietin-1 signaling, increased phosphorylated Tie2 mediated by knockdown of phosphatidylinositol-3-kinase regulatory subunit 2 and greater angiogenic potential mediated by both vascular endothelial growth factor/vascular endothelial growth factor R2 and angiopoietin-1 /Tie2 effects. UTMD of miR-126-3p resulted in targeted vascular transfection, peaking early after delivery and lasting for >3 days, and resulting in inhibition of sprouty-related protein-1 and phosphatidylinositol-3-kinase regulatory subunit 2, with minimal uptake in remote organs. Finally, UTMD of miR-126-3p to chronic ischemic hindlimb muscle resulted in improved perfusion, vessel density, enhanced arteriolar formation, pericyte coverage, and phosphorylated Tie2 levels, without affecting miR-126-5p or delta-like 1 homolog levels. CONCLUSIONS UTMD of miR-126 results in improved tissue perfusion and vascular density in the setting of chronic ischemia by repressing sprouty-related protein-1 and phosphatidylinositol-3-kinase regulatory subunit 2 and enhancing vascular endothelial growth factor and angiopoietin-1 signaling, with no effect on miR-126-5p. UTMD is a promising platform for microRNA delivery, with applications for therapeutic angiogenesis.
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Affiliation(s)
- Wei J Cao
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada
| | - Joshua D Rosenblat
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada
| | - Nathan C Roth
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada
| | - Michael A Kuliszewski
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada
| | - Pratiek N Matkar
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada
| | - Dmitriy Rudenko
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada
| | - Christine Liao
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada
| | - Paul J H Lee
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada
| | - Howard Leong-Poi
- From the Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada.
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Affiliation(s)
- Katey J. Rayner
- From University of Ottawa Heart Institute, Ottawa, ON, Canada; and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
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Abstract
PURPOSE OF REVIEW Observational studies have shown benefit of hormone therapy, particularly estrogen, in women who begin treatment in the perimenopausal/early postmenopausal period, whereas randomized controlled trials of such therapy in older postmenopausal women have reported harm. These apparently paradoxical findings have led to the 'timing hypothesis' which proposes that estrogen signaling is altered in older women, converting vasoprotective to vasotoxic effects. We reviewed recent literature on age-dependent effects of hormones (particularly estrogen) on the vasculature of women and the fundamental cellular/molecular mechanisms responsible for those effects. RECENT FINDINGS Observational studies have shown that early menopause is associated with adverse cardiovascular disease outcomes and that starting hormone therapy in the perimenopausal period reduces these outcomes. Mechanistic studies have shown that estrogen modulates injury-induced inflammation, growth factor expression, and oxidative stress in arteries and vascular smooth muscle cells isolated from young women but that these vasoprotective mechanisms are lost in women who are aged and/or deprived of estrogen for prolonged periods of time. SUMMARY The vasoprotective effects of estrogen are age-dependent and disappear with aging and/or estrogen deprivation. Future studies designed to preserve the vasoprotective effects of estrogen in older women are needed and may lead to innovative approaches to improving women's cardiovascular health.
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Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 2014; 142:375-415. [PMID: 24462787 DOI: 10.1016/j.pharmthera.2014.01.003] [Citation(s) in RCA: 425] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 01/08/2014] [Indexed: 12/14/2022]
Abstract
Cardiovascular disease is the primary cause of morbidity and mortality among the diabetic population. Both experimental and clinical evidence suggest that diabetic subjects are predisposed to a distinct cardiomyopathy, independent of concomitant macro- and microvascular disorders. 'Diabetic cardiomyopathy' is characterized by early impairments in diastolic function, accompanied by the development of cardiomyocyte hypertrophy, myocardial fibrosis and cardiomyocyte apoptosis. The pathophysiology underlying diabetes-induced cardiac damage is complex and multifactorial, with elevated oxidative stress as a key contributor. We now review the current evidence of molecular disturbances present in the diabetic heart, and their role in the development of diabetes-induced impairments in myocardial function and structure. Our focus incorporates both the contribution of increased reactive oxygen species production and reduced antioxidant defenses to diabetic cardiomyopathy, together with modulation of protein signaling pathways and the emerging role of protein O-GlcNAcylation and miRNA dysregulation in the progression of diabetic heart disease. Lastly, we discuss both conventional and novel therapeutic approaches for the treatment of left ventricular dysfunction in diabetic patients, from inhibition of the renin-angiotensin-aldosterone-system, through recent evidence favoring supplementation of endogenous antioxidants for the treatment of diabetic cardiomyopathy. Novel therapeutic strategies, such as gene therapy targeting the phosphoinositide 3-kinase PI3K(p110α) signaling pathway, and miRNA dysregulation, are also reviewed. Targeting redox stress and protective protein signaling pathways may represent a future strategy for combating the ever-increasing incidence of heart failure in the diabetic population.
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Affiliation(s)
- Karina Huynh
- Baker IDI Heart & Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Clayton, Victoria, Australia
| | | | - Julie R McMullen
- Baker IDI Heart & Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Physiology, Monash University, Clayton, Victoria, Australia.
| | - Rebecca H Ritchie
- Baker IDI Heart & Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Clayton, Victoria, Australia.
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Deddens JC, Colijn JM, Oerlemans MIFJ, Pasterkamp G, Chamuleau SA, Doevendans PA, Sluijter JPG. Circulating microRNAs as novel biomarkers for the early diagnosis of acute coronary syndrome. J Cardiovasc Transl Res 2013; 6:884-98. [PMID: 23897095 DOI: 10.1007/s12265-013-9493-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Accepted: 06/18/2013] [Indexed: 12/18/2022]
Abstract
Small non-coding microRNAs (miRNAs) are important physiological regulators of post-transcriptional gene expression. miRNAs not only reside in the cytoplasm but are also stably present in several extracellular compartments, including the circulation. For that reason, miRNAs are proposed as diagnostic biomarkers for various diseases. Early diagnosis of acute coronary syndrome (ACS), especially non-ST elevated myocardial infarction and unstable angina pectoris, is essential for optimal treatment outcome, and due to the ongoing need for additional identifiers, miRNAs are of special interest as biomarkers for ACS. This review highlights the nature and cellular release mechanisms of circulating miRNAs and therefore their potential role in the diagnosis of myocardial infarction. We will give an update of clinical studies addressing the role of circulating miRNA expression after myocardial infarction and explore the diagnostic value of this potential biomarker.
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Affiliation(s)
- J C Deddens
- Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, room G02.523, 3584, CX, Utrecht, The Netherlands
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